Pharmacy E change®

Transcription

Pharmacy E change®

Pharmacy E change
®
Volume 17, Number 1 February 2016 Web Version
New Appearance. Same Quality.
Artistic rendition of product. Not actual size.
In December 2015, we began shipping Mylan FENTANYL Transdermal System 100 mcg/hr
with a new product appearance. Specifically, the ink color on the patch has been changed from
white to blue. This change will continue to be implemented with the remaining strengths—
12 mcg/hr, 25 mcg/hr, 37.5 mcg/hr, 50 mcg/hr, 62.5 mcg/hr, 75 mcg/hr, 87.5 mcg/hr—
as inventory is depleted.
If you have any questions, please contact Customer Relations at 800.796.9526.
Indication
Fentanyl transdermal system is indicated for the management of pain
in opioid-tolerant patients, severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment
options are inadequate. Patients considered opioid-tolerant are those
who are taking, for one week or longer, at least 60 mg of morphine
daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral
hydromorphone daily, or an equianalgesic dose of another opioid.
12 mcg/hr
25 mcg/hr
75 mcg/hr
Limitations of Use
Because of the risks of addiction, abuse, and misuse with opioids, even
at recommended doses, and because of the greater risks of overdose
and death with extended-release opioid formulations, reserve fentanyl
transdermal system for use in patients for whom alternative treatment
options (i.e., non-opioid analgesics or immediate-release opioids) are
ineffective, not tolerated, or would be otherwise inadequate to provide
sufficient management of pain.
37.5 mcg/hr
87.5 mcg/hr
50 mcg/hr
62.5 mcg/hr
100 mcg/hr
Artistic rendition of products. Not actual size.
IMPORTANT SAFETY INFORMATION
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID
WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and EXPOSURE TO HEAT
Addiction, Abuse, and Misuse: Fentanyl transdermal system exposes patients and other users to the risks of opioid addiction, abuse, and
misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing fentanyl transdermal system, and monitor all
patients regularly for the development of these behaviors or conditions.
Life-threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of fentanyl transdermal
system, even when used as recommended. Monitor for respiratory depression, especially during initiation of fentanyl transdermal system or
following a dose increase. Because of the risk of respiratory depression, fentanyl transdermal system is contraindicated for use as an
as-needed analgesic, in non-opioid tolerant patients, in acute pain, and in postoperative pain.
Accidental Exposure: Deaths due to a fatal overdose of fentanyl have occurred when children and adults were accidentally exposed to
fentanyl transdermal system. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to
prevent accidental exposure.
Neonatal Opioid Withdrawal Syndrome: Prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal
syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by
neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid
withdrawal syndrome and ensure that appropriate treatment will be available.
Cytochrome P450 3A4 Interaction: The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors may result in
an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory
depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma
concentration. Monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor or inducer.
Exposure To Heat: Exposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources, such
as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase
fentanyl absorption and has resulted in fatal overdose of fentanyl and death. Patients wearing fentanyl transdermal systems who develop
fever or increased core body temperature due to strenuous exertion are also at risk for increased fentanyl exposure and may require an
adjustment in the dose of fentanyl transdermal system to avoid overdose and death.
Click here for additional IMPORTANT SAFETY INFORMATION. Click here for Prescribing Information for
Fentanyl Transdermal System, including Boxed WARNING and Medication Guide.
IMPORTANT SAFETY INFORMATION FOR FENTANYL TRANSDERMAL SYSTEM
Fentanyl transdermal system patches are for transdermal use, only.
Proper handling and disposal of fentanyl transdermal system is
necessary in order to prevent serious adverse outcomes, including
death, associated with accidental secondary exposure to fentanyl
transdermal system.
CONTRAINDICATIONS
Fentanyl transdermal system is contraindicated in the following patients and
situations due to the risk of fatal respiratory depression:
• in patients who are not opioid-tolerant.
• in the management of acute or intermittent pain, or in patients who require
opioid analgesia for a short period of time.
• in the management of post-operative pain, including use after out-patient
or day surgeries, (i.e., tonsillectomies).
• in the management of mild pain.
• in patients with significant respiratory compromise, especially if adequate
monitoring and resuscitative equipment are not readily available.
• in patients who have acute or severe bronchial asthma.
• in patients who have or are suspected of having paralytic ileus.
• in patients with known hypersensitivity to fentanyl or any components
of the transdermal system. Severe hypersensitivity reactions, including
anaphylaxis have been observed with fentanyl transdermal system.
Interactions with Central Nervous System Depressants: Hypotension,
profound sedation, coma, respiratory depression, and death may result if
fentanyl transdermal system is used concomitantly with alcohol or other
central nervous system (CNS) depressants (i.e., sedatives, anxiolytics,
hypnotics, neuroleptics, other opioids).
Use in Elderly, Cachectic, and Debilitated Patients: Respiratory
depression is more likely to occur in elderly, cachectic, or debilitated patients
as they may have altered pharmacokinetics due to poor fat stores, muscle
wasting, or altered clearance. Therefore, monitor these patients closely,
particularly when initiating therapy with fentanyl transdermal system and
when given in conjunction with other drugs that depress respiration.
Chronic Pulmonary Disease: Monitor patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and patients having a
substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when
initiating therapy with fentanyl transdermal system, as in these patients,
even usual therapeutic doses of fentanyl transdermal system may decrease
respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients if possible.
Head Injuries and Increased Intracranial Pressure: Avoid use of fentanyl
transdermal system in patients who may be particularly susceptible to the
intracranial effects of CO2 retention as fentanyl transdermal system may
reduce respiratory drive and CO2 retention can further increase intracranial
pressure. Opioids may obscure the clinical course of patients with head injury.
Hypotensive Effects: Fentanyl transdermal system may cause severe
hypotension including orthostatic hypotension and syncope in ambulatory
patients. There is an increased risk in patients whose ability to maintain
blood pressure has already been compromised by a reduced blood
volume or concurrent administration of certain CNS depressant drugs (i.e.,
phenothiazines or general anesthetics). Monitor these patients for signs
of hypotension after initiating or titrating the dose of fentanyl transdermal
system.
(CONT’D)
Cardiac Disease: Fentanyl transdermal system may produce bradycardia.
Monitor patients with bradyarrhythmias closely for changes in heart rate,
particularly when initiating therapy with fentanyl transdermal system.
Hepatic Impairment: Avoid use of fentanyl transdermal system in patients
with severe hepatic impairment. To avoid starting patients with mild to
moderate hepatic impairment on too high of a dose, start with one half of the
usual dosage of fentanyl transdermal system. Closely monitor for signs of
sedation and respiratory depression, including at each dosage increase.
Renal Impairment: Avoid the use of fentanyl transdermal system in
patients with severe renal impairment. To avoid starting patients with mild to
moderate renal impairment on too high of a dose, start with one half of the
usual dosage of fentanyl transdermal system. Closely monitor for signs of
sedation and respiratory depression, including at each dosage increase.
Use in Pancreatic/Biliary Tract Disease: Fentanyl transdermal system
may cause spasm of the sphincter of Oddi. Monitor patients with biliary
tract disease, including acute pancreatitis for worsened symptoms.
Fentanyl transdermal system may cause increases in the serum amylase
concentration.
Avoidance of Withdrawal: Opioid withdrawal symptoms (such as nausea,
vomiting, diarrhea, anxiety, and shivering) are possible in some patients after
conversion to another opioid or when decreasing or discontinuing fentanyl
transdermal system. Gradual reduction of the dose of fentanyl transdermal
system is recommended.
Driving and Operating Machinery: Warn patients not to drive or operate
dangerous machinery unless they are tolerant to the effects of the fentanyl
transdermal system.
Adverse Reactions: Most common adverse reactions (≥ 5%) are nausea,
vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis,
fatigue, feeling cold, anorexia, headache, and diarrhea.
Drug Interactions: Mixed agonist/antagonist and partial agonist opioid
analgesics: Avoid use with fentanyl transdermal system because they
may reduce analgesic effect of fentanyl transdermal system or precipitate
withdrawal symptoms.
Avoid use of fentanyl transdermal system in the patient who would require
the concomitant administration of a monoamine oxidase (MAO) inhibitor, or
within 14 days of stopping such treatment because severe and unpredictable
potentiation by MAO inhibitors has been reported with opioid analgesics.
Use In Specific Populations
Pregnancy: Based on animal data, may cause fetal harm.
Nursing Mothers: Breast-feeding is not advised in mothers treated with
fentanyl transdermal system.
Pediatric Use: Safety and efficacy in pediatric patients below the age of
2 years have not been established. To guard against accidental ingestion
by children, use caution when choosing the application site for fentanyl
transdermal system.
Geriatric Use: Administer fentanyl transdermal system with caution, and in
reduced dosages in elderly patients.
Hepatic or Renal Impairment: Administer fentanyl transdermal system with
caution. Monitor for signs of fentanyl toxicity and reduce dosage, if necessary.
Click here for accompanying full Prescribing Information
and Medication Guide.
For information about the Risk Evaluation and Mitigation
Strategy (REMS), go to www.er-la-opioidrems.com.
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Products Introduced Since September 11, 2015 (Products not actual size)
• ALMOTRIPTAN Tablets, USP—6.25 mg and 12.5 mg
Generic for: Axert ®‡ Tablets
• LINEZOLID Tablets—600 mg
Generic for: Zyvox ®‡ Tablets
6.25 mg
12.5 mg
Click here for full Prescribing Information and Patient Information.
25 mg
100 mg
Click here for full Prescribing Information, including Boxed WARNING regarding SEVERE
NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE;
SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY
PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.
20 mg
Click here for full Prescribing Information, including Boxed WARNING regarding
DRUG DEPENDENCE and Medication Guide.
• DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE,
DEXTROAMPHETAMINE SULFATE and AMPHETAMINE SULFATE Tablets
5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg and 30 mg
Generic for: Adderall®‡ Tablets
10 mg 12.5 mg 15 mg
400 mg
Click here for full Prescribing Information, including Boxed WARNING regarding TENDON
EFFECTS and MYASTHENIA GRAVIS and Medication Guide.
• NEVIRAPINE Extended-release Tablets—100 mg
Generic for: Viramune XR®‡ Tablets
100 mg
Click here for full Prescribing Information, including Boxed WARNING regarding
LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS and
Medication Guide.
•DEXMETHYLPHENIDATE HYDROCHLORIDE Extended-release
Capsules — 20 mg
Generic for: Focalin XR®‡ Capsules
7.5 mg
Click here for full Prescribing Information.
• MOXIFLOXACIN HYDROCHLORIDE Tablets—400 mg
Generic for: Avelox®‡ Tablets
• CLOZAPINE ORALLY DISINTEGRATING Tablets—25 mg and 100 mg
Generic for: Fazaclo ODT®‡ Tablets
5 mg
600 mg
20 mg
—
30 mg
Click here for full Prescribing Information, including Boxed WARNING regarding ABUSE,
DRUG DEPENDENCE and MISUSE THAT CAN LEAD TO SUDDEN DEATH and SERIOUS
CARDIOVASCULAR ADVERSE EVENTS and Medication Guide.
• DONEPEZIL HYDROCHLORIDE Tablets—23 mg
Generic for: Aricept®‡ 23 mg Tablets
• NORGESTIMATE and ETHINYL ESTRADIOL Tablets, USP—0.18 mg/0.025 mg,
0.215 mg/0.025 mg and 0.25 mg/0.025 mg
Generic for: Ortho-Tri-Cyclen Lo®‡ Tablets
0.18 mg/0.025 mg
0.215 mg/0.025 mg 0.25 mg/0.025 mg
Click here for full Prescribing Information, including Boxed WARNING regarding THE
INCREASED RISK OF SERIOUS CARDIOVASCULAR SIDE EFFECTS FROM CIGARETTE
SMOKING and FDA-approved Patient Labeling.
• PALIPERIDONE Extended-release Tablets—1.5 mg, 3 mg, 6 mg and 9 mg
Generic for: Invega®‡ Tablets
1.5 mg
3 mg
6 mg
9 mg
Click here for full Prescribing Information, including Boxed WARNING regarding INCREASED
MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.
• RISEDRONATE SODIUM Tablets, USP—5 mg, 30 mg and 35 mg
Generic for: Actonel®‡ Tablets
23 mg
Click here for full Prescribing Information and Patient Information.
Click here for full Prescribing Information
and Medication Guide.
• GLIPIZIDE Extended-release Tablets—5 mg and 10 mg
Generic for: Glucotrol XL®‡ Tablets
5 mg
Click here for full Prescribing Information and Patient Information Leaflet.
TELL US WHAT YOU THINK…
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10 mg
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© 2016 Mylan Pharmaceuticals Inc. All rights reserved. NON-2016-0093 MYNMKT597 (02/16)
5 mg
30 mg
35 mg
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALMOTRIPTAN TABLETS safely and effectively. See full prescribing
information for ALMOTRIPTAN TABLETS.
ALMOTRIPTAN tablets USP, for oral use
Initial U.S. Approval: 2001
•• Gastrointestinal ischemic events and peripheral vasospastic
reactions (e.g., Raynaud’s syndrome) (5.4)
•• Potentially life-threatening serotonin syndrome, particularly in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Monitor patients
for neurologic changes and gastrointestinal symptoms if concomitant treatment is clinically warranted (5.5, 7.3)
•• Medication overuse headache: Detoxification may be necessary (5.6)
•• Increase in blood pressure, very rarely associated with significant
clinical events (4.4, 5.7)
•• Use with caution in patients with a known hypersensitivity to
sulfonamides (5.8)
---------------------------- RECENT MAJOR CHANGES --------------------------Warnings and Precautions, Medication Overuse Headache (5.6)
08/2014
---------------------------- INDICATIONS AND USAGE --------------------------Almotriptan tablets, USP are a 5HT1B/1D receptor agonist (triptan)
indicated for:
•• Acute treatment of migraine attacks in adults with a history of
migraine with or without aura (1.1)
•• Acute treatment of migraine headache pain in adolescents age 12 to
17 years with a history of migraine with or without aura, and who
have migraine attacks usually lasting 4 hours or more (1.1)
Important Limitations:
•• Use only after a clear diagnosis of migraine has been established
(1.2)
•• In adolescents age 12 to 17 years, efficacy of almotriptan tablets on
migraine-associated symptoms was not established (1.2)
•• Not intended for the prophylactic therapy of migraine (1.2)
•• Not indicated for the treatment of cluster headache (1.2)
----------------------------- ADVERSE REACTIONS ----------------------------The most common adverse reactions (≥ 1% and greater than placebo)
are:
•• In adults: nausea, dry mouth and paresthesia (6.1)
•• In adolescents: dizziness, somnolence, headache, paresthesia,
nausea and vomiting (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan
Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA
at 1-800-FDA-1088 or www.fda.gov/medwatch.
----------------------------- DRUG INTERACTIONS ----------------------------•• Do not use almotriptan and ergotamine-containing or ergot-type
medications within 24 hours of each other (4.5, 7.1)
•• Do not use almotriptan and other 5-HT1 agonist (e.g., triptans)
within 24 hours of each other (4.6, 7.2)
•• SSRI or SNRI: life-threatening serotonin syndrome reported during
combined use with triptans (5.5, 7.3)
•• Ketoconazole: use single dose of almotriptan 6.25 mg; maximum
almotriptan daily dose 12.5 mg (7.4)
----------------------- DOSAGE AND ADMINISTRATION ----------------------Adults and adolescents age 12 to 17 years: 6.25 mg or 12.5 mg
single dose; may repeat after 2 hours if headache returns; benefit of
second dose in patients who have failed to respond to first dose has
not been established; maximum daily dose 25 mg (2.1)
•• Patients with hepatic or severe renal impairment: 6.25 mg starting
dose; maximum daily dose 12.5 mg (2.2, 2.3)
••
----------------------- USE IN SPECIFIC POPULATIONS ----------------------•• Pregnancy: based on animal data, may cause fetal harm (8.1)
•• Nursing mothers: use almotriptan with caution (8.3)
•• Pediatric use: almotriptan has not been studied in children under
12 years (8.4)
•• Geriatric use: insufficient safety and efficacy data; use with caution,
usually starting with the 6.25 mg dose (8.5)
•• Hepatic impairment: use single 6.25 mg tablet as a starting dose;
maximum daily dose 12.5 mg (2.2, 8.6)
•• Severe renal impairment: use single 6.25 mg tablet as a starting
dose; maximum daily dose 12.5 mg (2.3, 8.7)
---------------------- DOSAGE FORMS AND STRENGTHS --------------------Tablets: 6.25 mg and 12.5 mg (3)
----------------------------- CONTRAINDICATIONS -----------------------------•• Ischemic heart disease, coronary artery vasospasm, or other
significant underlying cardiovascular disease (4.1)
•• Cerebrovascular syndromes (e.g., history of stroke or TIA) (4.2)
•• Peripheral vascular disease (including ischemic bowel disease)
(4.3)
•• Uncontrolled hypertension (4.4)
•• Do not use almotriptan within 24 hours of an ergotamine-containing,
or ergot-type medication, or of another 5-HT1 agonist, e.g., another
triptan (4.5, 4.6)
•• Hemiplegic or basilar migraine (4.7)
•• Known hypersensitivity to almotriptan (4.8)
See 17 for PATIENT COUNSELING INFORMATION and FDA approved
patient labeling.
REVISED SEPTEMBER 2015
MX:ALMT:R2pt/MX:PL:ALMT:R2pt
------------------------ WARNINGS AND PRECAUTIONS ----------------------•• Serious adverse cardiac events, including acute myocardial infarction
and life-threatening disturbances of cardiac rhythm (5.1)
•• It is strongly recommended that almotriptan not be given to patients
in whom unrecognized coronary artery disease (CAD) is predicted by
the presence of risk factors. In very rare cases, serious cardiovascular
events have been reported in association with almotriptan use
in the absence of known cardiovascular disease. If almotriptan is
considered, patients should first have a cardiovascular evaluation.
If the evaluation is satisfactory, first dose should take place in a
physician’s office setting (5.1)
•• Sensations of pain, tightness, pressure, and heaviness in the chest,
throat, neck, and jaw: generally not associated with myocardial
ischemia, but patients with signs or symptoms suggestive of angina
should be evaluated for the presence of CAD (5.2)
•• Cerebrovascular events, some fatal (5.3)
1
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Acute Treatment of Migraine Attacks
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.2 Hepatic Impairment
2.3 Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
4.1 Ischemic or Vasospastic Coronary Artery Disease, or Other
Significant Underlying Cardiovascular Disease
4.2 Cerebrovascular Syndromes
4.3 Peripheral Vascular Disease
4.4 Uncontrolled Hypertension
4.5 Ergotamine-Containing and Ergot-Type Medications
4.6 Concomitant Use with 5-HT1 Agonists (e.g., Triptans)
4.7 Hemiplegic or Basilar Migraine
4.8Hypersensitivity
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Myocardial Ischemia and Infarction and Other Adverse
Cardiac Events
5.2 Sensations of Pain, Tightness, Pressure in the Chest and/or
Throat, Neck, and Jaw
5.3 Cerebrovascular Events and Fatalities
5.4 Other Vasospasm-Related Events, Including Peripheral Vascular
Ischemia and Colonic Ischemia
5.5 Serotonin Syndrome
5.6 Medication Overuse Headache
5.7 Increases in Blood Pressure
5.8 Hypersensitivity to Sulfonamides
5.9 Impaired Hepatic or Renal Function
5.10Binding to Melanin-Containing Tissues
5.11Corneal Opacities
6 ADVERSE REACTIONS
6.1 Commonly-Observed Adverse Reactions in Double-Blind,
Placebo-Controlled Almotriptan Clinical Trials
6.2 Other Adverse Reactions Observed in Almotriptan Clinical Trials
6.3 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Ergot-Containing Drugs
7.25-HT1 Agonists (e.g., Triptans)
7.3 Selective Serotonin Reuptake Inhibitors/Serotonin
Norepinephrine Reuptake Inhibitors
7.4 Ketoconazole and Other Potent CYP3A4 Inhibitors
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10OVERDOSAGE
10.1Signs and Symptoms
10.2Recommended Treatment
11DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action
12.2Pharmacodynamics
12.3Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1Adults
14.2Adolescents Age 12 to 17 Years
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1Risk of Myocardial Ischemia and/or Infarction, Other Adverse
Cardiac Events, Other Vasospasm-Related Events, and
Cerebrovascular Events
17.2Serotonin Syndrome
17.3Pregnancy
17.4Nursing Mothers
17.5Ability to Operate Machinery or Vehicles
FULL PRESCRIBING INFORMATION
The recommended starting dose of almotriptan tablets in patients with hepatic
impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over
a 24-hour period [see Warnings and Precautions (5.9) and Clinical Pharmacology
(12.3)].
*Sections or subsections omitted from the full prescribing information are
not listed.
1
INDICATIONS AND USAGE
Adults: Almotriptan tablets, USP are indicated for the acute treatment of migraine
attacks in patients with a history of migraine with or without aura.
Adolescents Age 12 to 17 Years: Almotriptan tablets are indicated for the acute
treatment of migraine headache pain in patients with a history of migraine attacks
with or without aura usually lasting 4 hours or more (when untreated).
1.2 Important Limitations
Almotriptan tablets should only be used where a clear diagnosis of migraine has
been established. If a patient has no response for the first migraine attack treated
with almotriptan tablets, the diagnosis of migraine should be reconsidered before
almotriptan tablets are administered to treat any subsequent attacks.
In adolescents age 12 to 17 years, efficacy of almotriptan tablets on migraineassociated symptoms (nausea, photophobia, and phonophobia) was not established.
Almotriptan tablets are not intended for the prophylactic therapy of migraine or for use
in the management of hemiplegic or basilar migraine [see Contraindications (4.7)].
Safety and effectiveness of almotriptan tablets have not been established for cluster
headache which is present in an older, predominantly male population.
2
DOSAGE AND ADMINISTRATION
The recommended dose of almotriptan tablets in adults and adolescents age 12
to 17 years is 6.25 mg to 12.5 mg, with the 12.5 mg dose tending to be a more
effective dose in adults. As individuals may vary in their response to different doses of
almotriptan tablets, the choice of dose should be made on an individual basis.
If the headache is relieved after the initial almotriptan tablet dose but returns, the
dose may be repeated after 2 hours. The effectiveness of a second dose has not been
established in placebo-controlled trials. The maximum daily dose should not exceed
25 mg. The safety of treating an average of more than four migraines in a 30-day
period has not been established.
The recommended starting dose of almotriptan tablets in patients with severe renal
a 24-hour period [see Warnings and Precautions (5.9) and Clinical Pharmacology
(12.3)].
3
DOSAGE FORMS AND STRENGTHS
Almotriptan Tablets, USP are available containing 8.75 mg or 17.50 mg of almotriptan
malate, USP equivalent to 6.25 mg or 12.5 mg of almotriptan, respectively.
••
The 6.25 mg tablets are white to off-white film-coated, round, unscored
tablets debossed with M on one side of the tablet and AL1 on the other side.
••
The 12.5 mg tablets are white to off-white film-coated, round, unscored
tablets debossed with M on one side of the tablet and AL2 on the other side.
4CONTRAINDICATIONS
4.1 Ischemic or Vasospastic Coronary Artery Disease, or Other Significant Underlying Cardiovascular Disease
Do not use almotriptan tablets in patients with ischemic heart disease (angina pectoris,
history of myocardial infarction, or documented silent ischemia), or in patients who
have symptoms or findings consistent with ischemic heart disease, coronary artery
vasospasm, including Prinzmetal’s variant angina, or other significant underlying
cardiovascular disease [see Warnings and Precautions (5.1)].
4.2 Cerebrovascular Syndromes
Do not use almotriptan tablets in patients with cerebrovascular syndromes including
(but not limited to) stroke of any type as well as transient ischemic attacks [see
Warnings and Precautions (5.3)].
2
4.3 Peripheral Vascular Disease
Do not use almotriptan tablets in patients with peripheral vascular disease including
(but not limited to) ischemic bowel disease [see Warnings and Precautions (5.4)].
4.4 Uncontrolled Hypertension
Because almotriptan may increase blood pressure, do not use almotriptan tablets
in patients with uncontrolled hypertension [see Warnings and Precautions (5.7)].
4.5 Ergotamine-Containing and Ergot-Type Medications
Do not use almotriptan tablets and ergotamine-containing or ergot-derived medications
like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each
other [see Drug Interactions (7.1)].
4.6 Concomitant Use with 5-HT1 Agonists (e.g., Triptans)
Almotriptan tablets and other 5-HT1 agonists (e.g., triptans) should not be administered
within 24 hours of each other [see Warnings and Precautions (5.1) and (5.2)].
4.7 Hemiplegic or Basilar Migraine
Do not use almotriptan tablets in patients with hemiplegic or basilar migraine.
4.8Hypersensitivity
Almotriptan tablets are contraindicated in patients with known hypersensitivity to
almotriptan or any of its inactive ingredients.
5
WARNINGS AND PRECAUTIONS
5.1 Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac
Events
Cardiac Events and Fatalities with 5-HT1 Agonists: Serious adverse cardiac events,
including acute myocardial infarction, have been reported within a few hours following
administration of almotriptan. Life-threatening disturbances of cardiac rhythm and
death have been reported within a few hours following the administration of other
triptans. Considering the extent of use of triptans in patients with migraine, the
incidence of these events is extremely low.
Almotriptan can cause coronary vasospasm; at least one of these events occurred
in a patient with no cardiac history and with documented absence of coronary
artery disease. Because of the close proximity of the events to use of almotriptan, a
causal relationship cannot be excluded. Patients who experience signs or symptoms
suggestive of angina following dosing should be evaluated for the presence of coronary
artery disease (CAD) or a predisposition to Prinzmetal’s variant angina before receiving
additional doses of medication, and should be monitored electrocardiographically if
dosing is resumed and similar symptoms recur.
Premarketing Experience with Almotriptan in Adults: Among the 3,865 subjects/
patients who received almotriptan in premarketing clinical trials, one patient was
hospitalized for observation after a scheduled electrocardiogram (ECG) was found
to be abnormal (negative T-waves on the left leads) 48 hours after taking a single
6.25 mg dose of almotriptan. The patient, a 48-year-old female, had previously taken
three other doses for earlier migraine attacks. Myocardial enzymes at the time of the
abnormal ECG were normal. The patient was diagnosed as having had myocardial
ischemia and that she had a family history of coronary disease. An ECG performed
2 days later was normal, as was a follow-up coronary angiography. The patient
recovered without incident.
Postmarketing Experience with Almotriptan in Adults: Serious cardiovascular events
have been reported in association with the use of almotriptan. The uncontrolled nature
of postmarketing surveillance, however, makes it impossible to definitively determine
the proportion of the reported cases that were actually caused by almotriptan or to
reliably assess causation in individual cases [see Adverse Reactions (6.3)].
Patients with Documented Coronary Artery Disease: Because of the potential of
this class of compound (5-HT1 agonists) to cause coronary vasospasm, almotriptan
should not be given to patients with documented ischemic or vasospastic coronary
artery disease [see Contraindications (4.1)].
Patients with Risk Factors for CAD: It is strongly recommended that almotriptan not
be given to patients in whom unrecognized CAD is predicted by the presence of risk
factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong
family history of CAD, female with surgical or physiological menopause, or male
over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical
evidence that the patient is reasonably free of coronary artery and ischemic myocardial
disease or other significant underlying cardiovascular disease. The sensitivity of
cardiac diagnostic procedures to detect cardiovascular disease or predisposition to
coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation,
the patient’s medical history, electrocardiographic or other investigations reveal
findings indicative of, or consistent with, coronary artery vasospasm or myocardial
ischemia, almotriptan should not be administered [see Contraindications (4.1)].
For patients with risk factors predictive of CAD, who are determined to have a
satisfactory cardiovascular evaluation, it is strongly recommended that administration
of the first dose of almotriptan take place in the setting of a physician’s office or
similar medically staffed and equipped facility unless the patient has previously
received almotriptan. Because cardiac ischemia can occur in the absence of clinical
symptoms, consideration should be given to obtaining on the first occasion of use
an ECG during the interval immediately following almotriptan, in these patients with
risk factors. It is recommended that patients who are intermittent long-term users
of almotriptan and who have or acquire risk factors predictive of CAD, as described
above, undergo periodic interval cardiovascular evaluation as they continue to use
almotriptan.
The systematic approach described above is intended to reduce the likelihood that
patients with unrecognized cardiovascular disease will be inadvertently exposed to
almotriptan. The ability of cardiac diagnostic procedures to detect all cardiovascular
diseases or predisposition to coronary artery vasospasm is modest at best. Cardiovascular events associated with triptan treatment have occurred in patients with no
cardiac history and with documented absence of coronary artery disease.
5.2 Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck,
and Jaw
As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness
in the precordium, throat, neck, and jaw have been reported after treatment with
almotriptan. Because 5-HT1 agonists may cause coronary vasospasm, patients
who experience signs or symptoms suggestive of angina following dosing should
be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant
angina before receiving additional doses of medication, and should be monitored
electrocardiographically if dosing is resumed and similar symptoms occur. Patients
shown to have CAD and those with Prinzmetal’s variant angina should not receive
5-HT1 agonists [see Contraindications (4.1) and Warnings and Precautions (5.1)].
5.3 Cerebrovascular Events and Fatalities
Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular
events have been reported in patients treated with other triptans and some events
have resulted in fatalities. In a number of cases, it appeared possible that the
cerebrovascular events were primary, the triptan having been administered in the
incorrect belief that the symptoms experienced were a consequence of migraine,
when they were not. As with other acute migraine therapies, before treating headaches
in patients not previously diagnosed as migraineurs and in migraineurs who present
with atypical symptoms, care should be taken to exclude other potentially serious
neurological conditions. It should be noted that patients with migraine may be at
increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and
transient ischemic attack) [see Contraindications (4.2)].
5.4 Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia
and Colonic Ischemia
Triptans, including almotriptan, may cause vasospastic reactions other than coronary
artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with
abdominal pain and bloody diarrhea. Very rare reports of transient and permanent
blindness and significant partial vision loss have been reported with the use of triptans. Visual disorders may also be part of a migraine attack. Patients who experience
symptoms or signs suggestive of decreased arterial flow following the use of any
triptan, such as ischemic bowel syndrome or Raynaud’s syndrome, are candidates
for further evaluation [see Contraindications (4.3)].
The development of a potentially life-threatening serotonin syndrome may occur
with triptans, including almotriptan, particularly during combined use with selective
serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors
(SNRIs). If concomitant treatment with almotriptan and an SSRI (e.g., fluoxetine,
paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g.,
venlafaxine, duloxetine) is clinically warranted, careful observation of the patient
is advised, particularly during treatment initiation and dose increases. Serotonin
syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal
symptoms (e.g., nausea, vomiting, diarrhea) [see Drug Interactions (7.3)].
5.6 Medication Overuse Headache
Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination
of these drugs for 10 or more days per month) may lead to exacerbation of headache
(medication overuse headache). Medication overuse headache may present as
migraine-like daily headaches or as a marked increase in frequency of migraine
attacks. Detoxification of patients, including withdrawal of the overused drugs, and
treatment of withdrawal symptoms (which often includes a transient worsening of
headache) may be necessary.
5.7 Increases in Blood Pressure
As with other triptans, significant elevations in systemic blood pressure have been
reported on rare occasions with almotriptan use in patients with and without a history
of hypertension; very rarely these increases in blood pressure have been associated
with significant clinical events. Almotriptan is contraindicated in patients with
uncontrolled hypertension [see Contraindications (4.4)]. In normotensive healthy
subjects and patients with hypertension controlled by medication, small, but clinically
insignificant, increases in mean systolic (0.21 and 4.87 mm Hg, respectively) and
diastolic (1.35 and 0.26 mm Hg, respectively) blood pressure relative to placebo
were seen over the first 4 hours after oral administration of 12.5 mg of almotriptan.
An 18% increase in mean pulmonary artery pressure was seen following dosing with
another triptan in a study evaluating subjects undergoing cardiac catheterization.
5.8 Hypersensitivity to Sulfonamides
Caution should be exercised when prescribing almotriptan to patients with known
hypersensitivity to sulfonamides. The chemical structure of almotriptan contains a
sulfonyl group, which is structurally different from a sulfonamide. Cross-sensitivity to
almotriptan in patients allergic to sulfonamides has not been systematically evaluated.
5.9 Impaired Hepatic or Renal Function
Almotriptan should be administered with caution to patients with diseases that may
3
The incidence of adverse events in controlled clinical trials was not affected by gender,
weight, age, presence of aura, or use of prophylactic medications or oral contraceptives.
There were insufficient data to assess the effect of race on the incidence of adverse
events.
Adolescents: Table 2 lists the adverse reactions reported by 1% or more of
almotriptan-treated adolescents age 12 to 17 years in one placebo-controlled, doubleblind clinical trial.
Table 2. Adverse Reactions Reported by ≥ 1% of Adolescent Patients Treated
with Almotriptan in One Placebo-Controlled, Double-Blind Clinical Trial
System/Organ Class Almotriptan 6.25 mg Almotriptan 12.5 mg Placebo
Adverse Reaction
(n = 180)
(n = 182)
(n = 172)
%
%
%
Nervous System
Disorders
Dizziness
4
3
2
Somnolence
<1
5
2
Headache
1
2
1
Paresthesia
<1
1
<1
Gastrointestinal
Disorders
Nausea
1
3
0
Vomiting
2
0
<1
alter the absorption, metabolism, or excretion of drugs, such as those with impaired
hepatic or renal function [see Dosage and Administration (2.2), (2.3) and Clinical
Pharmacology (12.3)].
5.10 Binding to Melanin-Containing Tissues
When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled
almotriptan, the elimination half-life of radioactivity from the eye was 22 days. This
finding suggests that almotriptan and/or its metabolites may bind to melanin in the
eye. Because almotriptan could accumulate in melanin-rich tissues over time, there is
the possibility that it could cause toxicity in these tissues with extended use. However,
no adverse retinal effects related to treatment with almotriptan were noted in a 52-week
toxicity study in dogs given up to 12.5 mg/kg/day (resulting in exposure [AUC] to parent
drug approximately 20 times that in humans receiving the maximum recommended
human dose of 25 mg/day). Although no systematic monitoring of ophthalmologic
function was undertaken in clinical trials, and no specific recommendations for
ophthalmologic monitoring are offered, prescribers should be aware of the possibility
of long-term ophthalmologic effects.
5.11 Corneal Opacities
Three male dogs (out of a total of 14 treated) in a 52-week toxicity study of oral
almotriptan developed slight corneal opacities that were noted after 51 weeks, but
not after 25 weeks of treatment. The doses at which this occurred were 2, 5, and
12.5 mg/kg/day. The opacity reversed after a 4-week drug-free period in the affected
dog treated with the highest dose. Systemic exposure (plasma AUC) to parent drug
at 2 mg/kg/day was approximately 2.5 times the exposure in humans receiving the
maximum recommended human daily dose of 25 mg. A no-effect dose was not
established.
6.2 Other Adverse Reactions Observed in Almotriptan Clinical Trials
In the paragraphs that follow, the frequencies of less commonly reported adverse
clinical reactions are presented. The reports include adverse reactions in five adult
controlled studies and one adolescent controlled study. Variability associated with
adverse reaction reporting, the terminology used to describe adverse reactions, etc.,
limit the value of the quantitative frequency estimates provided. Reaction frequencies
are calculated as the number of patients who used almotriptan and reported a
reaction divided by the total number of patients exposed to almotriptan (n = 3,047, all
doses). All reported reactions are included except those already listed in the previous
table, those too general to be informative, and those not reasonably associated with
the use of the drug. Reactions are further classified within system organ class
and enumerated in order of decreasing frequency using the following definitions:
frequent adverse reactions are those occurring in 1/100 or more patients, infrequent
adverse reactions are those occurring in fewer than 1/100 to 1/1,000 patients, and
rare adverse reactions are those occurring in fewer than 1/1,000 patients.
Body: Frequent: Headache. Infrequent: Abdominal cramp or pain, Asthenia, Chills, Back
pain, Chest pain, Neck pain, Fatigue, and Rigid neck. Rare: Fever and Photosensitivity
reaction.
Cardiovascular: Infrequent: Vasodilation, Palpitations, and Tachycardia. Rare:
Hypertension and Syncope.
Digestive: Infrequent: Diarrhea, Vomiting, Dyspepsia, Gastroenteritis, and Increased
thirst. Rare: Colitis, Gastritis, Esophageal reflux, and Increased salivation.
Metabolic: Infrequent: Hyperglycemia and Increased serum creatine phosphokinase.
Rare: Increased gamma glutamyl transpeptidase and Hypercholesteremia.
Musculoskeletal: Infrequent: Myalgia. Rare: Arthralgia, Arthritis, Myopathy, and
Muscle weakness.
Nervous: Frequent: Dizziness and Somnolence. Infrequent: Tremor, Vertigo, Anxiety,
Hypoesthesia, Restlessness, CNS stimulation, and Shakiness. Rare: Change in dreams,
Impaired concentration, Abnormal coordination, Depressive symptoms, Euphoria,
Hyperreflexia, Hypertonia, Nervousness, Neuropathy, Nightmares, Nystagmus, and
Insomnia.
Respiratory: Infrequent: Pharyngitis, Rhinitis, Dyspnea, Laryngismus, Sinusitis, and
Bronchitis. Rare: Hyperventilation, Laryngitis, Sneezing, and Epistaxis.
Skin: Infrequent: Diaphoresis, Pruritus, and Rash. Rare: Dermatitis and Erythema.
Special Senses: Infrequent: Ear pain and Tinnitus. Rare: Diplopia, Dry eyes, Eye pain,
Otitis media, Parosmia, Scotoma, Conjunctivitis, Eye irritation, Hyperacusis, and Taste
alteration.
Urogenital: Infrequent: Dysmenorrhea.
The following adverse reactions have been identified during postapproval use of
almotriptan. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
Immune System Disorders: Hypersensitivity reactions (including angioedema,
anaphylactic reactions and Anaphylactic shock)
Psychiatric Disorders: Confusional state, Restlessness
Nervous System Disorders: Hemiplegia, Hypoesthesia, Seizures
Eye Disorders: Blepharospasm, Visual impairment, Vision blurred
Ear and Labyrinth Disorders: Vertigo
Cardiac Disorders: Acute myocardial infarction, Coronary artery vasospasm, Angina
pectoris, Tachycardia
6
ADVERSE REACTIONS
Serious cardiac reactions, including myocardial infarction, have occurred following
the use of almotriptan tablets. These reactions are extremely rare and most have
been reported in patients with risk factors predictive of CAD. Reactions reported
in association with triptans have included coronary artery vasospasm, transient
myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular
fibrillation [see Contraindications (4.1) and Warnings and Precautions (5.1)].
The following adverse reactions are discussed in more detail in other sections of
the labeling:
••
Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events
[see Warnings and Precautions (5.1)]
••
Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and
Jaw [see Warnings and Precautions (5.2)]
••
Cerebrovascular Events and Fatalities [see Warnings and Precautions (5.3)]
••
Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia
and Colonic Ischemia [see Warnings and Precautions (5.4)]
••
Serotonin Syndrome [see Warnings and Precautions (5.5)]
••
Increases in Blood Pressure [see Warnings and Precautions (5.7)]
Adverse events were assessed in controlled clinical trials that included 1,840 adult
patients who received one or two doses of almotriptan and 386 adult patients who
received placebo. The most common adverse reactions during treatment with
almotriptan were nausea, somnolence, headache, paresthesia, and dry mouth. In
long-term open-label studies where patients were allowed to treat multiple attacks for
up to one year, 5% (63 out of 1,347 patients) withdrew due to adverse experiences.
Adverse events were assessed in controlled clinical trials that included 362 adolescent patients who received almotriptan and 172 adolescent patients who received
placebo. The most common adverse reactions during treatment with almotriptan
were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. In a longterm, open-label study where patients were allowed to treat multiple attacks for up
to one year, 2% (10 out of 420 adolescent patients) withdrew due to adverse events.
Because clinical studies are conducted under widely varying conditions, adverse
reaction rates observed in the clinical studies of a drug cannot be directly compared
to rates in the clinical studies of another drug and may not reflect the rates observed
in practice.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Almotriptan Clinical Trials
Adults: Table 1 lists the adverse events that occurred in at least 1% of the adult
patients treated with almotriptan, and at an incidence greater than in patients treated
with placebo, regardless of drug relationship.
Table 1. Incidence of Adverse Events in Controlled Clinical Trials (Reported
in at Least 1% of Adult Patients Treated with Almotriptan, and at an
Incidence Greater than Placebo)
System/Organ Class Almotriptan 6.25 mg Almotriptan 12.5 mg
Adverse Event
(n = 527)
(n = 1,313)
%
%
Digestive Disorders
Nausea
1
2
Dry Mouth
1
1
Nervous System
Disorders
Paresthesia
1
1
Placebo
(n = 386)
%
1
0.5
0.5
4
Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Abdominal pain
upper, Colitis, Hypoesthesia oral, Swollen tongue
Skin and Subcutaneous Tissue Disorders: Cold sweat, Erythema, Hyperhidrosis
Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, Myalgia, Pain
in extremity
Reproductive System and Breast Disorders: Breast pain
General Disorders: Malaise, Peripheral coldness.
Postmarketing experience with other triptans include a limited number of reports
that describe pediatric patients who have experienced clinically serious adverse
events that are similar in nature to those reported rarely in adults.
8.5 Geriatric Use
Clinical studies of almotriptan did not include sufficient numbers of subjects age
65 and over to determine whether they respond differently from younger subjects.
Clearance of almotriptan was lower in elderly volunteers than in younger individuals,
but there were no observed differences in the safety and tolerability between the
two populations [see Clinical Pharmacology (12.3)]. In general, dose selection for
an elderly patient should be cautious, usually starting at the low dose, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The recommended dose of almotriptan for elderly
patients with normal renal function for their age is the same as that recommended
for younger adults.
The recommended starting dose of almotriptan in patients with hepatic impairment
is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour
period [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
The recommended starting dose of almotriptan in patients with severe renal
a 24-hour period [see Dosage and Administration (2.3) and Clinical Pharmacology
(12.3)].
7
DRUG INTERACTIONS
7.1 Ergot-Containing Drugs
These drugs have been reported to cause prolonged vasospastic reactions. Because,
in theory, vasospastic effects may be additive, ergotamine-containing or ergot-type
medications (like dihydroergotamine, ergotamine tartrate, or methysergide) and
almotriptan should not be used within 24 hours of each other [see Contraindications
(4.5)].
7.25-HT1 Agonists (e.g., Triptans)
Concomitant use of other 5-HT1 agonists (e.g., triptans) within 24 hours of treatment
with almotriptan is contraindicated [see Contraindications (4.6)].
7.3 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine
Reuptake Inhibitors
Cases of life-threatening serotonin syndrome have been reported during combined
use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin
norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.5),
Clinical Pharmacology (12.3)].
7.4 Ketoconazole and Other Potent CYP3A4 Inhibitors
Co-administration of almotriptan and oral ketoconazole, a potent CYP3A4 inhibitor,
resulted in an approximately 60% increase in exposure of almotriptan. Increased
exposures to almotriptan may be expected when almotriptan is used concomitantly
with other potent CYP3A4 inhibitors [see Clinical Pharmacology (12.3)].
In patients concomitantly using potent CYP3A4 inhibitors, the recommended
starting dose of almotriptan is 6.25 mg. The maximum daily dose should not exceed
12.5 mg within a 24-hour period. Concomitant use of almotriptan and potent CYP3A4
inhibitors should be avoided in patients with renal or hepatic impairment [see Clinical
Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1Pregnancy
Teratogenic Effects: Pregnancy Category C: In animal studies, almotriptan produced
developmental toxicity (increased embryolethality and fetal skeletal variations,
and decreased offspring body weight) at doses greater than those used clinically.
There are no adequate and well-controlled studies in pregnant women; therefore,
almotriptan should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to
pregnant rats throughout the period of organogenesis, increased incidences of fetal
skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or
greater and an increase in embryolethality was seen at the highest dose. The no-effect
dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately
100 times the maximum recommended human dose (MRHD) of 25 mg/day on a
body surface area (mg/m2) basis. Similar studies in pregnant rabbits conducted
with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in
embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental
toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m2
basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats
throughout the periods of gestation and lactation, gestation length was increased
and litter size and offspring body weight were decreased at the highest dose. The
decrease in pup weight persisted throughout lactation. The no-effect dose in this study
(100 mg/kg/day) is 40 times the MRHD on a mg/m2 basis.
The effect of almotriptan on labor and delivery in humans is unknown.
8.3 Nursing Mothers
It is not known whether almotriptan is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when almotriptan
is administered to a nursing woman. Levels of almotriptan in rat milk were up to 7
times higher than in rat plasma.
8.4 Pediatric Use
Safety and efficacy of almotriptan in pediatric patients under the age of 12 years have
not been established. The pharmacokinetics, efficacy, and safety of almotriptan have
been evaluated in adolescent patients, age 12 to 17 years [see Clinical Pharmacology
(12.3) and Clinical Studies (14.2)].
In a clinical study, almotriptan 6.25 mg and 12.5 mg were found to be effective for the
relief of migraine headache pain in adolescent patients age 12 to 17 years. Efficacy on
migraine-associated symptoms (nausea, photophobia, and phonophobia) was not
established. The most common adverse reactions (incidence of ≥ 1%) associated
with almotriptan treatment were dizziness, somnolence, headache, paresthesia,
nausea, and vomiting [see Adverse Reactions (6.1)]. The safety and tolerability
profile of almotriptan treatment in adolescents is similar to the profile observed in
adults.
10OVERDOSAGE
10.1 Signs and Symptoms
Patients and volunteers receiving single oral doses of 100 mg to 150 mg of almotriptan
did not experience significant adverse events. Six additional normal volunteers
received single oral doses of 200 mg without serious adverse events. During clinical
trials with almotriptan, one patient ingested 62.5 mg in a 5-hour period and another
patient ingested 100 mg in a 38-hour period. Neither patient experienced adverse
reactions.
Based on the pharmacology of triptans, hypertension or other more serious cardiovascular symptoms could occur after overdosage.
10.2 Recommended Treatment
There is no specific antidote to almotriptan. In cases of severe intoxication, intensive
care procedures are recommended, including establishing and maintaining a patent
airway, ensuring adequate oxygenation and ventilation, and monitoring and support
of the cardiovascular system.
Clinical and electrocardiographic monitoring should be continued for at least 20 hours
even if clinical symptoms are not observed.
It is unknown what effect hemodialysis or peritoneal dialysis has on plasma
concentrations of almotriptan.
11DESCRIPTION
Almotriptan tablets, USP contain almotriptan malate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist. Almotriptan malate is chemically designated as 1-[[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine
(±)-hydroxybutanedioate (1:1) and its structural formula is:
Its molecular formula is C17H25N3O2S•C4H6O5, representing a molecular weight of
469.56. Almotriptan is a white to light yellow color crystalline powder that is soluble
in water and dimethyl formamide. Almotriptan tablets, USP for oral administration
contain 8.75 mg or 17.50 mg of almotriptan malate, USP equivalent to 6.25 mg or
12.5 mg of almotriptan, respectively. Each compressed tablet contains the following
inactive ingredients: hypromellose, mannitol, microcrystalline cellulose, polyethylene
glycol, povidone, sodium starch glycolate, sodium stearyl fumarate and titanium
dioxide.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors.
Almotriptan has weak affinity for 5-HT1A and 5-HT7 receptors, but has no significant
affinity or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT6; alpha or beta
adrenergic; adenosine (A1, A2); angiotensin (AT1, AT2); dopamine (D1, D2); endothelin
(ETA, ETB); or tachykinin (NK1, NK2, NK3) binding sites.
Current theories on the etiology of migraine headache suggest that symptoms
are due to local cranial vasodilatation and/or to the release of vasoactive and proinflammatory peptides from sensory nerve endings in an activated trigeminal system.
The therapeutic activity of almotriptan in migraine can most likely be attributed to
5
agonist effects at 5-HT1B/1D receptors on the extracerebral, intracranial blood vessels
that become dilated during a migraine attack and on nerve terminals in the trigeminal
system. Activation of these receptors results in cranial vessel constriction, inhibition
of neuropeptide release, and reduced transmission in trigeminal pain pathways.
Absorption: The absolute bioavailability of almotriptan is about 70%, with peak
plasma levels occurring 1 to 3 hours after administration; food does not affect
pharmacokinetics.
Distribution: Almotriptan is minimally protein bound (approximately 35%) and the
mean apparent volume of distribution is approximately 180 to 200 liters.
Metabolism: Almotriptan is metabolized by two major and one minor pathways.
Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of
the dose), and cytochrome P450-mediated oxidation (approximately 12% of the dose)
are the major routes of metabolism, while flavin monooxygenase is the minor route.
MAO-A is responsible for the formation of the indoleacetic acid metabolite, whereas
cytochrome P450 (3A4 and 2D6) catalyzes the hydroxylation of the pyrrolidine ring
to an intermediate that is further oxidized by aldehyde dehydrogenase to the gammaaminobutyric acid derivative. Both metabolites are inactive.
Excretion: Almotriptan has a mean half-life of 3 to 4 hours. Almotriptan is eliminated
primarily by renal excretion (about 75% of the oral dose), with approximately 40%
of an administered dose excreted unchanged in urine. Renal clearance exceeds the
glomerular filtration rate by approximately 3-fold, indicating an active mechanism.
Approximately 13% of the administered dose is excreted via feces, both unchanged
and metabolized.
Drug-Drug Interactions: All drug interaction studies were performed in healthy
volunteers using a single 12.5 mg dose of almotriptan and multiple doses of the other
drug.
Monoamine Oxidase Inhibitors: Co-administration of almotriptan and moclobemide
(150 mg twice daily for 8 days) resulted in a 27% decrease in almotriptan clearance
and an increase in Cmax of approximately 6%. No dose adjustment is necessary.
Propranolol: Co-administration of almotriptan and propranolol (80 mg twice daily for
7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.
Fluoxetine: Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days),
a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal
concentrations of almotriptan were increased 18%. This difference is not clinically
significant.
Verapamil: Co-administration of almotriptan and verapamil (120 mg sustained-release
tablets twice daily for 7 days), an inhibitor of CYP3A4, resulted in a 20% increase
in the area under the plasma concentration-time curve, and in a 24% increase in
maximal plasma concentrations of almotriptan. Neither of these changes is clinically
significant. No dose adjustment is necessary.
Ketoconazole and Other Potent CYP3A4 Inhibitors: Co-administration of almotriptan
and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60%
increase in exposure of almotriptan. Increased exposures to almotriptan may be
expected when almotriptan is used with other potent CYP3A4 inhibitors.
Special Populations: Geriatric: Renal and total clearance, and amount of drug excreted
in the urine, were lower in elderly healthy volunteers (age 65 to 76 years) than in
younger healthy volunteers (age 19 to 34 years), resulting in longer terminal half-life
(3.7 hours vs. 3.2 hours) and a 25% higher area under the plasma concentration-time
curve in the elderly subjects. The differences, however, do not appear to be clinically
significant.
Pediatric: A pharmacokinetics study of almotriptan was conducted in adolescents
(12 to 17 years) and adults (18 to 55 years) with or without a history of migraine.
No differences were observed in the rate or extent of absorption of almotriptan in
adolescents compared with adults.
Gender: No significant gender differences were observed in pharmacokinetic
parameters.
Race: No significant differences were observed in pharmacokinetic parameters
between Caucasian and African-American volunteers.
Hepatic Impairment: The pharmacokinetics of almotriptan have not been assessed in
patients with hepatic impairment. Based on the known mechanisms of clearance of
almotriptan, the maximum decrease expected in almotriptan clearance due to hepatic
impairment would be 60% [see Dosage and Administration (2.2)].
Renal Impairment: The clearance of almotriptan was approximately 65% lower in
patients with severe renal impairment (Cl/F = 19.8 L/hour; creatinine clearance between
10 and 30 mL/min) and approximately 40% lower in patients with moderate renal
impairment (Cl/F = 34.2 L/hour; creatinine clearance between 31 and 71 mL/min) than
in healthy volunteers (Cl/F = 57 L/hour). Maximal plasma concentrations of almotriptan
increased by approximately 80% in these patients [see Dosage and Administration
(2.3)].
approximately 40 and 80 times, in mice and rats respectively, the plasma AUC in
humans at the maximum recommended human dose (MRHD) of 25 mg/day. Because
of high mortality rates in both studies, which reached statistical significance in highdose female mice, all female rats, all male mice, and high-dose female mice were
terminated between weeks 96 and 98. There was no increase in tumors related to
almotriptan administration.
Mutagenesis: Almotriptan was not mutagenic in two in vitro gene mutation assays,
the Ames test, and the mouse lymphoma tk assay. Almotriptan was not clastogenic
in an in vivo mouse micronucleus assay.
Impairment of Fertility: When male and female rats received almotriptan (25, 100,
or 400 mg/kg/day) orally prior to and during mating and gestation, prolongation
of the estrous cycle was observed at the mid-dose and greater, and fertility was
impaired at the highest dose. Subsequent mating of treated with untreated animals
indicated that the decrease in fertility was due to an effect on females. The no-effect
dose for reproductive toxicity in rats (25 mg/kg/day) is approximately 10 times the
MRHD on a mg/m2 basis.
14
CLINICAL STUDIES
14.1Adults
The efficacy of almotriptan was established in three multi-center, randomized, doubleblind, placebo-controlled European trials. Patients enrolled in these studies were
primarily female (86%) and Caucasian (more than 98%), with a mean age of 41 years
(range of 18 to 72). Patients were instructed to treat a moderate to severe migraine
headache. Two hours after taking one dose of study medication, patients evaluated
their headache pain. If the pain had not decreased in severity to mild or no pain, the
patient was allowed to take an escape medication. If the pain had decreased to mild
or no pain at 2 hours but subsequently increased in severity between 2 and 24 hours,
it was considered a relapse and the patient was instructed to take a second dose
of study medication. Associated symptoms of nausea, vomiting, photophobia, and
phonophobia were also evaluated.
In these studies, the percentage of patients achieving a response (mild or no pain)
2 hours after treatment was significantly greater in patients who received either
almotriptan 6.25 mg or 12.5 mg, compared with those who received placebo. A higher
percentage of patients reported pain relief after treatment with the 12.5 mg dose than
with the 6.25 mg dose. Doses greater than 12.5 mg did not lead to significantly better
response. These results are summarized in Table 3.
Table 3. Response Rates 2 Hours Following Treatment of Initial Headache
in Adults
Placebo
Almotriptan
Almotriptan
6.25 mg
12.5 mg
58.5%†
Study 1
33.8%
55.4%*
(n = 166)
(n = 164)
(n = 80)
Study 2
40%
--57.1%‡
(n = 95)
(n = 175)
Study 3
33%
55.6%†
64.9%†
(n = 176)
(n = 360)
(n = 370)
*p
†p
‡p
value 0.002 in comparison with placebo
value < 0.001 in comparison with placebo
The estimated probability of achieving pain relief within 2 hours following initial
treatment with almotriptan in adults is shown in Figure 1.
Figure 1. Estimated Probability of Achieving an Initial Headache Response (Mild
or No Pain) in 2 Hours in Adults
This Kaplan-Meier plot is based on data obtained in the three placebo-controlled
clinical trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not
achieving pain relief by 2 hours were censored at 2 hours.
For patients with migraine-associated photophobia, phonophobia, nausea, and
vomiting at baseline, there was a decreased incidence of these symptoms following
administration of almotriptan compared with placebo.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Almotriptan was administered to mice and rats for up to 103 to
104 weeks at oral doses up to 250 mg/kg/day and 75 mg/kg/day, respectively.
These doses were associated with plasma exposures (AUC) to parent drug that were
6
Two to 24 hours following the initial dose of study medication, patients were allowed
to take an escape medication or a second dose of study medication for pain response.
The estimated probability of patients taking escape medication or a second dose of
study medication over the 24 hours following the initial dose of study medication is
shown in Figure 2.
Figure 2. Estimated Probability of Adult Patients Taking Escape Medication or a
Second Dose of Study Medication Over the 24 Hours Following the Initial Dose of
Study Treatment
The prevalence of the migraine-associated symptoms (nausea, photophobia, and
phonophobia) at 2 hours after taking the dose was not significantly different between
patients who received almotriptan 6.25 mg or 12.5 mg and those who received
placebo.
16
HOW SUPPLIED/STORAGE AND HANDLING
Almotriptan Tablets, USP are available containing 8.75 mg or 17.50 mg of almotriptan
malate, USP equivalent to 6.25 mg or 12.5 mg of almotriptan, respectively.
The 6.25 mg tablets are white to off-white film-coated, round, unscored tablets
debossed with M on one side of the tablet and AL1 on the other side. They are
available as follows:
NDC 0378-5245-56
bottles of 6 tablets
NDC 0378-5245-93
NDC 0378-5245-01
NDC 0378-5245-85
carton of 6 unit-dose tablets (1 x 6)
The 12.5 mg tablets are white to off-white film-coated, round, unscored tablets
debossed with M on one side of the tablet and AL2 on the other side. They are
available as follows:
NDC 0378-5246-96
NDC 0378-5246-93
NDC 0378-5246-01
NDC 0378-5246-85
carton of 12 unit-dose tablets (2 x 6)
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Dispense in a tight, light-resistant container as defined in the USP using a childresistant closure.
PHARMACIST: Dispense a Patient Information Leaflet with each prescription.
This Kaplan-Meier plot is based on data obtained in the three placebo-controlled
trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not using
additional treatment were censored at 24 hours. Remedication was not allowed
within 2 hours after the initial dose of almotriptan.
The efficacy of almotriptan was unaffected by the presence of aura; by gender, weight,
or age of the patient; or by concomitant use of common migraine prophylactic drugs
(e.g., beta-blockers, calcium channel blockers, and tricyclic antidepressants); or oral
contraceptives. There were insufficient data to assess the effect of race on efficacy.
14.2 Adolescents Age 12 to 17 Years
The efficacy of almotriptan in adolescent patients age 12 to 17 years was evaluated in
a double-blind, randomized, placebo-controlled study. Patients enrolled in that study
had at least a one-year history of migraine attacks with or without aura usually lasting
4 hours or more (when untreated). Patients enrolled in the study were primarily
females (60%) and Caucasian (75%), while 15% of patients were black, and 10%
were of other races. Patients were instructed to treat a moderate to severe migraine
headache. Two hours after taking one dose of study medication, patients evaluated
their headache pain. Associated symptoms of nausea, photophobia, and phonophobia
were also evaluated.
In this study, the percentage of patients achieving a pain relief response (mild or no
pain) 2 hours after treatment was statistically significantly greater in patients who
received almotriptan 6.25 mg or 12.5 mg compared with those who received placebo.
There was no additional benefit on pain relief provided by the 12.5 mg dose. The
2-hour pain relief results are summarized in Table 4.
Table 4. Response Rates 2 Hours Following Treatment of Initial Headache in
Adolescents Age 12 to 17 Years
Placebo
Almotriptan 6.25 mg
Almotriptan 12.5 mg
Study 1
55.3%
71.8%*
72.9%†
(n/N = 94/170)
(n/N = 127/177)
(n/N = 132/181)
*p
†p
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Drug Interactions: Advise patients to talk with their physician or pharmacist before
taking any new medicines, including prescription and non-prescription drugs and
supplements [see Contraindications (4.5) and (4.6) and Drug Interactions (7)].
Hypersensitivity: Inform patients to tell their physician if they develop a rash,
itching, or breathing difficulties after taking almotriptan tablets [see Warnings and
Precautions (5.8)].
17.1 Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac
Events, Other Vasospasm-Related Events, and Cerebrovascular Events
Inform patients that almotriptan tablets may cause serious cardiovascular side effects
such as myocardial infarction or stroke, which may result in hospitalization and even
death. Although serious cardiovascular events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, or slurring of speech, and should ask for medical advice when
observing any indicative signs or symptoms. Apprise the patient of the importance of
this follow-up [see Warnings and Precautions (5.1), (5.2), (5.3), and (5.4)].
Caution patients about the risk of serotonin syndrome with the use of almotriptan
tablets or other triptans, particularly during combined use with selective serotonin
reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
[see Warnings and Precautions (5.5)].
Medication Overuse Headache: Inform patients that use of acute migraine drugs for
10 or more days per month may lead to an exacerbation of headache and encourage
patients to record headache frequency and drug use (e.g., by keeping a headache
diary) [see Warnings and Precautions (5.6)].
17.3Pregnancy
Advise patients to notify their physician if they become pregnant during treatment or
intend to become pregnant [see Use in Specific Populations (8.1)].
17.4 Nursing Mothers
Advise patients to notify their physician if they are breastfeeding or plan to breastfeed
[see Use in Specific Populations (8.3)].
17.5 Ability to Operate Machinery or Vehicles
Counsel patients that almotriptan tablets may cause dizziness, somnolence, visual
disturbances, and other CNS symptoms that can interfere with driving or operating
machinery. Accordingly, advise the patient not to drive, operate complex machinery,
or engage in other hazardous activities until they have gained sufficient experience
with almotriptan to gauge whether it affects their mental or visual performance
adversely.
value < 0.001 in comparison with placebo
The estimated probability of achieving pain relief within 2 hours following initial
treatment with almotriptan in adolescents age 12 to 17 years is shown in Figure 3.
Figure 3. Estimated Probability of Achieving an Initial Headache Response (Mild
or No Pain) in 2 Hours in the Adolescent Study
7
••
past or present high blood pressure, chest pain, shortness of
breath, or heart disease.
•• liver or kidney problems.
•• risk factors for heart disease, such as:
– high blood pressure
–diabetes
– high cholesterol
–overweight
–smoking
– family members with heart disease
– you are past menopause
– you are a male over 40 years old.
•• allergic reactions to sulfonamides, also known as sulfa drugs
(ask your doctor if you are not sure what sulfonamide drugs
are).
•• medicines you take or plan to take, including prescription and
non-prescription medicines and herbal supplements. Be sure
to include medicines you normally take for a migraine.
Talk to your doctor about using almotriptan tablets if you are pregnant,
planning to become pregnant, or breastfeeding.
PATIENT INFORMATION
ALMOTRIPTAN TABLETS, USP
(al″ moe trip′ tan)
6.25 mg and 12.5 mg
Please read this information before you start taking almotriptan
tablets. Also, read this leaflet each time you renew your prescription
just in case anything has changed. Remember, this leaflet does not
take the place of careful discussions with your doctor. You and your
doctor should discuss almotriptan tablets when you start taking your
medication and at regular checkups.
What is almotriptan and what is it used for?
Almotriptan is a medication used to treat migraine attacks in adults
and adolescents age 12 to 17 years. Almotriptan is a member of a
class of drugs called selective serotonin receptor agonists.
Use almotriptan tablets only for a migraine attack. Do not use
almotriptan tablets to treat headaches that might be caused by other
conditions. Tell your doctor about your symptoms. Your doctor will
decide if you have migraine.
There is more information about migraine at the end of this leaflet.
How should I take almotriptan tablets?
•• When you have a migraine headache, take your medicine as
directed by your doctor.
•• If your headache comes back after your first dose, you may take
a second dose 2 hours or more after the first dose. If your pain
continues after the first dose, do not take a second dose without
first checking with your doctor.
•• Do not take more than two almotriptan tablets in a 24-hour
period.
•• Some people who take migraine medicines, like almotriptan
tablets, for 10 or more days every month may have worse
headaches (medication overuse headache). If your headaches
get worse, your healthcare provider may decide to stop your
treatment with almotriptan tablets.
•• If you take too much medicine, contact your doctor, hospital
emergency department, or poison control center right away.
Who should not take almotriptan tablets?
Do not take almotriptan tablets if you:
•• have ever had heart disease.
•• have uncontrolled high blood pressure.
•• have hemiplegic or basilar migraine. If you are not sure, ask your
doctor.
•• have taken another serotonin receptor agonist (e.g., another
triptan) in the last 24 hours. These include naratriptan
(AMERGE®), rizatriptan (MAXALT®), sumatriptan (IMITREX®,
TREXIMET®), or zolmitriptan (ZOMIG®).
•• have taken ergotamine-type medicines in the last 24 hours.
These include ergotamine (BELLERGAL-S®, CAFERGOT®,
ERGOMAR®, WIGRAINE®), dihydroergotamine (D.H.E. 45®), or
methysergide (SANSERT®).
•• had an allergic reaction to almotriptan tablets or any of its
ingredients. The active ingredient is almotriptan malate. Ask your
doctor or pharmacist about inactive ingredients.
Tell your doctor if you take:
•• monoamine oxidase (MAO) inhibitors, such as phenelzine
sulfate (NARDIL®) or tranylcypromine sulfate (PARNATE®) for
depression or another condition, or if it has been less than 2
weeks since you stopped taking an MAO inhibitor.
•• ketoconazole (NIZORAL®), itraconazole (SPORANOX®),
ritonavir (NORVIR®), or erythromycin (EMYCIN®), or if it has
been less than one week since you stopped taking one of these
drugs.
•• selective serotonin reuptake inhibitors (SSRIs) or serotonin
norepinephrine reuptake inhibitors (SNRIs), two types of
drugs for depression or other disorders. Common SSRIs are
CELEXA® (citalopram HBr), LEXAPRO® (escitalopram oxalate),
PAXIL® (paroxetine), PROZAC®/SARAFEM® (fluoxetine),
SYMBYAX® (olanzapine/fluoxetine), ZOLOFT® (sertraline), and
fluvoxamine. Common SNRIs are CYMBALTA® (duloxetine)
and EFFEXOR® (venlafaxine).
These medicines may affect how almotriptan tablets work, or
almotriptan tablets may affect how these medicines work.
To help your doctor decide if almotriptan tablets are right for you or
if you need to be checked while taking almotriptan tablets, tell your
doctor about any:
•• past or present medical problems.
What should I avoid while taking almotriptan tablets?
Check with your doctor before you take any new medicines, including
prescription and non-prescription medicines and supplements.
There are some medicines that you should not take during the period
24 hours before and 24 hours after taking almotriptan tablets. Some
of them are listed in the section “Who should not take almotriptan
tablets?”.
What are the possible side effects of almotriptan tablets?
The side effects are usually mild and do not last long. The following
is not a complete list of side effects. Ask your doctor to tell you
about the other side effects.
The most common side effects in adults are:
•• nausea
•• sleepiness
•• tingling or burning feeling (paresthesia)
•• headache
•• dry mouth
The most common side effects in adolescents are:
•• dizziness
•• sleepiness
•• nausea
•• headache
•• tingling or burning feeling (paresthesia)
•• vomiting
If you feel dizzy or sleepy, or if you notice any changes in your
8
and your doctor can change your lifestyle to avoid those triggers.
vision, you should evaluate your ability to perform complex tasks,
such as driving or operating heavy machinery.
Tell your doctor about any other symptoms that you develop while
taking almotriptan tablets. If the symptoms continue or worsen, get
medical help right away. Also, tell your doctor if you develop any of
the following after taking almotriptan tablets.
•• a swollen face, lips, mouth, tongue or throat
•• difficulty swallowing or breathing
•• an itchy rash (hives).
These may be a sign that you are allergic to the medicine.
In very rare cases, patients taking this class of medicines experience
serious heart problems, stroke, or increased blood pressure.
Extremely rarely, patients have died. Therefore, tell your doctor
right away if you feel tightness, pain, pressure, or heaviness in your
chest, throat, neck, or jaw after taking almotriptan tablets. Do not
take almotriptan tablets again until your doctor has checked you.
Some people may have a reaction called serotonin syndrome,
which can be life-threatening, when they use almotriptan tablets. In
particular, this reaction may occur when they use almotriptan tablets
together with certain types of antidepressants known as SSRIs or
SNRIs. Symptoms may include mental changes (hallucinations,
agitation, or coma), fast heartbeat, changes in blood pressure,
high body temperature or sweating, tight muscles, trouble walking,
nausea, vomiting, or diarrhea. Call your doctor immediately if you
have any of these symptoms after taking almotriptan tablets.
This is not a complete list of side effects. Talk to your doctor if you
develop any symptoms that concern you.
Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.
How do almotriptan tablets work during a migraine attack?
Treatment with almotriptan tablets:
•• reduces swelling of blood vessels surrounding the brain. This
swelling is associated with the headache pain of a migraine
attack.
•• blocks the release of substances from nerve endings that cause
more pain and other symptoms of migraine.
•• interrupts the sending of specific pain signals to your brain.
It is thought that each of these actions contributes to relief of your
symptoms by almotriptan tablets.
How should I store almotriptan tablets?
Keep your medicine in a safe place where children cannot reach it.
It may be harmful to children. Store your medicine away from heat,
light, or moisture at a controlled room temperature. If your medicine
has expired, throw it away as instructed. If your doctor decides to
stop your treatment, do not keep any leftover medicine unless your
doctor tells you to do so. Throw away your medicine as instructed.
Be sure that discarded tablets are out of the reach of children.
General advice about prescription medicines:
Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use almotriptan for
a condition for which it was not prescribed. Do not give almotriptan
tablets to other people even if they have the same symptoms you
have. People may be harmed if they take medicines that have not
been prescribed for them.
This leaflet provides a summary of information about almotriptan
tablets. If you have any questions or concerns about either almotriptan tablets or migraines, talk to your doctor. In addition, talk to
your pharmacist or other healthcare provider.
For more information, call Mylan Pharmaceuticals Inc. at
1-877-446-3679 (1-877-4-INFO-RX).
What to do in case of an overdose?
Call your doctor or poison control center or go to the ER.
What is a migraine and how does it differ from other headaches?
A migraine is an intense, throbbing, typically one-sided headache. It
often includes nausea, vomiting, sensitivity to light, and sensitivity
to sound. The pain and symptoms from a migraine headache may
be worse than the pain and symptoms of a common headache.
Some people have visual symptoms before the headache, such as
flashing lights or wavy lines, called an aura.
Migraine attacks typically last for hours or, rarely, for more than a
day. They can return often. The strength and frequency of migraine
attacks may vary.
Based on your symptoms, your doctor will decide whether you have
a migraine.
Migraine headaches tend to occur in members of the same family.
Both men and women get migraines, but it is more common in
women.
The brands listed are trademarks of their respective owners.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Manufactured in India by:
Mylan Laboratories Limited
Hyderabad — 500 034, India
Code No.: MH/DRUGS/25/NKD/89
What may trigger a migraine attack?
Certain things may trigger migraine attacks in some people. Some
of these triggers are:
•• certain foods or drinks, such as cheese, chocolate, citrus fruit
(oranges, grapefruit, lemons, limes, and others), caffeine, and
alcohol.
•• stress.
•• a change in behavior, such as too much or too little sleep,
missing a meal, or a change in diet.
•• hormone changes in women, such as during monthly menstrual
periods.
You may be able to prevent migraine attacks or make them come
less often if you understand what triggers your attacks. Keeping
a headache diary may help you identify and monitor the possible
triggers that cause your migraine. Once you identify the triggers, you
75056143MX:ALMT:R2pt
9
------------------------------- DOSAGE FORMS AND STRENGTHS ------------------------------Orally disintegrating tablets: 25 mg and 100 mg (3).
------------------------------------- CONTRAINDICATIONS ------------------------------------•• Known serious hypersensitivity to clozapine or any other component of clozapine orally disintegrating tablets (4.1).
-------------------------------- WARNINGS AND PRECAUTIONS -------------------------------•• Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur (5.7).
•• QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT
interval (disorders and drugs) (5.8).
•• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic
changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes
include:
oHyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including
polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients
with diabetes or at risk for diabetes (5.9).
oDyslipidemia: Undesirable alterations in lipids have occurred in patients treated with
atypical antipsychotics (5.9).
oWeight Gain: Significant weight gain has occurred. Monitor weight gain (5.9).
•• Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions (5.10).
•• Fever: Evaluate for infection and for neutropenia, NMS (5.11).
•• Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep-vein
thrombosis occur (5.12).
•• Anticholinergic Toxicity: Use cautiously in presence of specific conditions (e.g., narrow
angle glaucoma, use of anticholinergic drugs) (5.13).
•• Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles (5.14).
------------------------------------- ADVERSE REACTIONS ------------------------------------Most common adverse reactions (≥ 5%) were: CNS reactions (sedation, dizziness/vertigo,
headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope);
autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at
1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.
------------------------------------- DRUG INTERACTIONS ------------------------------------•• Concomitant use of Strong CYP1A2 Inhibitors: Reduce clozapine orally disintegrating tablets dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin) (2.7, 7.1).
•• Concomitant use of Strong CYP3A4 Inducers is not recommended (2.7, 7.1).
•• Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing clozapine orally disintegrating tablets dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g.,
carbamazepine) are discontinued (2.7, 7.1).
----------------------------- USE IN SPECIFIC POPULATIONS ---------------------------------•• Nursing Mothers: Discontinue drug or discontinue nursing, taking into consideration importance of drug to mother (8.3).
See Section 17 for PATIENT COUNSELING INFORMATION
These highlights do not include all the information needed to use CLOZAPINE ORALLY DISINTEGRATING TABLETS safely and effectively. See full prescribing information for CLOZAPINE
ORALLY DISINTEGRATING TABLETS.
CLOZAPINE orally disintegrating tablets, for oral use
WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND
SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN
ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
•• Severe Neutropenia: Clozapine orally disintegrating tablets can cause severe neutropenia, which can lead to serious and fatal infections. Patients initiating and continuing treatment with clozapine orally disintegrating tablets must have a baseline blood
absolute neutrophil count (ANC) measured before treatment initiation and regular
ANC monitoring during treatment (2.1, 5.1).
•• Clozapine orally disintegrating tablets are available only through a restricted program called the Clozapine REMS (5.2).
•• Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting
dose is 12.5 mg. Titrate gradually and use divided dosages (2.2, 2.6, 5.3).
•• Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure (2.2, 5.4).
•• Myocarditis and Cardiomyopathy: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions (5.5).
•• Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clozapine
orally disintegrating tablets are not approved for this condition (5.6).
----------------------------------- RECENT MAJOR CHANGES ----------------------------------Indications and Usage (1.1)
09/2015
Boxed Warning, Severe Neutropenia
09/2015
Dosage and Administration, Required Laboratory Testing Prior to Initiation and
During Therapy (2.1), Discontinuation of Treatment (2.5)
09/2015
Contraindications, History of Clozapine-induced Agranulocytosis or Severe
Granulocytopenia (4.1), Hypersensitivity (4.1)
09/2015
Warnings and Precautions Severe Neutropenia (5.1), Clozapine REMS Program (5.2)09/2015
----------------------------------- INDICATIONS AND USAGE ----------------------------------Clozapine orally disintegrating tablets are an atypical antipsychotic indicated for:
•• Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study
(1.1, 14.1).
•• Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study (1.2, 14.2).
-------------------------------- DOSAGE AND ADMINISTRATION -------------------------------•• Starting Dose: 12.5 mg once daily or twice daily (2.3).
•• Use cautious titration and divided dosage schedule (2.3, 5.3).
•• Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if
well-tolerated (2.3).
•• Target Dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks (2.3).
•• Subsequent Increases: increase in increments of 100 mg or less, once or twice weekly (2.3).
• Maximum Daily Dose: 900 mg (2.3). Tablets rapidly disintegrate after placement in the mouth
and may be chewed if desired. No water is needed (2.3).
WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN
ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
1.1 Treatment-Resistant Schizophrenia
1.2
Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder
2.1Required Laboratory Testing Prior to Initiation
and During Therapy
2.2 Important Administration Instructions
2.3 Dosing Information
2.4 Maintenance Treatment
2.5 Discontinuation of Treatment
2.6 Re-Initiation of Treatment
2.7Dosage Adjustments with Concomitant Use of
CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2,
CYP3A4 Inducers
2.8Renal or Hepatic Impairment, or CYP2D6 Poor
Metabolizers
4CONTRAINDICATIONS
4.1 Hypersensitivity
5.1 Severe Neutropenia
5.2
Clozapine REMS Program
5.3
Orthostatic Hypotension, Bradycardia, and Syncope
REVISED OCTOBER 2015
CLOZOD:R6
5.4Seizures
5.5 Myocarditis and Cardiomyopathy
5.6Increased Mortality in Elderly Patients with Dementia-Related Psychosis
5.7Eosinophilia
5.8 QT Interval Prolongation
5.9 Metabolic Changes
5.10 Neuroleptic Malignant Syndrome
5.11Fever
5.12 Pulmonary Embolism
5.13 Anticholinergic Toxicity
5.14
Interference with Cognitive and Motor Performance
5.15 Tardive Dyskinesia
5.16 Patients with Phenylketonuria
5.17 Cerebrovascular Adverse Reactions
5.18
Recurrence of Psychosis and Cholinergic Rebound After Abrupt Discontinuation of Clozapine
Orally Disintegrating Tablets
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1Potential for Other Drugs to Affect Clozapine
Orally Disintegrating Tablets
7.2Potential for Clozapine Orally Disintegrating Tablets to Affect Other Drugs
8.1Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
1
8.6 Patients with Renal or Hepatic Impairment
8.7 CYP2D6 Poor Metabolizers
8.8 Hospice Patients
10OVERDOSAGE
10.1 Overdosage Experience
10.2 Management of Overdosage
11DESCRIPTION
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14 CLINICAL STUDIES
14.2Recurrent Suicidal Behavior in Schizophrenia or
Schizoaffective Disorder
16.1 How Supplied
16.2 Storage and Handling
*Sections or subsections omitted from the full prescribing information are not listed.
increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to
450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose
can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum
dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and
syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided
dosages [see Warnings and Precautions (5.3)].
Clozapine orally disintegrating tablets can be taken with or without food [see Pharmacokinetics (12.3)].
2.4 Maintenance Treatment
Generally, patients responding to clozapine orally disintegrating tablets should continue maintenance treatment on their effective dose beyond the acute episode.
2.5 Discontinuation of Treatment
Method of treatment discontinuation will vary depending on the patient’s last ANC:
••
See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if
abrupt treatment discontinuation is necessary because of moderate to severe neutropenia.
••
Reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine
orally disintegrating tablets therapy is planned and there is no evidence of moderate
to severe neutropenia.
••
For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation
of the existing ANC monitoring is recommended for general population patients until their
ANC is ≥ 1500/μL and for BEN patients until their ANC is ≥ 1000/μL or above their baseline.
••
Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see
••
Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related
to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.
2.6 Re-Initiation of Treatment
When restarting clozapine orally disintegrating tablets in patients who have discontinued
clozapine orally disintegrating tablets (i.e., 2 days or more since the last dose), re-initiate
with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension,
bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well-tolerated,
the dose may be increased to the previously therapeutic dose more quickly than recommended
for initial treatment.
2.7 Dosage Adjustments with Concomitant Use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or
CYP1A2, CYP3A4 Inducers
Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral
contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers
(e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].
Table 1: Dose Adjustments in Patients Taking Concomitant Medications
Co-medications
Scenarios
Discontinuing a
Initiating clozapine Adding a co-mediorally disintegrating cation while taking co-medication while continutablets while taking clozapine orally dis- ing clozapine orally disintegrating tablets
a co-medication integrating tablets
Strong CYP1A2
Use one-third of the clozapine orally dis- Increase clozapine orally
Inhibitors
integrating tablets dose.
disintegrating tablets dose
based on clinical response.
Moderate or Weak Monitor for adverse reactions. Consider Monitor for lack of effectiveCYP1A2 Inhibitors reducing the clozapine orally disintegrat- ness. Consider increasing
clozapine orally disintegrating tablets dose if necessary.
CYP2D6 or CYing tablets dose if necessary.
P3A4 Inhibitors
WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND
SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY
IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Severe Neutropenia
Clozapine orally disintegrating tablets treatment has caused severe neutropenia, defined
as an absolute neutrophil count (ANC) less than 500/μL. Severe neutropenia can lead to
serious infection and death. Prior to initiating treatment with clozapine orally disintegrating tablets, a baseline ANC must be at least 1500/μL for the general population; and
must be at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN).
During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever,
weakness, lethargy, or sore throat) [see Dosage and Administration (2.1) and Warnings
and Precautions (5.1)].
Because of the risk of severe neutropenia, clozapine orally disintegrating tablets are
available only through a restricted program under a Risk Evaluation Mitigation Strategy
(REMS) called the Clozapine REMS Program [see Warnings and Precautions (5.2)].
Orthostatic Hypotension, Bradycardia, Syncope
Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with
clozapine treatment. The risk is highest during the initial titration period, particularly
with rapid dose escalation. These reactions can occur with the first dose, with doses
as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate
slowly; and use divided dosages. Use clozapine orally disintegrating tablets cautiously
in patients with cardiovascular or cerebrovascular disease or conditions predisposing
to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and
Administration (2.3 and 2.6) and Warnings and Precautions (5.3)].
Seizures
Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering clozapine orally disintegrating tablets to patients with a history of seizures or other
predisposing risk factors for seizure (CNS pathology, medications that lower the seizure
threshold, alcohol abuse). Caution patients about engaging in any activity where sudden
loss of consciousness could cause serious risk to themselves or others [see Dosage and
Administration (2.3) and Warnings and Precautions (5.4)].
Myocarditis and Cardiomyopathy
Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue clozapine orally disintegrating tablets and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine orally disintegrating tabletsrelated myocarditis or cardiomyopathy should not be rechallenged with clozapine orally
disintegrating tablets. Consider the possibility of myocarditis or cardiomyopathy if chest
pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG
changes occur [see Warnings and Precautions (5.5)].
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at
an increased risk of death. Clozapine orally disintegrating tablets are not approved for
use in patients with dementia-related psychosis [see Warnings and Precautions (5.6)].
1
Clozapine orally disintegrating tablets are indicated for the treatment of severely ill patients
with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, clozapine orally
disintegrating tablets should be used only in patients who have failed to respond adequately
to standard antipsychotic treatment [see Warnings and Precautions (5.1, 5.4)].
The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a
6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1)].
1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder
Clozapine orally disintegrating tablets are indicated for reducing the risk of recurrent suicidal
behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at
chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.
Suicidal behavior refers to actions by a patient that put him/herself at risk for death.
The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT™ trial [see Clinical Studies (14.2)].
Strong CYP3A4
Inducers
Concomitant use is not recommended.
However, if the inducer is necessary, it
may be necessary to increase the clozapine orally disintegrating tablets dose.
Monitor for decreased effectiveness.
Monitor for decreased effectiveness.
Moderate or
Weak CYP1A2 or Consider increasing the clozapine orally
CYP3A4 Inducers disintegrating tablets dose if necessary.
Reduce clozapine orally disintegrating tablets dose based
on clinical response.
Monitor for adverse reactions.
Consider reducing the clozapine orally disintegrating
tablets dose if necessary.
2.8 Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers
It may be necessary to reduce the clozapine orally disintegrating tablets dose in patients with
significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific
Populations (8.6, 8.7)].
2
2.1 Required Laboratory Testing Prior to Initiation and During Therapy
Prior to initiating treatment with clozapine orally disintegrating tablets, a baseline ANC must
be obtained. The baseline ANC must be at least 1500/μL for the general population, and at
least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN). To continue
treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1)].
Clozapine orally disintegrating tablets should be immediately placed in the mouth after removing the tablet from the blister pack or bottle. The tablet disintegrates rapidly after placement in the mouth. The tablets can be allowed to disintegrate, or they may be chewed. They
may be swallowed with saliva. No water is necessary for administration.
The orally disintegrating tablets in a blister pack should be left in the unopened blister until
the time of use. Just prior to use, peel the foil from the blister and gently remove the orally
disintegrating tablet. Do not push the tablets through the foil, because this could damage
the tablet.
2.3 Dosing Information
The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in
3
Clozapine orally disintegrating tablets are available as 25 mg and 100 mg round, peach, orally
disintegrating tablets.
4CONTRAINDICATIONS
4.1Hypersensitivity
Clozapine orally disintegrating tablets are contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or
Stevens-Johnson Syndrome) or any other component of clozapine orally disintegrating tablets
[see Adverse Reactions (6.2)].
5
5.1 Severe Neutropenia
Background: Clozapine orally disintegrating tablets can cause neutropenia (a low absolute
neutrophil count [ANC]), defined as a reduction below pre-treatment normal levels of blood
2
Table 3: Patients with Benign Ethnic Neutropenia (BEN); Clozapine Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring
neutrophils. The ANC is usually available as a component of the complete blood count (CBC),
including differential, and is more relevant to drug-induced neutropenia than is the white
blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC
equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the
differential (neutrophil “segs” plus neutrophil “bands”). Other granulocytes (basophils and
eosinophils) contribute minimally to neutropenia and their measurement is not necessary [see
Adverse Reactions (6.2)]. Neutropenia may be mild, moderate, or severe (see Tables 2 and 3).
To improve and standardize understanding, “severe neutropenia” replaces the previous terms
severe leukopenia, severe granulocytopenia, or agranulocytosis.
Severe neutropenia, ANC less than (<) 500/μL, occurs in a small percentage of patients taking
clozapine orally disintegrating tablets and is associated with an increase in the risk of serious
and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks
on treatment and then declines. The mechanism by which clozapine causes neutropenia is
unknown and is not dose-dependent.
Two separate management algorithms are provided below, the first for patients in the general
population, and the second for patients identified to have baseline neutropenia.
Clozapine Treatment and Monitoring in the General Patient Population (see Table 2):
Obtain a CBC, including the ANC value, prior to initiating treatment with clozapine orally
disintegrating tablets to ensure the presence of a normal baseline neutrophil count (equal to
or greater than 1500/μL) and to permit later comparisons. Patients in the general population
with an ANC equal to or greater than (≥) 1500/μL are considered within normal range (Table
2) and are eligible to initiate treatment. Weekly ANC monitoring is required for all patients
during the first 6 months of treatment. If a patient’s ANC remains equal to or greater than
1500/μL for the first 6 months of treatment, monitoring frequency may be reduced to every
2 weeks for the next 6 months. If the ANC remains equal to or greater than 1500/μL for the
second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once
every 4 weeks thereafter.
Table 2: Clozapine Treatment Recommendations Based on Absolute Neutrophil Count (ANC)
Monitoring for the General Patient Population
Clozapine Treatment
ANC Monitoring
ANC Level
Recommendations
Normal range
•• Initiate treatment
•• Weekly from initiation to 6 months
(≥ 1500/μL)
•• If treatment interrupted:
•• Every 2 weeks from 6 to 12 months
- < 30 days, continue
•• Monthly after 12 months
monitoring as before
- ≥ 30 days, monitor as if
new patient
•• Discontinuation for reasons •• See Section 2.5
other than neutropenia
Mild Neutropenia •• Continue treatment
•• Three times weekly until ANC
(1000 to 1499/μL)*
≥ 1500/μL
•• Once ANC ≥ 1500/μL, return to
patient’s last “Normal Range”
ANC monitoring interval**
Moderate
Neutropenia
(500 to 999/µL)*
Severe
Neutropenia
(less than
500/µL)*
•• Recommend hematology
consultation
•• Interrupt treatment for
suspected clozapine induced
neutropenia
•• Resume treatment once ANC
≥ 1000/µL
consultation
•• Interrupt treatment for suspected clozapine-induced
neutropenia
•• Do not rechallenge unless
prescriber determines benefits outweigh risks
ANC Level
Treatment Recommendations
Normal BEN Range •• Obtain at least two base(Established ANC
line ANC levels before
baseline ≥ 1000/µL )
initiating treatment
•• If treatment interrupted:
- < 30 days, continue
monitoring as before
- ≥ 30 days, monitor as if
new patient
•• Discontinuation of treatment for reasons other
than neutropenia
BEN
Neutropenia
(500 to 999/µL)*
ANC Monitoring
•• Weekly from initiation to 6 months
•• Every 2 weeks from 6 to 12
months
•• Monthly after 12 months
•• See Section 2.5
consultation
•• Continue treatment
≥ 1000/µL or ≥ patient’s known
baseline
•• Once ANC ≥ 1000/µL, or at
patient’s known baseline, check
ANC weekly for 4 weeks, then
return to patient’s last “Normal
BEN Range” ANC monitoring
interval**
BEN
•• Daily until ANC ≥ 500/µL, then
Severe Neutropenia
consultation
(less than 500/µL)* •• Interrupt treatment for sus≥ patient’s baseline
pected clozapine-induced •• If patient rechallenged, resume
neutropenia
treatment as a new patient under
“Normal Range” monitoring once
•• Do not rechallenge unless
ANC ≥ 1000/µL or at patient’s
prescriber determines benefits outweigh risks
baseline
*Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours
**If clinically appropriate
General Guidelines for Management of All Patients with Fever or with Neutropenia:
••
Fever: Interrupt clozapine orally disintegrating tablets as a precautionary measure in
any patient who develops fever, defined as a temperature of 38.5°C [101.3°F] or greater,
and obtain an ANC level. Fever is often the first sign of neutropenic infection.
••
ANC less than 1000/µL: If fever occurs in any patient with an ANC less than 1000/µL,
initiate appropriate workup and treatment for infection and refer to Tables 2 or 3 for
management.
••
Consider hematology consultation.
••
See Neuroleptic Malignant Syndrome [NMS] and Fever under WARNINGS and PRECAUTIONS (5) and Instructions for Patients, under PATIENT COUNSELING INFORMATION (17).
Rechallenge after an ANC less than 500/µL (severe neutropenia): For some patients who
experience severe clozapine-related neutropenia, the risk of serious psychiatric illness from
discontinuing clozapine orally disintegrating tablets treatment may be greater than the risk
of rechallenge (e.g. patients with severe schizophrenic illness who have no treatment options other than clozapine orally disintegrating tablets). A hematology consultation may be
useful in deciding to rechallenge a patient. In general, however, do not rechallenge patients
who develop severe neutropenia with clozapine orally disintegrating tablets or a clozapine
product.
If a patient will be rechallenged, the clinician should consider thresholds provided in Tables 2
and 3, the patient’s medical and psychiatric history, a discussion with the patient and his/her
caregiver about the benefits and risks of clozapine orally disintegrating tablets rechallenge,
and the severity and characteristics of the neutropenic episode.
Using Clozapine Orally Disintegrating Tablets with Other Drugs Associated with Neutropenia: It is unclear if concurrent use of other drugs known to cause neutropenia increases the
risk or severity of clozapine-induced neutropenia. There is no strong scientific rationale to
avoid clozapine treatment in patients concurrently treated with these drugs. If clozapine is
used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic
agents), consider monitoring patients more closely than the treatment guidelines provided
in Tables 2 and 3. Consult with the treating oncologist in patients receiving concomitant
chemotherapy.
5.2 Clozapine REMS Program
Clozapine orally disintegrating tablets are only available through a restricted program under a
REMS called the Clozapine REMS Program because of the risk of severe neutropenia.
Notable requirements of the Clozapine REMS Program include:
••
Healthcare professionals who prescribe clozapine orally disintegrating tablets must be
certified with the program by enrolling and completing training
••
Patients who receive clozapine orally disintegrating tablets must be enrolled in the program and comply with the ANC testing and monitoring requirements
••
Pharmacies dispensing clozapine orally disintegrating tablets must be certified with the
program by enrolling and completing training and must only dispense to patients who
are eligible to receive clozapine orally disintegrating tablets
Further information is available at www.clozapinerems.com or 1-844-267-8678.
5.3 Orthostatic Hypotension, Bradycardia, and Syncope
Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid doseescalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These
reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).
≥ 1500/µL
•• Once ANC ≥ 1500/µL, check ANC
weekly for 4 weeks, then return to
patient’s last “Normal Range”
ANC monitoring interval**
≥ 1500/µL
•• If patient rechallenged, resume
treatment as a new patient under
“Normal Range” monitoring once
ANC ≥ 1500/µL
* Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours
** If clinically appropriate
Clozapine Treatment and Monitoring in Patients with Benign Ethnic Neutropenia (see Table
3): Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose
average ANC values are lower than “standard” laboratory ranges for neutrophils. It is most
commonly observed in individuals of African descent (approximate prevalence of 25-50%),
some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups with darker
skin. BEN is more common in men. Patients with BEN have normal hematopoietic stem-cell
number and myeloid maturation, are healthy, and do not suffer from repeated or severe infections. They are not at increased risk for developing clozapine-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider
hematology consultation before initiating or during clozapine orally disintegrating tablets
treatment as necessary.
Patients with BEN require a different ANC algorithm for clozapine management due to their
lower baseline ANC levels. Table 3 provides guidelines for managing clozapine orally disintegrating tablets treatment and ANC monitoring in patients with BEN.
3
clozapine orally disintegrating tablets under careful monitoring. If the total eosinophil count
continues to increase over several weeks in the absence of systemic disease, the decision to
interrupt clozapine orally disintegrating tablets therapy and rechallenge after the eosinophil
count decreases should be based on the overall clinical assessment, in consultation with an
internist or hematologist.
5.8 QT Interval Prolongation
QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias,
cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing
clozapine orally disintegrating tablets, consider the presence of additional risk factors for
QT prolongation and serious cardiovascular reactions. Conditions that increase these risks
include the following: history of QT prolongation, long QT syndrome, family history of long QT
syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine orally disintegrating
tablets, and electrolyte abnormalities.
Prior to initiating treatment with clozapine orally disintegrating tablets, perform a careful
physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue
clozapine orally disintegrating tablets if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes or other arrhythmias (e.g., syncope,
presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue clozapine orally disintegrating tablets.
Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol,
pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin),
Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate,
methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine
is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with
inhibitors of these enzymes can increase the concentration of clozapine [see Drug Interactions
(7.1) and Clinical Pharmacology (12.3)].
Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can
result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients
at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes.
Correct electrolyte abnormalities before initiating treatment with clozapine orally disintegrating tablets.
Atypical antipsychotic drugs, including clozapine have been associated with metabolic
changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic
drugs may produce some metabolic changes, each drug in the class has its own specific risk
profile.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated
with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with
atypical antipsychotics including clozapine. Assessment of the relationship between atypical
antipsychotic use and glucose abnormalities is complicated by the possibility of an increased
background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not
completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical
antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients
treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on clozapine orally
disintegrating tablets should be monitored regularly for worsening of glucose control. Patients
with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at
the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia,
polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during
treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some
cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation
of the suspect drug.
In a pooled data analysis of eight studies in adult subjects with schizophrenia, the mean
changes in fasting glucose concentration in the clozapine and chlorpromazine groups were
+11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to
the chlorpromazine group (Table 4). The clozapine doses were 100 mg to 900 mg per day (mean
modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean
modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine
and chlorpromazine.
Table 4: Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with
Schizophrenia
Category Change
Treatment Arm
N
n (%)
Laboratory Parameter
(at least once) from Baseline
Clozapine
198 53 (27)
Normal (< 100 mg/dL) to
High (≥ 126 mg/dL)
Chlorpromazine 135 14 (10)
Fasting Glucose
Borderline
Clozapine
57 24 (42)
(100 to 125 mg/dL) to High
Chlorpromazine 43 12 (28)
(≥ 126 mg/dL)
Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by
the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly,
in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.3)]. Consider reducing the dose if
hypotension occurs. When restarting patients who have had even a brief interval off
clozapine orally disintegrating tablets (i.e., 2 days or more since the last dose), re-initiate
treatment at 12.5 mg once daily or twice daily [see Dosage and Administration (2.6)].
Use clozapine orally disintegrating tablets cautiously in patients with cardiovascular disease
(history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g.,
concomitant use of antihypertensives, dehydration and hypovolemia).
5.4Seizures
Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61
of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing
(i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low
dose (12.5 mg), titrate slowly, and use divided dosing.
Use caution when administering clozapine orally disintegrating tablets to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS
pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of
the substantial risk of seizure associated with clozapine orally disintegrating tablets use, caution patients about engaging in any activity where sudden loss of consciousness could cause
serious risk to themselves or others (e.g., driving an automobile, operating complex machinery,
swimming, climbing).
5.5 Myocarditis and Cardiomyopathy
Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions
can be fatal. Discontinue clozapine orally disintegrating tablets and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of
clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with clozapine orally disintegrating tablets. However, if the benefit of clozapine orally disintegrating tablets treatment is judged to outweigh the potential risks of recurrent myocarditis or
cardiomyopathy, the clinician may consider rechallenge with clozapine orally disintegrating
tablets in consultation with a cardiologist, after a complete cardiac evaluation, and under
close monitoring.
Consider the possibility of myocarditis or cardiomyopathy in patients receiving clozapine orally
disintegrating tablets who present with chest pain, dyspnea, persistent tachycardia at rest,
palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure,
or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first
2 months of clozapine orally disintegrating tablets treatment. Symptoms of cardiomyopathy
generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment
with clozapine orally disintegrating tablets. It is common for nonspecific flu-like symptoms
such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt
signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated
creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest
roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left
ventricular dysfunction.
5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at
an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10
weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated
patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational
studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional
antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic
drug as opposed to some characteristic(s) of the patients is not clear. Clozapine orally disintegrating tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].
5.7Eosinophilia
Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred
with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug
induced hypersensitivity syndrome (DIHS). If eosinophilia develops during clozapine
orally disintegrating tablets treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue clozapine
orally disintegrating tablets immediately.
If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen
vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause
and continue clozapine orally disintegrating tablets.
Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can
resolve without intervention. There are reports of successful rechallenge after discontinuation
of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue
4
Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine orally disintegrating tablets,
is recommended.
In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL
and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine
group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of two studies
in adult subjects with schizophrenia, clozapine treatment was associated with increases in
fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in
the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition,
clozapine treatment was associated with categorical increases in serum total cholesterol and
triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in
total cholesterol or fasting triglyceride increased with the duration of exposure. The median
duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The
clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was
1800 mg daily.
Table 5: Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in
Adult Subjects with Schizophrenia
Treatment Arm
Baseline Total Cholesterol
Change from Baseline
Concentration (mg/dL)
mg/dL (%)
Clozapine (N = 334)
Chlorpromazine (185)
Clozapine (N = 6)
Chlorpromazine (N = 7)
184
182
Baseline Triglyceride
Concentration (mg/dL)
130
110
Table 8: Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥ 7% Relative to Baseline Body Weight
Weight Change
Clozapine
Olanzapine
Chlorpromazine
N
669
442
155
≥ 7% (inclusive)
236 (35%)
203 (46%)
13 (8%)
Antipsychotic drugs including clozapine orally disintegrating tablets can cause a potentially
fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic
instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria,
rhabdomyolysis, and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. It is important to
consider the presence of other serious medical conditions (e.g., severe neutropenia, infection,
heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms,
and drug fever).
The management of NMS should include (1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and
medical monitoring, and (3) treatment of comorbid medical conditions. There is no general
agreement about specific pharmacological treatments for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if
restarting treatment with antipsychotics.
NMS has occurred with clozapine monotherapy and with concomitant CNS-active medications,
including lithium.
5.11Fever
During clozapine therapy, patients have experienced transient, clozapine-related fever. The
peak incidence is within the first 3 weeks of treatment. While this fever is generally benign
and self-limited, it may necessitate discontinuing treatment. The fever can be associated
with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out
severe neutropenia or infection. Consider the possibility of NMS [see Warnings and Precautions (5.10)].
5.12 Pulmonary Embolism
Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deepvein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms.
Whether pulmonary embolus and deep vein thrombosis can be attributed to clozapine or some
characteristic(s) of patients is not clear.
5.13 Anticholinergic Toxicity
Clozapine orally disintegrating tablets have potent anticholinergic effects. Treatment with clozapine orally disintegrating tablets can result in CNS and peripheral anticholinergic toxicity. Use
with caution in the presence of narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to
significant adverse reactions.
Treatment with clozapine orally disintegrating tablets can result in gastrointestinal adverse
reactions, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus.
Such reactions can be fatal. Constipation should be initially treated by ensuring adequate
hydration and use of ancillary therapy such as bulk laxatives. Consultation with a gastroenterologist is advisable in more serious cases.
5.14 Interference with Cognitive and Motor Performance
Clozapine orally disintegrating tablets can cause sedation and impairment of cognitive and
motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clozapine orally disintegrating tablets do not
affect them adversely. These reactions may be dose-related. Consider reducing the dose if
they occur.
Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase
with greater durations of treatment and higher total cumulative doses. However, the syndrome
can develop after relatively brief treatment periods at low doses. Prescribe clozapine orally
disintegrating tablets in a manner that is most likely to minimize the risk of developing TD. Use
the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing treatment if TD occurs.
However, some patients may require treatment with clozapine orally disintegrating tablets
despite the presence of the syndrome.
There is no known treatment for TD. However, the syndrome may remit partially or completely
if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The
effect of symptom suppression on the long-term course of TD is unknown.
5.16 Patients with Phenylketonuria
Phenylketonuric patients should be informed that clozapine orally disintegrating tablets
contain phenylalanine (a component of aspartame). Each 25 mg, orally disintegrating tablet
contains 1.90 mg phenylalanine. Each 100 mg, orally disintegrating tablet contains 7.59 mg
phenylalanine.
5.17 Cerebrovascular Adverse Reactions
In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse
reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for
this increased risk is not known. An increased risk cannot be excluded for clozapine orally
disintegrating tablets or other antipsychotics or other patient populations. Clozapine orally
disintegrating tablets should be used with caution in patients with risk factors for cerebro-
+13 (7)
+15 (8)
Change from Baseline
mg/dL (%)
+71 (54)
+39 (35)
Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with
Schizophrenia
Category Change
Treatment Arm
N
n (%)
Laboratory Parameter (at least once) from
Baseline
Clozapine
334
111 (33)
Increase by ≥ 40 mg/dL Chlorpromazine
185
46 (25)
Total Cholesterol
(random or fasting)
Triglycerides (fasting)
Normal (< 200 mg/
dL) to
Clozapine
Chlorpromazine
222
132
18 (8)
3 (2)
Borderline
(200 to 239 mg/dL) to
Clozapine
Chlorpromazine
79
34
30 (38)
14 (41)
Clozapine
Increase by ≥ 50 mg/dL Chlorpromazine
6
7
3 (50)
3 (43)
Normal (< 150 mg/
dL) to
Clozapine
Chlorpromazine
4
6
0 (0)
2 (33)
Borderline (≥ 150 mg/
dL and
< 200 mg/dL) to
Clozapine
Chlorpromazine
1
1
1 (100)
0 (0)
Weight Gain: Weight gain has occurred with the use of antipsychotics, including clozapine.
Monitor weight during treatment with clozapine orally disintegrating tablets. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine
and active comparators. The median duration of exposure was 609, 728, and 42 days, in the
clozapine, olanzapine, and chlorpromazine group, respectively.
Table 7: Mean Change in Body Weight (kg) by Duration of Exposure from Studies in Adult
Subjects with Schizophrenia
Metabolic
Exposure Duration Clozapine Olanzapine Chlorpromazine
Parameter
(N = 669) (N = 442)
(N = 155)
n Mean n Mean
n
Mean
2 weeks (Day 11 to 17) 6 +0.9 3 +0.7
2
-0.5
4 weeks (Day 21 to 35) 23 +0.7 8 +0.8 17
+0.6
8 weeks (Day 49 to 63) 12 +1.9 13 +1.8 16
+0.9
Weight change 12 weeks (Day 70
17 +2.8 5 +3.1
0
0
from baseline to 98)
24 weeks (Day 154
42 -0.6 12 +5.7
0
0
to 182)
48 weeks (Day 322
3 +3.7 3 +13.7 0
0
to 350)
Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥ 7% of body weight relative to baseline. The median duration of
exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group,
respectively.
5
vascular adverse reactions.
5.18 Recurrence of Psychosis and Cholinergic Rebound After Abrupt Discontinuation of
Clozapine Orally Disintegrating Tablets
If abrupt discontinuation of clozapine orally disintegrating tablets is necessary (because of
severe neutropenia or another medical condition, for example) [see Dosage and Administration (2.5), Warnings and Precautions (5.1)], monitor carefully for the recurrence of psychotic
symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating,
headache, nausea, vomiting, and diarrhea.
Body System
Adverse Reactions
Central Nervous System
Seizures (convulsions)
Rigidity
Akathisia
Confusion
Fatigue
Insomnia
Cardiovascular
Tachycardia
Hypotension
Hypertension
Gastrointestinal
Constipation
Nausea
Abdominal Discomfort/Heartburn
Nausea/Vomiting
Vomiting
Diarrhea
Urogenital
Urinary Abnormalities
Autonomic Nervous System
Salivation
Sweating
Dry Mouth
Visual Disturbances
Skin
Rash
Hemic/Lymphatic
Leukopenia/Decreased WBC/Neutropenia
Miscellaneous
Fever
Weight Gain
6
ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling:
••
Severe Neutropenia [see Warnings and Precautions (5.1)].
••
Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.3)].
••
Seizures [see Warnings and Precautions (5.4)].
••
Myocarditis and Cardiomyopathy [see Warnings and Precautions (5.5)].
••
Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings
••
Eosinophilia [see Warnings and Precautions (5.7)].
••
QT Interval Prolongation [see Warnings and Precautions (5.8)].
••
Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight
Gain) [see Warnings and Precautions (5.9)].
••
Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.10)].
••
Fever [see Warnings and Precautions (5.11)].
••
Pulmonary Embolism [see Warnings and Precautions (5.12)].
••
Anticholinergic Toxicity [see Warnings and Precautions (5.13)].
••
Interference with Cognitive and Motor Performance [see Warnings and Precautions
(5.14)].
••
Tardive Dyskinesia [see Warnings and Precautions (5.15)].
••
Patients with Phenylketonuria [see Warnings and Precautions (5.16)].
••
Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.17)].
••
Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in clinical practice.
The most commonly reported adverse reactions (≥ 5%) across clozapine clinical trials were:
CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular
reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most
commonly reported adverse reactions (≥ 5%) in clozapine-treated patients (compared to
chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant
schizophrenia.
Table 9: Common Adverse Reactions (≥ 5%) in the 6-Week, Randomized, ChlorpromazineControlled Trial in Treatment-Resistant Schizophrenia
Chlorpromazine
Adverse Reaction
Clozapine
(N = 142)
(N = 126)
(%)
(%)
Sedation
21
13
Tachycardia
17
11
Constipation
16
12
Dizziness
14
16
Hypotension
13
38
Fever (hyperthermia)
13
4
Hypersalivation
13
1
Hypertension
12
5
Headache
10
10
Nausea/vomiting
10
12
Dry mouth
5
20
Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT™ Study).
These rates are not adjusted for duration of exposure.
Table 10: Adverse Reactions (≥ 2%) Reported in Clozapine-Treated Patients (N = 842)
Across All Clozapine Studies (Excluding the 2-Year InterSePT™ Study)
Body System
Clozapine
Adverse Reactions
N = 842
Percentage of Patients
Central Nervous System
Drowsiness/Sedation
39
Dizziness/Vertigo
19
Headache
7
Tremor
6
Syncope
6
Disturbed Sleep/Nightmares
4
Restlessness
4
Hypokinesia/Akinesia
4
Agitation
4
continued
Clozapine
N = 842
3†
3
3
3
2
2
25†
9
4
14
5
4
3
3
2
2
31
6
6
5
2
3
5
4
† Rate
based on population of approximately 1,700 exposed during premarket clinical evaluation of clozapine.
Table 11 summarizes the most commonly reported adverse reactions (≥ 10% of the clozapine
or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled,
2-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of
suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not
adjusted for duration of exposure.
Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine
in the InterSePT™ Study (≥ 10% in the Clozapine or Olanzapine Group)
Olanzapine
Adverse Reactions
Clozapine
N = 477
N = 479
% Reporting
% Reporting
Salivary hypersecretion
48%
6%
Somnolence
46%
25%
Weight increased
31%
56%
Dizziness (excluding vertigo)
27%
12%
Constipation
25%
10%
Insomnia
20%
33%
Nausea
17%
10%
Vomiting
17%
9%
Dyspepsia
14%
8%
Dystonia: Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of treatment. Dystonic
symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the
throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these
symptoms can occur at low doses, they occur more frequently and with greater severity with
high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of
acute dystonia is observed in males and younger age groups.
The following adverse reactions have been identified during post-approval use of clozapine.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Central Nervous System: Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.
Cardiovascular System: Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, and periorbital
edema.
Endocrine System: Pseudopheochromocytoma.
Gastrointestinal System: Acute pancreatitis, dysphagia, salivary gland swelling.
Hepatobiliary System: Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed),
and liver failure.
Immune System Disorders: Angioedema, leukocytoclastic vasculitis.
Urogenital System: Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure.
6
Skin and Subcutaneous Tissue Disorders: Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome.
Musculoskeletal System and Connective Tissue Disorders: Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.
Respiratory System: Aspiration, pleural effusion, pneumonia, lower respiratory tract infection.
Hemic and Lymphatic System: Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.
Vision Disorders: Narrow-angle glaucoma.
Miscellaneous: Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight
loss.
In peri/postnatal developmental studies, pregnant female rats were administered clozapine
over the last third of pregnancy and until day 21 postpartum. Observations were made on
fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual
maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects
on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD
of 900 mg/day on a mg/m2 body surface area basis.
8.3 Nursing Mothers
Clozapine is present in human milk. Because of the potential for serious adverse reactions
in nursing infants from clozapine orally disintegrating tablets, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine orally disintegrating tablets to determine whether those over 65 years of age differ from
younger subjects in their response to clozapine orally disintegrating tablets.
Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5.3)]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.
Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine,
such as urinary retention and constipation [see Warnings and Precautions (5.13)].
Carefully select clozapine orally disintegrating tablets doses in elderly patients, taking into
consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well
as other concomitant disease and other drug therapy. Clinical experience suggests that the
prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly
women [see Warnings and Precautions (5.15)].
8.6 Patients with Renal or Hepatic Impairment
Dose reduction may be necessary in patients with significant impairment of renal or hepatic
function. Clozapine concentrations may be increased in these patients, because clozapine is
almost completely metabolized and then excreted [see Dosage and Administration (2.8) and
Clinical Pharmacology (12.3)].
8.7 CYP2D6 Poor Metabolizers
Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine
concentrations may be increased in these patients, because clozapine is almost completely
metabolized and then excreted [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].
8.8 Hospice Patients
For hospice patients (i.e., terminally ill patients with an estimated life expectancy of 6 months
or less), the prescriber may reduce the ANC monitoring frequency to once every 6 months, after
a discussion with the patient and his/her caregiver. Individual treatment decisions should
weigh the importance of monitoring ANC in the context of the need to control psychiatric symptoms and the patient’s terminal illness.
7
DRUG INTERACTIONS
7.1 Potential for Other Drugs to Affect Clozapine Orally Disintegrating Tablets
Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4,
and CYP2D6. Use caution when administering clozapine orally disintegrating tablets concomitantly with drugs that are inducers or inhibitors of these enzymes.
CYP1A2 Inhibitors: Concomitant use of clozapine orally disintegrating tablets and CYP1A2
inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions.
Reduce the clozapine orally disintegrating tablets dose to one third of the original dose when
clozapine orally disintegrating tablets are coadministered with strong CYP1A2 inhibitors
(e.g., fluvoxamine, ciprofloxacin, or enoxacin). The clozapine orally disintegrating tablets dose
should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is
discontinued [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].
Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients
closely when clozapine orally disintegrating tablets are coadministered with these inhibitors.
Consider reducing the clozapine orally disintegrating tablets dosage if necessary [see Dosage
and Administration (2.7)].
CYP2D6 and CYP3A4 Inhibitors: Concomitant treatment with clozapine orally disintegrating tablets and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin,
paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase
clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3)]. Use caution and monitor patients closely when using such inhibitors. Consider reducing the clozapine
orally disintegrating tablets dose [see Dosage and Administration (2.7)].
CYP1A2 and CYP3A4 Inducers: Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness
of clozapine orally disintegrating tablets. Tobacco smoke is a moderate inducer of CYP1A2. Strong
CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be
necessary to increase the clozapine orally disintegrating tablets dose if used concomitantly with
inducers of these enzymes. However, concomitant use of clozapine orally disintegrating tablets
and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7)].
Consider reducing the clozapine orally disintegrating tablets dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased
clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.7)].
Drugs that Cause QT Interval Prolongation: Use caution when administering concomitant
medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that
cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g.,
erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g.,
pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions (5.8)].
7.2 Potential for Clozapine Orally Disintegrating Tablets to Affect Other Drugs
Concomitant use of clozapine orally disintegrating tablets with other drugs metabolized by
CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering
clozapine orally disintegrating tablets with other drugs that are metabolized by CYP2D6. It
may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics
(e.g., propafenone, flecainide, and encainide).
10OVERDOSAGE
10.1 Overdosage Experience
The most commonly reported signs and symptoms associated with clozapine orally disintegrating tablets overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory
depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac
arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at
doses above 2500 mg. There have also been reports of patients recovering from overdoses
well in excess of 4 g.
For the most up-to-date information on the management of clozapine orally disintegrating
tablets overdosage, contact a certified Regional Poison Control Center (1-800-222-1222).
Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’
Desk Reference ®, a registered trademark of PDR Network. Establish and maintain an airway;
ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for clozapine orally
disintegrating tablets.
In managing overdosage, consider the possibility of multiple-drug involvement.
8
8.1Pregnancy
Teratogenic Effects. Pregnancy Category B: Risk Summary: There are no adequate or wellcontrolled studies of clozapine in pregnant women.
Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9
times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a
mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or
harm to the fetus due to clozapine. Because animal reproduction studies are not always
predictive of human response, clozapine orally disintegrating tablets should be used during
pregnancy only if clearly needed.
Clinical Considerations: Consider the risk of exacerbation of psychosis when discontinuing or
changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.9)]. Neonates exposed to antipsychotic drugs during
the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor,
somnolence, respiratory distress, and feeding difficulties. The severity of complications can
vary from self-limited symptoms to some neonates requiring intensive care unit support and
prolonged hospitalization.
Animal Data: In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits
during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of
900 mg/day on a mg/m2 body surface area basis.
11DESCRIPTION
Clozapine orally disintegrating tablets, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.
The structural formula is:
CH3
N
N
N
Cl
NH
C18H19ClN4
Mol. Wt. 326.83
Clozapine orally disintegrating tablets are available as peach, orally disintegrating tablets of
25 mg or 100 mg for oral administration without water. Clozapine orally disintegrating tablets
may be chewed.
Each orally disintegrating tablet contains clozapine equivalent to 25 mg or 100 mg.
7
istration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated about 3-fold compared to
baseline steady-state concentrations.
Paroxetine, Fluoxetine, and Sertraline: In a study of schizophrenic patients (n = 14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only
minor changes in the levels of clozapine and its metabolites. However, other published reports
describe modest elevations (less than 2-fold) of clozapine and metabolite concentrations
when clozapine was taken with paroxetine, fluoxetine, and sertraline.
Specific Population Studies: Renal or Hepatic Impairment: No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with
significant renal or hepatic impairment when given usual doses.
CYP2D6 Poor Metabolizers: A subset (3% to 10%) of the population has reduced activity of
CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected
plasma concentrations of clozapine when given usual doses.
The active component of clozapine orally disintegrating tablets is clozapine. The remaining
components are aspartame, crospovidone, FD&C Yellow No. 6 Aluminum Lake, magnesium
stearate, mannitol, microcrystalline cellulose, peppermint flavor, silicon dioxide and sodium
stearyl fumarate.
THIS PRODUCT CONTAINS ASPARTAME AND IS NOT INTENDED FOR USE BY INFANTS. PHENYLKETONURICS: CONTAINS PHENYLALANINE [see Warnings and Precautions (5.16)]. Phenylalanine is a component of aspartame. Each 25 mg, orally disintegrating tablet contains 3.38 mg
aspartame, thus, 1.90 mg phenylalanine. Each 100 mg, orally disintegrating tablet contains
13.52 mg aspartame, thus, 7.59 mg phenylalanine. The allowable daily intake of aspartame is
50 mg per kilogram of body weight per day.
The mechanism of action of clozapine is unknown. However, it has been proposed that the
therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. Clozapine also acts as an
antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic
receptors.
Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM),
adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine
D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A
(Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM),
and dopamine D3 (Ki 555 nM).
Clozapine orally disintegrating tablets cause little or no prolactin elevation.
Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and
theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp
wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased
to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost
immediately after falling asleep.
Absorption: In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Clozapine orally disintegrating tablets are bioequivalent to Clozaril® (clozapine) tablets, a
registered trademark of Novartis Pharmaceuticals Corporation. Following a dosage of 100 mg b.i.d., the
average steady-state peak plasma concentration was 413 ng/mL (range: 132 to 854 ng/mL), occurring
at the average of 2.3 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at
steady-state was 168 ng/mL (range: 45 to 574 ng/mL), after 100 mg b.i.d. dosing.
A comparative bioequivalence/bioavailability study was conducted in 32 patients (with schizophrenia
or schizoaffective disorder) comparing clozapine orally disintegrating 200 mg tablets to 2 × clozapine
orally disintegrating 100 mg tablets (the approved reference product) under fasted conditions. The
study also evaluated the effect of food and chewing on the pharmacokinetics of the 200 mg tablet. Under fasted conditions, the mean AUCss and Cmin,ss of clozapine for the 200 mg tablets were equivalent
to those of the 2 x 100 mg tablets. The mean Cmax,ss of clozapine for clozapine orally disintegrating
200 mg tablets was 85% that for 2 x 100 mg clozapine orally disintegrating tablets. This decrease in
Cmax,ss for clozapine orally disintegrating 200 mg tablets is not clinically significant.
For clozapine orally disintegrating 200 mg tablets, food significantly increased the Cmin,ss of clozapine
by 21%. However, this increase is not clinically significant. The mean AUCss and Cmax,ss of clozapine
under fed conditions were equivalent to those under fasted conditions. Food delayed clozapine absorption by 1.5 hours, from a median Tmax of 2.5 hours under fasted conditions to 4 hours under fed
conditions.
The mean Cmax,ss of clozapine under chewed conditions for clozapine orally disintegrating 200 mg
tablets was about 86% that for 2 x 100 mg clozapine orally disintegrating tablets under non-chewed
conditions, while the AUCss and Cmin,ss values were similar between the chewed and non-chewed
conditions.
In a food-effect study, a single dose of clozapine orally disintegrating tablets 12.5 mg was administered to healthy volunteers under fasting conditions and after a high-fat meal. When clozapine orally
disintegrating tablets was administered after a high-fat meal, the Cmax of both clozapine and its
active metabolite, desmethylclozapine, were decreased by approximately 20%, compared to administration under fasting conditions, while the AUC values were unchanged. This decrease in Cmax is not
clinically significant. Therefore, clozapine orally disintegrating tablets can be taken without regard
to meals.
Distribution: Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be
important [see Drug Interactions (7)].
Metabolism and Excretion: Clozapine is almost completely metabolized prior to excretion,
and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is
a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.
Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.
The demethylated, hydroxylated, and N-oxide derivatives are components in both urine and
feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have
only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean
elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours),
compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving
steady-state with 100 mg twice daily dosing.
A comparison of single-dose and multiple-dose administration of clozapine demonstrated that
the elimination half-life increased significantly after multiple dosing relative to that after
single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady-state, approximately dose-proportional changes with respect
to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were
observed after administration of 37.5 mg, 75 mg, and 150 mg twice daily.
Drug-Drug Interaction Studies: Fluvoxamine: A pharmacokinetic study was conducted in 16
schizophrenic patients who received clozapine under steady-state conditions. After coadmin-
Carcinogenesis: No carcinogenic potential was demonstrated in long-term studies in mice
and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended
human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis.
Mutagenesis: Clozapine was not genotoxic when tested in the following gene mutation and
chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese
hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes, or the in vivo micronucleus assay in mice.
Impairment of Fertility: Clozapine had no effect on any parameters of fertility, pregnancy,
fetal weight, or postnatal development when administered orally to male rats 70 days before
mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of
900 mg/day on a mg/m2 body surface area basis.
14 CLINICAL STUDIES
The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a
DSM-III diagnosis of schizophrenia who had inadequate responses to at least three different
antipsychotics (from at least two different chemical classes) during the preceding 5 years. The
antipsychotic trials must have been judged adequate; the antipsychotic dosages must have
been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least
6 weeks, each without significant reduction of symptoms. There must have been no period of
good functioning within the preceding 5 years. Patients must have had a baseline score of
at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item
BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum
potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition,
patients must have had a score of at least 4 on at least two of the following four individual
BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual
thought content. Patients must have had a Clinical Global Impressions - Severity Scale score
of at least 4 (moderately ill).
In the prospective, lead-in phase of the trial, all patients (N = 305) initially received singleblind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80%
of patients completed the 6-week trial. Patients with an inadequate response to haloperidol
(n = 268) were randomized to double-blind treatment with clozapine (N = 126) or chlorpromazine (N = 142). The maximum daily clozapine dose was 900 mg; the mean daily dose
was > 600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose
was > 1200 mg.
The primary endpoint was treatment response, predefined as a decrease in BPRS score of at
least 20% and either (1) a CGI-S score of ≤ 3 (mildly ill), or (2) a BPRS score of ≤ 35, at the
end of 6 weeks of treatment. Approximately 88% of patients from the clozapine and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the clozapine
group responded to treatment, and 4% of the chlorpromazine group responded to treatment.
The difference was statistically significant (p < 0.001). The mean change in total BPRS score
was -16 and -5 in the clozapine and chlorpromazine group, respectively; the mean change
in the four key BPRS item scores was -5 and -2 in the clozapine and chlorpromazine group,
respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the clozapine and
chlorpromazine group, respectively. These changes in the clozapine group were statistically
significantly greater than in the chlorpromazine group (p < 0.001 in each analysis).
14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder
The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed
in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of clozapine versus olanzapine (Zyprexa®, a
registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only
about one-fourth of these patients (27%) were considered resistant to standard antipsychotic
drug treatment. To enter the trial, patients must have met one of the following criteria:
••
They had attempted suicide within the 3 years prior to their baseline evaluation.
••
They had been hospitalized to prevent a suicide attempt within the 3 years prior to their
baseline evaluation.
••
They demonstrated moderate-to-severe suicidal ideation with a depressive component
within one week prior to their baseline evaluation.
••
They demonstrated moderate-to-severe suicidal ideation accompanied by command
hallucinations to do self-harm within one week prior to their baseline evaluation.
Dosing regimens for each treatment group were determined by individual investigators and
were individualized by patient. Dosing was flexible, with a dose range of 200 to 900 mg/day
for clozapine and 5 to 20 mg/day for olanzapine. For the 956 patients who received clozapine
8
or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with
antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the
patients in the olanzapine group.
The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of
surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality
severity as demonstrated by “much worsening” or “very much worsening” from baseline in the
Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist
(CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above
was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data.
A total of 980 patients were randomized to the study and 956 received study medication. Sixtytwo percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were
diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than
females in the study (61% of all patients were male). The mean age of patients entering the
study was 37 years of age (range 18 to 69). Most patients were Caucasian (71%), 15% were
Black, 1% were Asian, and 13% were classified as being of “other” races.
Patients treated with clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as
evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and
not a demonstration of the superior efficacy of clozapine over olanzapine.
The probability of experiencing (1) a significant suicide attempt, including a completed suicide,
or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for clozapine patients than
for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI of the
difference: 2%, 14% (Figure 1).
Figure 1: Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of
Suicidality
integrating tablets about the risk of developing severe neutropenia and infection.
Instruct patients to immediately report to their physician any symptom or sign of
infection (e.g., flu-like illness; fever; lethargy; general weakness or malaise; mucus
membrane ulceration; skin, pharyngeal, vaginal, urinary, or pulmonary infection;
or extreme weakness or lethargy) occurring at any time during clozapine orally
disintegrating tablets therapy, to aid in evaluation for neutropenia and to institute
prompt and appropriate management [see Warnings and Precautions (5.1), (5.10),
and (5.11)].
- Inform patients and caregivers clozapine orally disintegrating tablets are available
only through a restricted program called the Clozapine REMS Program designed
to ensure the required blood monitoring, in order to reduce the risk of developing
severe neutropenia. Advise patients and caregivers of the importance of having
blood tested as follows:
•• Weekly blood tests are required for the first 6 months.
•• An ANC is required every 2 weeks for the next 6 months if an acceptable ANC is
maintained during the first 6 months of continuous therapy.
•• An ANC is required once every 4 weeks thereafter if an acceptable ANC is maintained during the second 6 months of continuous therapy.
- Clozapine orally disintegrating tablets are available only from certified pharmacies participating in the program. Provide patients (and caregivers) with website
information and the telephone number on how to obtain the product.
Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers
about the risk of orthostatic hypotension and syncope, especially during the period of
initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration. Advise patients to consult their clinician immediately if they
feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or
arrhythmia [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)].
Seizures: Inform patients and caregivers about the significant risk of seizure during clozapine orally disintegrating tablets treatment. Caution them about driving and any other
potentially hazardous activity while taking clozapine orally disintegrating tablets [see
QT Interval Prolongation: Advise patients to consult their clinician immediately if they
feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia.
Instruct patients to not take clozapine orally disintegrating tablets with other drugs that
cause QT interval prolongation. Instruct patients to inform their clinicians that they are
taking clozapine orally disintegrating tablets before any new drug [see Warnings and
Precautions (5.8) and Drug Interactions (7.1)].
Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, Weight
Gain): Educate patients and caregivers about the risk of metabolic changes and the
need for specific monitoring. The risks include hyperglycemia and diabetes mellitus,
dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus
(e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these
symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes
(obesity, family history of diabetes) should have their fasting blood glucose monitored
before beginning treatment and periodically during treatment. Patients who develop
symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.9)].
Patients with Phenylketonuria: Inform patients and caregivers that clozapine orally
disintegrating tablets contain phenylalanine (a component of aspartame) [see Warnings and Precautions (5.16)].
Interference with Cognitive and Motor Performance: Because clozapine tablets may
have the potential to impair judgment, thinking, or motor skills, patients should be
cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that clozapine orally disintegrating tablets therapy does not affect
them adversely [see Warnings and Precautions (5.14)].
Missed Doses and Re-Initiating Treatment: Inform patients and caregivers that if the
patient misses taking clozapine orally disintegrating tablets for more than 2 days, he or
she should not restart his or her medication at the same dosage but should contact their
physician for dosing instructions [see Dosage and Administration (2.6) and Warnings
and Precautions (5.1, 5.3)].
Pregnancy: Patients and caregivers should notify the clinician if the patient becomes
pregnant or intends to become pregnant during therapy [see Use in Specific Populations
(8.1)].
Nursing: Advise patients and caregivers that the patient should not breast feed an
infant if they are taking clozapine orally disintegrating tablets [see Use in Specific
Populations (8.3)].
Concomitant Medication: Advise patients to inform their health care provider if they are
taking, or plan to take, any prescription or over-the-counter drugs; there is a potential
for significant drug-drug interactions [see Dosage and Administrations (2.6), Drug Interactions (7.1), and Table 1].
Administration: Patients should be advised that clozapine orally disintegrating tablets
should remain in the original package until immediately before use [see Dosage and
Administrations (2.2)].
-
••
••
••
••
16.1 How Supplied
Clozapine Orally Disintegrating Tablets are available containing 25 mg or 100 mg of clozapine, USP.
The 25 mg tablets are peach, round, unscored tablets debossed with C over 25 on one side of
the tablet and blank on the other side. They are available as follows:
••
••
NDC 0378-3813-01
NDC 0378-3813-05
••
The 100 mg tablets are peach, round, unscored tablets debossed with C over 100 on one side
of the tablet and blank on the other side. They are available as follows:
NDC 0378-3815-01
NDC 0378-3815-05
••
••
16.2 Storage and Handling
Protect from moisture.
Keep out of reach of children.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant
closure.
Clozapine orally disintegrating tablets must remain in the original package until used by the
patient.
Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for ANC
testing every 2 weeks, then a 2-week supply of clozapine orally disintegrating tablets can
be dispensed. If a patient is eligible for ANC testing every 4 weeks, then a 4-week supply of
clozapine orally disintegrating tablets can be dispensed. Dispensing should be contingent
upon the ANC testing results.
••
••
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Discuss the following issues with patients and caregivers:
••
Severe Neutropenia:
- Instruct patients (and caregivers) beginning treatment with clozapine orally dis-
REVISED OCTOBER 2015
CLOZOD:R6
9
•
These highlights do not include all the information needed to use DEXMETHYLPHENIDATE HYDROCHLORIDE EXTENDED-RELEASE CAPSULES safely and effectively. See full prescribing information
for DEXMETHYLPHENIDATE HYDROCHLORIDE EXTENDED-RELEASE CAPSULES.
•
•
DEXMETHYLPHENIDATE HYDROCHLORIDE extended-release capsules, for oral use
WARNING: DRUG DEPENDENCE
Dexmethylphenidate hydrochloride extended-release capsules should be given cautiously to
patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked
tolerance and psychological dependence, with varying degrees of abnormal behavior.
•
•
•
--------------------------------------- INDICATIONS AND USAGE ------------------------------------Dexmethylphenidate hydrochloride extended-release capsules are a CNS stimulant indicated for the
treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older. (1)
------------------------------------ DOSAGE AND ADMINISTRATION ----------------------------------•
Dexmethylphenidate hydrochloride extended-release capsules are intended for oral administration once daily in the morning. Dexmethylphenidate hydrochloride extended-release capsules may be swallowed whole, or capsule contents can be sprinkled on applesauce. Dexmethylphenidate hydrochloride extended-release capsules and/or their contents should not be
crushed, chewed, or divided. (2)
•
For patients new to methylphenidate: Begin treatment with dexmethylphenidate hydrochloride
extended-release capsules at 5 mg/day for pediatrics and 10 mg/day for adults, titrating the
dose weekly in 5 mg increments for pediatrics and in 10 mg increments for adults. Doses
above 30 mg/day in children and 40 mg/day in adults have not been studied. (2.1)
•
For patients already using methylphenidate: Initiate dexmethylphenidate hydrochloride extendedrelease capsules therapy with half (1/2) the current total daily dose of methylphenidate. (2.2)
•
Patients already using dexmethylphenidate hydrochloride immediate-release: Switch to the
same daily dose of dexmethylphenidate hydrochloride extended-release capsules. (2.2)
----------------------------------- DOSAGE FORMS AND STRENGTHS --------------------------------Extended-release capsules: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg (3)
----------------------------------------- CONTRAINDICATIONS ---------------------------------------•
Agitation, marked anxiety, and tension (4.1)
•
Known hypersensitivity to methylphenidate or product components (4.2)
•
Glaucoma (4.3)
•
History of motor tics or a family history or diagnosis of Tourette’s syndrome (4.4)
•
During, or within a minimum of 14 days following discontinuation of treatment with a
monoamine oxidase inhibitor (MAOI) (4.5)
------------------------------------- WARNINGS AND PRECAUTIONS ---------------------------------•
Serious Cardiovascular Events: Sudden death has been reported in association with CNS
stimulant treatment at usual doses in children and adolescents with structural cardiac
abnormalities or other serious heart problems. Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Stimulant
products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other
serious heart problems. (5.1)
•
Increased Blood Pressure and Heart Rate: have been reported. Monitor patients for changes in
blood pressure and heart rate. Caution should be exercised in treating patients whose underlying
medical conditions might be compromised by increases in blood pressure or heart rate. (5.2)
2.1 Patients New to Methylphenidate
2.2 Patients Currently Using Methylphenidate
2.3 Maintenance/Extended Treatment
2.4 Dose Reduction and Discontinuation
4 CONTRAINDICATIONS
4.1 Agitation
4.2 Hypersensitivity to Methylphenidate
4.3 Glaucoma
4.4 Tics
4.5 Monoamine Oxidase Inhibitors
5.1 Sudden Death and Preexisting Structural Cardiac
Abnormalities or Other Serious Heart Problems
5.2 Hypertension and Other Cardiovascular Conditions
5.3 Assessing Cardiovascular Status in Patients being
Treated with Stimulant Medications
5.4 Preexisting Psychosis
5.5 Bipolar Illness
5.6 Emergence of New Psychotic or Manic Symptoms
5.7 Aggression
5.8 Long-Term Suppression of Growth
•
•
•
•
•
Assess Cardiovascular Status: prior to stimulant treatment, assess for cardiac disease with
history and exam and, if suggested by findings, conduct further cardiac evaluation. Patients
with emerging symptoms suggestive of cardiac disease should undergo a prompt cardiac
evaluation. (5.3)
Psychotic Symptoms: may be exacerbated in patients with psychotic disorders. (5.4)
Bipolar Disorder: Use with particular care in ADHD patients with comorbid Bipolar Disorder.
Before initiating stimulant therapy, obtain a detailed psychiatric history for patients with
comorbid depressive symptoms, in order to determine risk for Bipolar Disorder. (5.5)
Emergence of New Psychotic or Manic Symptoms: Treatment-emergent psychotic or manic
symptoms without a prior history can be caused by stimulants at usual doses. Discontinuation of stimulant therapy may be indicated. (5.6)
Aggression: Monitor for appearance of or worsening of aggressive behavior or hostility. (5.7)
Long-Term Suppression of Growth: monitor height and weight in pediatric patients at appropriate intervals. Patients who are not growing or gaining weight as expected may need to have
their treatment interrupted. (5.8)
Seizures: The threshold for seizures may be lowered. In the presence of seizure, discontinue
treatment. (5.9)
Priapism: Cases of painful and prolonged penile erections and priapism have been reported
with methylphenidate products. Immediate medical attention should be sought if signs and
symptoms of prolonged penile erections or priapism are observed. (5.10)
Peripheral Vasculopathy, Including Raynaud’s Phenomenon: Stimulants used to treat ADHD
are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Careful
observation for digital changes is necessary during treatment with ADHD stimulants. (5.11)
Visual Disturbance: difficulties with accommodation and blurring of vision have been reported
with stimulant treatment. (5.12)
Hematologic Monitoring: periodic monitoring of CBC with differential is advised during prolonged therapy. (5.14)
----------------------------------------- ADVERSE REACTIONS ---------------------------------------Most common adverse reactions (at least 5% and twice the incidence among placebo-treated
patients) are dyspepsia, decreased appetite, headache, and anxiety for pediatric patients and dry
mouth, dyspepsia, headache, and anxiety for adult patients. (6)
1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
----------------------------------------- DRUG INTERACTIONS ---------------------------------------•
Dexmethylphenidate hydrochloride extended-release capsules should not be used in patients
being treated (currently or within the preceding 2 weeks) with MAO Inhibitors. (4.5)
•
Dexmethylphenidate hydrochloride extended-release capsules should be used cautiously with
pressor agents. (7)
•
Antacids or acid suppressants could alter the release of dexmethylphenidate hydrochloride
extended-release capsules. (7)
•
Racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants, and tricyclic drugs. (7)
------------------------------------- USE IN SPECIFIC POPULATIONS -------------------------------•
Dexmethylphenidate hydrochloride extended-release capsules should not be used in children
under 6 years of age. (5.13, 8.4)
•
Pregnancy: Limited human data. Based on animal data, may cause fetal harm. (8.1)
•
Nursing Mothers: Caution should be exercised when administered to a nursing woman. (8.3)
See Section 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
DEXM:R18mmh/MG:DEXM:R17m/MG:DEXM:R17mh
5.9 Seizures
5.10 Priapism
5.11 Peripheral Vasculopathy, Including Raynaud’s Phenomenon
5.12 Visual Disturbance
5.13 Use in Children Under 6 Years of Age
5.14 Hematologic Monitoring
6 ADVERSE REACTIONS
6.1 Adverse Events Associated with Discontinuation of
Treatment in Acute Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules –
Children
6.2 Adverse Events Occurring at an Incidence of 5% or More
Among Dexmethylphenidate Hydrochloride ExtendedRelease Capsules-Treated Patients – Children
6.3 Adverse Events Associated with Discontinuation of
Treatment in Clinical Studies with Dexmethylphenidate
Hydrochloride Extended-Release Capsules – Adults
6.4 Adverse Events Occurring at an Incidence of 5% or More
Among Dexmethylphenidate Hydrochloride ExtendedRelease Capsules-Treated Patients – Adults
6.6 Adverse Events with Other Methylphenidate Hydrochloride Dosage Forms
7 DRUG INTERACTIONS
8.1 Pregnancy
1
9
10
11
12
13
14
15
16
17
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance Class
9.2 Abuse, Dependence, Tolerance
OVERDOSAGE
10.2 Poison Control Center
DESCRIPTION
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13.1 Carcinogenesis, Mutagenesis, and Impairment of
Fertility
CLINICAL STUDIES
14.1 Children and Adolescents
14.2 Adults
REFERENCES
2.3 Maintenance/Extended Treatment
There is no body of evidence available from controlled trials to indicate how long the patient
with ADHD should be treated with dexmethylphenidate hydrochloride extended-release capsules. It is generally agreed, however, that pharmacological treatment of ADHD may be needed
for extended periods. Nevertheless, the physician who elects to use dexmethylphenidate hydrochloride extended-release capsules for extended periods in patients with ADHD should periodically reevaluate the long-term usefulness of the drug for the individual patient with periods
off medication to assess the patient’s functioning without pharmacotherapy. Improvement may
be sustained when the drug is either temporarily or permanently discontinued.
2.4 Dose Reduction and Discontinuation
If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be
reduced, or, if necessary, the drug should be discontinued.
If improvement is not observed after appropriate dosage adjustment over a one month period,
the drug should be discontinued.
Dexmethylphenidate hydrochloride extended-release capsules should be given cautiously to
patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to
marked tolerance and psychological dependence with varying degrees of abnormal behavior.
Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is
required during withdrawal from abusive use, since severe depression may occur. Withdrawal
following chronic therapeutic use may unmask symptoms of the underlying disorder that may
require follow-up.
1
Dexmethylphenidate hydrochloride extended-release capsules are indicated for the treatment
of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older.
The effectiveness of dexmethylphenidate hydrochloride extended-release capsules in the treatment of ADHD in patients aged 6 years and older was established in two placebo-controlled
studies in patients meeting DSM-IV criteria for ADHD [see Clinical Studies (14)].
A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of
hyperactive-impulsive or inattentive symptoms that caused impairment and were present
before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social,
academic, or occupational functioning, and be present in two or more settings, e.g., school (or
work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at
least 6 months: lack of attention to details/careless mistakes; lack of sustained attention;
poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive
Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities;
“on the go”; excessive talking; blurting answers; can’t wait turn; intrusive. The Combined
Types requires both inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations: Specific etiology of this syndrome is unknown, and there
is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of
special psychological, educational, and social resources. Learning may or may not be
impaired. The diagnosis must be based upon a complete history and evaluation of the child
and not solely on the presence of the required number of DSM-IV characteristics.
Need for Comprehensive Treatment Program: Dexmethylphenidate hydrochloride extendedrelease capsules are indicated as an integral part of a total treatment program for ADHD that
may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants
are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational
placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon
the physician’s assessment of the chronicity and severity of the child’s symptoms.
Long-Term Use: The effectiveness of dexmethylphenidate hydrochloride extended-release capsules for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in
controlled trials. Therefore, the physician who elects to use dexmethylphenidate hydrochloride
extended-release capsules for extended periods should periodically reevaluate the long-term
usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].
3
5 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg extended-release capsules
4
CONTRAINDICATIONS
4.1 Agitation
Dexmethylphenidate hydrochloride extended-release capsules are contraindicated in patients
with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.
4.2 Hypersensitivity to Methylphenidate
known to be hypersensitive to methylphenidate, or other components of the product. Hypersensitivity reactions, including angioedema and anaphylactic reactions, have been observed
in patients treated with methylphenidate [see Adverse Reactions (6.5, 6.6)].
4.3 Glaucoma
with glaucoma.
4.4 Tics
with motor tics or with a family history or diagnosis of Tourette’s syndrome [see Adverse Reactions (6.1)].
Dexmethylphenidate hydrochloride extended-release capsules are contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).
5
5.1 Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious
Heart Problems
Children and Adolescents: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an
increased risk of sudden death, stimulant products generally should not be used in children
or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious
heart rhythm abnormalities, or other serious cardiac problems that may place them at
increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults: Sudden death, stroke, and myocardial infarction have been reported in adults taking
stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases
is also unknown, adults have a greater likelihood than children of having serious structural
cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery
disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.
5.2 Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2 to
4 mmHg) and average heart rate (about 3 to 6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences,
all patients should be monitored for larger changes in heart rate and blood pressure. Caution
is indicated in treating patients whose underlying medical conditions might be compromised
by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart
failure, recent myocardial infarction, or ventricular arrhythmia.
5.3 Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death
or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and
should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain,
unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
5.4 Preexisting Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought
disorder in patients with a preexisting psychotic disorder.
5.5 Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid
bipolar disorder because of concern for possible induction of a mixed/manic episode in such
patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive
symptoms should be adequately screened to determine if they are at risk for bipolar disorder;
such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
2
Dexmethylphenidate hydrochloride extended-release capsules are for oral administration once
daily in the morning.
Dexmethylphenidate hydrochloride extended-release capsules may be swallowed as whole
capsules or alternatively may be administered by sprinkling the capsule contents on a small
amount of applesauce (see specific instructions below). Dexmethylphenidate hydrochloride
extended-release capsules and/or their contents should not be crushed, chewed, or divided.
The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce.
The mixture of drug and applesauce should be consumed immediately in its entirety. The drug
and applesauce mixture should not be stored for future use.
Dosage should be individualized according to the needs and responses of the patient.
2.1 Patients New to Methylphenidate
The recommended starting dose of dexmethylphenidate hydrochloride extended-release capsules for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg/day for
pediatric patients and 10 mg/day for adult patients.
Dosage may be adjusted in 5 mg increments for pediatric patients and in 10 mg increments
for adult patients. In general, dosage adjustments may proceed at approximately weekly intervals. The patient should be observed for a sufficient duration at a given dose to ensure that
a maximal benefit has been achieved before a dose increase is considered. In dose-response
(fixed-dose) studies (pediatric from 10 to 30 mg/day and adult from 20 to 40 mg/day), all
doses were effective vs. placebo. There was no clear finding, however, of greater average benefits for the higher doses compared to the lower doses. Adverse events and discontinuations,
however, were dose related. Doses above 30 mg/day in pediatrics and 40 mg/day in adults
have not been studied and are not recommended.
2.2 Patients Currently Using Methylphenidate
For patients currently using methylphenidate, the recommended starting dose of dexmethylphenidate hydrochloride extended-release capsules is half the total daily dose of racemic
methylphenidate. Patients currently using dexmethylphenidate hydrochloride tablets may
be switched to the same daily dose of dexmethylphenidate hydrochloride extended-release
capsules.
2
5.6 Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking,
or mania in children and adolescents without a prior history of psychotic illness or mania can
be caused by stimulants at usual doses. If such symptoms occur, consideration should be
given to a possible causal role of the stimulant, and discontinuation of treatment may be
appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such
symptoms occurred in about 0.1% (four patients with events out of 3,482 exposed to
methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
5.7 Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and
has been reported in clinical trials and the postmarketing experience of some medications
indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants
cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.
5.8 Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to
either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication treated children
over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children
(i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth
rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight
over 3 years), without evidence of growth rebound during this period of development. In the
7-week, double-blind placebo-controlled study of dexmethylphenidate hydrochloride extended-release capsules, the mean weight gain was greater for patients receiving placebo
(+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended-release capsules (-0.5 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely
have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to
have their treatment interrupted.
5.9 Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients
with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures,
and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures.
In the presence of seizures, the drug should be discontinued.
5.10 Priapism
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not
reported with drug initiation but developed after some time on the drug, often subsequent to
an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and
painful erections should seek immediate medical attention.
5.11 Peripheral Vasculopathy, Including Raynaud’s Phenomenon
Stimulants, including dexmethylphenidate hydrochloride extended-release capsules, used to
treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon.
Signs and symptoms are usually intermittent and mild; however, very rare sequelae include
digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including
Raynaud’s phenomenon, were observed in postmarketing reports at different times and at
therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms
generally improve after reduction in dose or discontinuation of drug. Careful observation for
digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
5.12 Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant
treatment.
5.13 Use in Children Under 6 Years of Age
Dexmethylphenidate hydrochloride extended-release capsules should not be used in children
under 6 years of age, since safety and efficacy in this age group have not been established.
5.14 Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
insomnia, and tachycardia (approximately 1% each). None of the 53 dexmethylphenidate hydrochloride extended-release capsules-treated pediatric patients discontinued treatment due to
adverse events in the 7-week, placebo-controlled study.
6.2 Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release Capsules-Treated Patients - Children
Table 1 enumerates treatment-emergent adverse events for the placebo-controlled, parallelgroup study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride
extended-release capsules doses of 5 to 30 mg/day. The table includes only those events that
occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extendedrelease capsules and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release capsules was at least twice the incidence in placebo-treated patients.
The prescriber should be aware that these figures cannot be used to predict the incidence of
adverse events in the course of usual medical practice where patient characteristics and other
factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the
adverse event incidence rate in the population studied.
Table 1: Treatment-Emergent Adverse Events1 Occurring During Double-Blind Treatment –
Pediatric Patients
Dexmethylphenidate Hydrochloride
Extended-release Capsules
Placebo
N = 53
N = 47
No. of Patients with AEs
Total
76%
57%
Primary System Organ Class/
Adverse Event Preferred Term
Gastrointestinal Disorders
38%
19%
Dyspepsia
8%
4%
Metabolism and Nutrition Disorders
34%
11%
Decreased appetite
30%
9%
Nervous System Disorders
30%
13%
Headache
25%
11%
Psychiatric Disorders
26%
15%
Anxiety
6%
0%
1Events, regardless of causality, for which the incidence for patients treated with dexmethylphenidate hydrochloride extended-release capsules was at least 5% and twice the incidence
among placebo-treated patients. Incidence has been rounded to the nearest whole number.
Table 2 below enumerates the incidence of dose related adverse events that occurred during a
fixed-dose, double-blind, placebo controlled trial of dexmethylphenidate hydrochloride extendedrelease capsules up to 30 mg/day versus placebo in children and adolescents with ADHD.
Table 2: Dose Related Adverse Events from a Fixed-Dose Study of Double-Blind Treatment
in Pediatric Patients by Organ-System and Preferred Term
ADVERSE EVENT
Dexmethylphenidate
Dexmethylphenidate
Dexmethylphenidate
Placebo
Hydrochloride
Hydrochloride
Hydrochloride
Extended-release
Extended-release
Extended-release
Capsules
Capsules
Capsules
10 mg/d
20 mg/d
30 mg/d
N = 64
N = 60
N = 58
N = 63
Gastrointestinal
22%
23%
29%
24%
Disorders
Vomiting
2%
8%
9%
0
Metabolism and
16%
17%
22%
5%
Nutritional Disorders
Anorexia
5%
5%
7%
0
19%
20%
38%
8%
Insomnia
5%
8%
17%
3%
Depression
0
0
3%
0
Mood swings
0
0
3%
2%
Other Adverse Events
Irritability
0
2%
5%
0
Nasal congestion
0
0
5%
0
Pruritus
0
0
3%
0
6
ADVERSE REACTIONS
Dexmethylphenidate hydrochloride extended-release capsules were administered to 46 children and seven adolescents with ADHD for up to 7 weeks and 206 adults with ADHD in clinical studies. During the clinical studies, 101 adult patients were treated for at least 6 months.
Adverse events during exposure were obtained primarily by general inquiry and recorded by
clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse
events without first grouping similar types of events into a smaller number of standardized
event categories. In the tables and listings that follow, MedDRA terminology has been used to
classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of
the type listed. An event was considered treatment emergent if it occurred for the first time
or worsened while receiving therapy following baseline evaluation.
6.1 Adverse Events Associated with Discontinuation of Treatment in Acute Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules - Children
Overall, 50 of 684 children treated with dexmethylphenidate hydrochloride immediate-release formulation (7.3%) experienced an adverse event that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia,
6.3 Adverse Events Associated with Discontinuation of Treatment in Clinical Studies with
Dexmethylphenidate Hydrochloride Extended-Release Capsules - Adults
In the adult placebo-controlled study, 10.7% of the dexmethylphenidate hydrochloride extendedrelease capsules-treated patients and 7.5% of the placebo-treated patients discontinued for
adverse events. Among dexmethylphenidate hydrochloride extended-release capsules-treated
patients, insomnia (1.8%, n = 3), feeling jittery (1.8%, n = 3), anorexia (1.2%, n = 2), and anxiety (1.2%, n = 2) were the reasons for discontinuation reported by more than one patient.
6.4 Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release Capsules-Treated Patients - Adults
Table 3 enumerates treatment-emergent adverse events for the placebo-controlled, parallelgroup study in adults with ADHD at fixed dexmethylphenidate hydrochloride extended-release
capsules doses of 20, 30, and 40 mg/day. The table includes only those events that occurred
in 5% or more of patients in a dexmethylphenidate hydrochloride extended-release capsules
dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release capsules appeared to increase with dose. The prescriber should be
3
aware that these figures cannot be used to predict the incidence of adverse events in the
course of usual medical practice where patient characteristics and other factors differ from
those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments,
uses, and investigators. The cited figures, however, do provide the prescribing physician with
some basis for estimating the relative contribution of drug and non-drug factors to the
adverse event incidence rate in the population studied.
Table 3: Treatment-Emergent Adverse Events1 Occurring During Double-Blind Treatment Adults
Dexmethylphenidate
Dexmethylphenidate
Dexmethylphenidate
Placebo
Hydrochloride
Hydrochloride
Hydrochloride
Extended-release
Extended-release
Extended-release
Capsules
Capsules
Capsules
20 mg
30 mg
40 mg
N = 57
N = 54
N = 54
N = 53
No. of Patients with AEs
Total
84%
94%
85%
68%
Primary System Organ Class/
Adverse Event Preferred Term
28%
32%
44%
19%
Dry mouth
7%
20%
20%
4%
Dyspepsia
5%
9%
9%
2%
37%
39%
50%
28%
Headache
26%
30%
39%
19%
40%
43%
46%
30%
Anxiety
5%
11%
11%
2%
Respiratory, Thoracic and
16%
9%
15%
8%
Mediastinal Disorders
Pharyngolaryngeal pain
4%
4%
7%
2%
1Events, regardless of causality, for which the incidence was at least 5% in a dexmethylphenidate hydrochloride extended-release capsules group and which appeared to increase
with randomized dose. Incidence has been rounded to the nearest whole number.
Two other adverse reactions occurring in clinical trials with dexmethylphenidate hydrochloride
extended-release capsules at a frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively).
Table 4 summarizes changes in vital signs and weight that were recorded in the adult study
(N = 218) of dexmethylphenidate hydrochloride extended-release capsules in the treatment of
ADHD.
Table 4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During DoubleBlind Treatment – Adults
Dexmethylphenidate Dexmethylphenidate
Dexmethylphenidate Placebo
Hydrochloride
Hydrochloride
Hydrochloride
Extended-release
Extended-release
Extended-release
Capsules
Capsules
Capsules
20 mg
30 mg
40 mg
(N = 57)
(N = 54)
(N = 54)
(N = 53)
Pulse (bpm)
3.1 ± 11.1
4.3 ± 11.7
6 ± 10.1
-1.4 ± 9.3
Diastolic BP (mmHg)
-0.2 ± 8.2
1.2 ± 8.9
2.1 ± 8
0.3 ± 7.8
Weight (kg)
-1.4 ± 2
-1.2 ± 1.9
-1.7 ± 2.3
-0.1 ± 3.9
Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most
of these, patients were concurrently receiving therapies associated with NMS. In a single
report, a 10-year-old boy who had been taking methylphenidate for approximately 18 months
experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It
is uncertain whether this case represented a drug-drug interaction, a response to either drug
alone, or some other cause.
7
DRUG INTERACTIONS
Dexmethylphenidate hydrochloride extended-release capsules should not be used in patients
being treated (currently or within the preceding 2 weeks) with MAO Inhibitors [see Contraindications (4.5)].
Because of possible effects on blood pressure, dexmethylphenidate hydrochloride extendedrelease capsules should be used cautiously with pressor agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.
Dexmethylphenidate is metabolized primarily to d-ritalinic acid by de-esterification and not
through oxidative pathways.
The effects of gastrointestinal pH alterations on the absorption of dexmethylphenidate from
dexmethylphenidate hydrochloride extended-release capsules have not been studied. Since
the modified release characteristics of dexmethylphenidate hydrochloride extended-release
capsules are pH dependent, the coadministration of antacids or acid suppressants could alter
the release of dexmethylphenidate.
Human pharmacologic studies have shown that racemic methylphenidate may inhibit the
metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin,
primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose
adjustments of these drugs may be required when given concomitantly with methylphenidate.
It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in the
case of coumarin, coagulation times), when initiating or discontinuing methylphenidate.
8
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C: There are no adequate and well controlled
studies of dexmethylphenidate in pregnant women. Dexmethylphenidate did not cause major
malformations in rats or rabbits; however, it did cause delayed skeletal ossification and
decreased postweaning weight gain in rats. Dexmethylphenidate hydrochloride extendedrelease capsules should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
In studies conducted in rats and rabbits, dexmethylphenidate was administered orally at
doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of teratogenic activity was found in either the rat or rabbit study; however, delayed fetal
skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate
was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day,
postweaning body weight gain was decreased in male offspring at the highest dose, but no
other effects on postnatal development were observed. At the highest doses tested, plasma
levels (AUCs) of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and
1 times, respectively, those in adults dosed with 20 mg/day.
Racemic methylphenidate has been shown to have teratogenic effects in rabbits when given
in doses of 200 mg/kg/day throughout organogenesis.
Dexmethylphenidate hydrochloride extended-release capsules have not been studied in labor
and delivery.
8.3 Nursing Mothers
It is not known whether dexmethylphenidate is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised if dexmethylphenidate hydrochloride
extended-release capsules are administered to a nursing woman. Information from four published case reports on the use of racemic methylphenidate during breast-feeding suggest that
at maternal doses of 35 to 80 mg/day, milk concentrations of methylphenidate range from
undetectable to 15.4 ng/mL. Based on these limited data, the calculated infant daily dose for
an exclusively breastfed infant would be about 0.4 to 2.9 mcg/kg/day or about 0.2% to 0.7%
of the maternal weight adjusted dose.
8.4 Pediatric Use
The safety and efficacy of dexmethylphenidate hydrochloride extended-release capsules in
children under 6 years old have not been established. Long-term effects of dexmethylphenidate in children have not been well established [see Warnings and Precautions (5.11)].
In a study conducted in young rats, racemic methylphenidate was administered orally at doses
of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7)
and continuing through sexual maturity (Postnatal Week 10). When these animals were
tested as adults (Postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was
observed in males and females previously treated with 50 mg/kg/day (approximately 6 times
the maximum recommended human dose [MRHD] of racemic methylphenidate on a mg/m2
basis) or greater, and a deficit in the acquisition of a specific learning task was seen in
females exposed to the highest dose (12 times the racemic MRHD on a mg/m2 basis). The no
effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the
racemic MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral
effects observed in rats is unknown.
8.5 Geriatric Use
Dexmethylphenidate hydrochloride extended-release capsules have not been studied in the
geriatric population.
The following additional adverse reactions have been identified during postapproval use of
dexmethylphenidate hydrochloride extended-release capsules. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency:
Musculoskeletal: rhabdomyolysis
Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis
6.6 Adverse Events with Other Methylphenidate Hydrochloride Dosage Forms
Nervousness and insomnia are the most common adverse reactions reported with other
methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during
prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the
other adverse reactions listed below may also occur.
Other reactions include:
Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia
Gastrointestinal: abdominal pain, nausea
Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative
dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and
thrombocytopenic purpura
Metabolism/Nutrition: anorexia, weight loss during prolonged therapy
Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis
Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion
Although a definite causal relationship has not been established, the following have been
reported in patients taking methylphenidate:
Blood/Lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma
Psychiatric: transient depressed mood, aggressive behavior, libido changes
Skin/Subcutaneous: scalp hair loss
Urogenital: priapism
9
9.1 Controlled Substance Class
Dexmethylphenidate hydrochloride extended-release capsules, like other methylphenidate
products, are classified as a Schedule II controlled substance by Federal regulation.
4
9.2 Abuse, Dependence, Tolerance
See complete boxed warning for drug abuse and dependence information at the beginning of
Full Prescribing Information.
postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT
interval (QTcF). The maximum mean prolongation of QTcF intervals was < 5 ms, and the upper
limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.
Absorption: Dexmethylphenidate hydrochloride extended-release capsules produce a bi-modal
plasma concentration-time profile (i.e., two distinct peaks approximately 4 hours apart) when
orally administered to healthy adults. The initial rate of absorption for dexmethylphenidate
hydrochloride extended-release capsules is similar to that of dexmethylphenidate hydrochloride
tablets as shown by the similar rate parameters between the two formulations, i.e., first peak
concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (tminip) is slightly shorter,
and time to the second peak (tmax2) is slightly longer for dexmethylphenidate hydrochloride
extended-release capsules given once daily (about 6.5 hours, range 4.5 to 7 hours) compared
to dexmethylphenidate hydrochloride tablets given in two doses 4 hours apart (see Figure 1),
although the ranges observed are greater for dexmethylphenidate hydrochloride extendedrelease capsules.
Dexmethylphenidate hydrochloride extended-release capsules given once daily exhibit a lower
second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and
fewer peak and trough fluctuations than dexmethylphenidate hydrochloride tablets given in
two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption
from the delayed-release beads (see Figure 1).
The AUC (exposure) after administration of dexmethylphenidate hydrochloride extendedrelease capsules given once daily is equivalent to the same total dose of dexmethylphenidate
hydrochloride tablets given in two doses 4 hours apart. The variability in Cmax, Cmin, and AUC
is similar between dexmethylphenidate hydrochloride extended-release capsules and dexmethylphenidate hydrochloride IR with approximately a 3-fold range in each.
Radiolabeled racemic methylphenidate is well absorbed after oral administration with approximately 90% of the radioactivity recovered in urine. However, due to first pass metabolism the
mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.
Figure 1: Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration
of 1 x 20 mg Dexmethylphenidate Hydrochloride Extended-Release Capsules (n = 24) and
2 x 10 mg Dexmethylphenidate Hydrochloride Immediate-Release Tablets (n = 25)
10 OVERDOSAGE
Signs and symptoms of acute methylphenidate overdosage, resulting principally from
overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be
followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing,
headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Rhabdomyolysis has also been reported in overdose.
10.2 Poison Control Center
The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate.
As with the management of all overdosage, the possibility of multiple drug ingestion should
be considered.
When treating overdose, practitioners should bear in mind that there is a prolonged release of
dexmethylphenidate from dexmethylphenidate hydrochloride extended-release capsules.
Treatment consists of appropriate supportive measures. The patient must be protected
against self-injury and against external stimuli that would aggravate overstimulation already
present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other
measures to detoxify the gut include administration of activated charcoal and a cathartic.
Intensive care must be provided to maintain adequate circulation and respiratory exchange;
external cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis for dexmethylphenidate overdosage has not been established.
11 DESCRIPTION
Dexmethylphenidate hydrochloride extended-release capsules are an extended-release formulation of dexmethylphenidate with a bi-modal release profile. Each bead-filled dexmethylphenidate hydrochloride extended-release capsule contains half the dose as immediaterelease beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of dexmethylphenidate and a second delayed release of dexmethylphenidate.
Dexmethylphenidate hydrochloride extended-release capsules are available as 5 mg, 10 mg,
15 mg, 20 mg, 30 mg and 40 mg extended-release capsules. Dexmethylphenidate hydrochloride extended-release capsules 5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg provide in a
single dose the same amount of dexmethylphenidate as a dose of 2.5 mg, 5 mg, 7.5 mg,
10 mg, 15 mg or 20 mg of dexmethylphenidate given b.i.d. as tablets.
Dexmethylphenidate hydrochloride, the d-threo enantiomer of racemic methylphenidate hydrochloride, is a central nervous system (CNS) stimulant.
Dexmethylphenidate hydrochloride is Methyl (2R )-phenyl[(2R )-piperidin-2-yl]acetate hydrochloride. Its molecular formula is C14H19NO2·HCl. Its molecular weight is 269.77 and its
structural formula is:
CH3
O
O
HCl
H
N
Dose Proportionality: Dose proportionality of dexmethylphenidate hydrochloride extendedrelease capsules was evaluated in a randomized, single-dose, five-period, cross-over study
with administration of single doses of 5 mg, 10 mg, 20 mg, 30 mg and 40 mg to healthy
adults. Results confirmed dose proportionality within this dose range.
Food Effects: Administration times relative to meals and meal composition may need to be
individually titrated.
No food effect study was performed with dexmethylphenidate hydrochloride extended-release
capsules. However, the effect of food has been studied in adults with racemic
methylphenidate in the same type of extended-release formulation. The findings of that study
are considered applicable to dexmethylphenidate hydrochloride extended-release capsules.
After a high fat breakfast, there was a longer lag time until absorption began and variable
delays in the time until the first peak concentration, the time until the interpeak minimum,
and the time until the second peak. The first peak concentration and the extent of absorption
were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined. There is no evidence of
dose dumping in the presence or absence of food. There were no differences in the plasma
concentration-time profile, when administered with applesauce, compared to administration
in the fasting condition. The results are expected not to differ for dexmethylphenidate hydrochloride extended-release capsules.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and
administered [see Dosage and Administration (2)].
Distribution: The plasma protein binding of dexmethylphenidate is not known; racemic
methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration.
Dexmethylphenidate shows a volume of distribution of 2.65 ± 1.11 L/kg. Plasma dexmethylphenidate concentrations decline monophasically following oral administration of dexmethylphenidate hydrochloride extended-release capsules.
Metabolism and Excretion: In humans, dexmethylphenidate is metabolized primarily to d-αphenyl-piperidine acetic acid (also known as d-ritalinic acid) by de-esterification. This
metabolite has little or no pharmacological activity. There is no in vivo interconversion to the
l-threo-enantiomer, based on a finding of no levels of l-threo-methylphenidate being
detectable after administration of up to 40 mg dexmethylphenidate in adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was
Dexmethylphenidate hydrochloride is a white crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in
chloroform and in acetone.
Inactive Ingredients: ammonio methacrylate copolymer type B, gelatin, hypromellose,
methacrylic acid copolymer type A, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide
and triethyl citrate. The 5 mg capsules also contain FD&C Blue No. 2. The 10 mg, 15 mg, 30 mg
and 40 mg capsules also contain black iron oxide. The 10 mg and 30 mg capsules also contain
red iron oxide. The 10 mg, 15 mg, 30 mg and 40 mg capsules also contain yellow iron oxide.
The imprinting ink for the 5 mg capsules contains the following: ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide.
The imprinting ink for the 10 mg, 15 mg, 20 mg and 40 mg capsules contains the following:
ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.
The imprinting ink for the 30 mg capsules contains the following: ammonium hydroxide, black
iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue
No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
Dexmethylphenidate hydrochloride, the active ingredient in dexmethylphenidate hydrochloride
extended-release capsules, is a central nervous system stimulant. Dexmethylphenidate, the
more pharmacologically active d-enantiomer of racemic methylphenidate, is thought to block
the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the
release of these monoamines into the extraneuronal space. The mode of therapeutic action in
Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Effects on QT Interval: The effect of dexmethylphenidate hydrochloride extended-release capsules on the QT interval was evaluated in a double-blind, placebo- and open-label active
(moxifloxacin)-controlled study following single doses of dexmethylphenidate hydrochloride
extended-release capsules 40 mg in 75 healthy volunteers. ECGs were collected up to 12 hours
5
recovered in urine. The main urinary metabolite of racemic (d,l-) methylphenidate was
d,l-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent
compound accounted for 0.5% of an intravenous dose.
In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes
at concentrations observed after therapeutic doses.
Intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/kg.h-1
corresponding to 0.56 ± 0.18 L/min. The mean terminal elimination half-life of dexmethylphenidate was just over 3 hours in healthy adults and typically varied between 2 and 4.5 hours
with an occasional subject exhibiting a terminal half-life between 5 and 7 hours. Children tend
to have slightly shorter half-lives with means of 2 to 3 hours.
Special Populations: Gender: After administration of dexmethylphenidate hydrochloride
extended-release capsules the first peak, (Cmax1), was on average 45% higher in women. The
interpeak minimum and the second peak also tended to be slightly higher in women although
the difference was not statistically significant, and these patterns remained even after weight
normalization. Pharmacokinetic parameters for dexmethylphenidate after dexmethylphenidate
hydrochloride immediate-release tablets were similar for boys and girls.
Race: There is insufficient experience with the use of dexmethylphenidate hydrochloride
extended-release capsules to detect ethnic variations in pharmacokinetics.
Age: The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride
extended-release capsules administration have not been studied in children less than
18 years of age. When a similar formulation of racemic methylphenidate was examined in 15
children between 10 and 12 years of age and three children with ADHD between 7 and 9 years
of age, the time to the first peak was similar, although the time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After administration of the same dose to children and adults, concentrations
in children were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in
dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution)
are observed after normalization to dose and weight.
Renal Insufficiency: There is no experience with the use of dexmethylphenidate hydrochloride
extended-release capsules in patients with renal insufficiency. After oral administration of
radiolabeled racemic methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of
racemic ritalinic acid which is pharmacologically inactive. Very little unchanged drug is
excreted in the urine, thus renal insufficiency is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride extended-release capsules.
Hepatic Insufficiency: There is no experience with the use of dexmethylphenidate hydrochloride
extended-release capsules in patients with hepatic insufficiency [see Drug Interactions (7)].
treated patients using an intent-to-treat analysis of the primary efficacy outcome measure,
the DSM-IV total subscale score of the Conners ADHD/DSM-IV Scales for teachers (CADS-T).
There was a statistically significant treatment effect in favor of dexmethylphenidate hydrochloride extended-release capsules. There were insufficient adolescents enrolled in this study
to assess the efficacy for dexmethylphenidate hydrochloride extended-release capsules in the
adolescent population. However, pharmacokinetic considerations and evidence of effectiveness of immediate-release dexmethylphenidate in adolescents support the effectiveness of
dexmethylphenidate hydrochloride extended-release capsules in this population.
In two additional studies in pediatric patients aged 6 to 12 years who received 20 mg dexmethylphenidate hydrochloride extended-release capsules or placebo in a cross-over design, dexmethylphenidate hydrochloride extended-release capsules were found to have a statistically significant
treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn & Pelham (SKAMP) rating
scale combined score at all time points after dosing in each study (0.5, 1, 3, 4, 5, 7, 9, 10, 11 and
12 hours in one study and 1, 2, 4, 6, 8, 9, 10, 11 and 12 hours in the other study). A treatment
effect was also observed 0.5 hours after administration of dexmethylphenidate hydrochloride
extended-release capsules 20 mg in an additional study of ADHD patients aged 6 to 12 years. The
SKAMP is a reliable and validated scale that assesses specific classroom behaviors related to
attention (e.g., getting started, sticking with activities, completing work, and stopping for transition) and deportment or behavior (e.g., remaining quiet, remaining seated, interacting with other
students, and interacting with the teacher.) Each item is rated on a 7-point impairment scale, and
an average rating per item is calculated for the subscales of Attention and Deportment.
14.2 Adults
The effectiveness of dexmethylphenidate hydrochloride extended-release capsules was established in a randomized, double-blind, placebo-controlled, parallel-group study in 221 adult
patients (ages 18 to 60) who met DSM-IV criteria for ADHD. Patients were randomized to
receive either a fixed dose of dexmethylphenidate hydrochloride extended-release capsules
(20, 30, or 40 mg/day) or placebo once daily for 5 weeks. Patients randomized to dexmethylphenidate hydrochloride extended-release capsules were initiated on a 10 mg/day
starting dose and titrated in increments of 10 mg/week to the randomly assigned fixed dose.
Patients were maintained on their fixed dose (20, 30 or 40 mg/day) for a minimum of 2 weeks.
Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline
to endpoint for dexmethylphenidate hydrochloride extended-release capsules- and placebotreated patients using an intent-to-treat analysis of the primary efficacy outcome measure,
the investigator-administered DSM-IV Attention-Deficit/Hyperactivity Disorder Rating Scale
(DSM-IV ADHD RS).
All three dexmethylphenidate hydrochloride extended-release capsules doses were statistically significantly superior to placebo. There was no obvious increase in effectiveness with
increasing dose.
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis: Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate
caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. Hepatoblastoma is a relatively rare rodent
malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain
used is sensitive to the development of hepatic tumors, and the significance of these results to
humans is unknown.
Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity
study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day.
In a 24-week study of racemic methylphenidate in the transgenic mouse strain p53+/-, which
is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Mice were fed
diets containing the same concentrations as in the lifetime carcinogenicity study; the highdose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate.
Mutagenesis: Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation
assay, the in vitro mouse lymphoma cell forward mutation assay, or the in vivo mouse bone
marrow micronucleus test.
Racemic methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or
the in vitro mouse lymphoma cell forward mutation assay, and was negative in vivo in the
mouse bone marrow micronucleus assay. However, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro
assay of racemic methylphenidate in cultured Chinese Hamster Ovary (CHO) cells.
Impairment of Fertility: Racemic methylphenidate did not impair fertility in male or female
mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The
study was conducted at doses of up to 160 mg/kg/day.
15 REFERENCES
American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders. 4th
ed. Washington DC: American Psychiatric Association 1994.
14 CLINICAL STUDIES
The effectiveness of dexmethylphenidate hydrochloride extended-release capsules in the
treatment of ADHD was established in randomized, double-blind, placebo-controlled studies
in children and adolescents and in adults who met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD [see Indications and Usage (1)].
14.1 Children and Adolescents
The effectiveness of dexmethylphenidate hydrochloride extended-release capsules was established in a randomized, double-blind, placebo-controlled, parallel-group study in 103 pediatric patients (ages 6 to 12, n = 86; ages 13 to 17, n = 17) who met DSM-IV criteria for ADHD.
Patients were randomized to receive either a flexible dose of dexmethylphenidate hydrochloride extended-release capsules (5 to 30 mg/day) or placebo once daily for 7 weeks. During the
first 5 weeks of treatment patients were titrated to their optimal dose and in the last 2 weeks
of the study patients remained on their optimal dose without dose changes or interruption.
Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline
to endpoint for dexmethylphenidate hydrochloride extended-release capsules- and placebo-
The 15 mg capsule is a gray opaque cap and gray opaque body, hard-shell gelatin capsule
filled with white to off-white beads. The capsule is axially printed with MYLAN over DE 15 in
black ink on cap and body. They are available as follows:
Dexmethylphenidate Hydrochloride Extended-release Capsules are available containing 5 mg,
10 mg, 15 mg, 20 mg, 30 mg or 40 mg of dexmethylphenidate hydrochloride.
The 5 mg capsule is a dark blue opaque cap and dark blue opaque body, hard-shell gelatin
capsule filled with white to off-white beads. The capsule is axially printed with MYLAN over
DE 5 in white ink on cap and body. They are available as follows:
NDC 0378-4080-93
bottles of 30 capsules
NDC 0378-4080-01
NDC 0378-4080-05
The 10 mg capsule is a light brown opaque cap and light brown opaque body, hard-shell gelatin capsule filled with white to off-white beads. The capsule is axially printed with MYLAN
over DE 10 in black ink on cap and body. They are available as follows:
NDC 0378-4081-93
NDC 0378-4081-01
NDC 0378-4081-05
NDC 0378-4082-93
NDC 0378-4082-01
NDC 0378-4082-05
The 20 mg capsule is a white opaque cap and white opaque body, hard-shell gelatin capsule
NDC 0378-4083-93
6
NDC 0378-4083-01
NDC 0378-4083-05
• increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects,
high bloodpressure, or a family history of these problems.
Your doctor should check you or your child carefully for heart problems before
starting dexmethylphenidate hydrochloride extended-release capsules.
Your doctor should check your or your child’s blood pressure and heart rate
regularly during treatment with dexmethylphenidate hydrochloride
extended-release capsules.
Call your doctor right away if you or your child has any signs of
heart problems such as chest pain, shortness of breath, or fainting
while taking dexmethylphenidate hydrochloride extended-release
capsules.
2. Mental (Psychiatric) problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing
things that are not true, are suspicious) or new manic symptoms
Tell your doctor about any mental problems you or your child have, or
about a family history of suicide, bipolar illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking dexmethylphenidate
hydrochloride extended-release capsules, especially seeing or hearing things that are not real, believing things that are not real, or are
suspicious.
3. Circulation problems in fingers and toes [Peripheral vasculopathy,
including Raynaud’s phenomenon]: fingers or toes may feel numb, cool,
painful, and/or may change color from pale, to blue, to red.
• Tell your doctor if you have or your child has numbness, pain, skin
color change, or sensitivity to temperature in your fingers or toes.
• Call your doctor right away if you have or your child has any signs
of unexplained wounds appearing on fingers or toes while taking
dexmethylphenidate hydrochloride extended-release capsules.
The 30 mg capsule is a light brown opaque cap and white opaque body, hard-shell gelatin
capsule filled with white to off-white beads. The capsule is axially printed with MYLAN over
DE 30 in black ink on cap and body. They are available as follows:
NDC 0378-4084-93
NDC 0378-4084-01
NDC 0378-4084-05
The 40 mg capsule is a gray opaque cap and white opaque body, hard-shell gelatin capsule
NDC 0378-4085-93
NDC 0378-4085-01
NDC 0378-4085-05
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Information for Patients: Prescribers or other health professionals should inform patients,
their families, and their caregivers about the benefits and risks associated with treatment
with dexmethylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for dexmethylphenidate hydrochloride extended-release capsules. The
prescriber or health professional should instruct patients, their families, and their caregivers
to read the Medication Guide and should assist them in understanding its contents. Patients
should be given the opportunity to discuss the contents of the Medication Guide and to obtain
answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Priapism: Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention
in the event of priapism [see Warnings and Precautions (5.10)].
Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s
Phenomenon]:
• Instruct patients beginning treatment with dexmethylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynaud’s
phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool,
painful, and/or may change color from pale, to blue, to red.
• Instruct patients to report to their physician any new numbness, pain, skin color
change, or sensitivity to temperature in fingers or toes.
• Instruct patients to call their physician immediately with any signs of unexplained
wounds appearing on fingers or toes while taking dexmethylphenidate hydrochloride extended-release capsules.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain
patients.
What are dexmethylphenidate hydrochloride extended-release capsules?
Dexmethylphenidate hydrochloride extended-release capsules are a central
nervous system stimulant prescription medicine. It is used for the treatment
of attention deficit and hyperactivity disorder (ADHD). Dexmethylphenidate
hydrochloride extended-release capsules may help increase attention and
decrease impulsiveness and hyperactivity in patients with ADHD.
Dexmethylphenidate hydrochloride extended-release capsules should be
used as a part of a total treatment program for ADHD that may include
counseling or other therapies.
Dexmethylphenidate hydrochloride is a federally controlled substance
(CII) because it can be abused or lead to dependence. Keep dexmethylphenidate hydrochloride extended-release capsules in a safe place
to prevent misuse and abuse. Selling or giving away dexmethylphenidate hydrochloride extended-release capsules may harm others,
and is against the law.
Tell your doctor if you or your child have (or have a family history of)
ever abused or been dependent on alcohol, prescription medicines or
street drugs.
MEDICATION GUIDE
DEXMETHYLPHENIDATE HYDROCHLORIDE
EXTENDED-RELEASE CAPSULES
(dex meth" il fen' i date hye" droe klor' ide)
5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg
Read the Medication Guide that comes with dexmethylphenidate hydrochloride
extended-release capsules before you or your child starts taking it and each
time you get a refill. There may be new information. This Medication Guide
does not take the place of talking to your doctor about your or your child’s
treatment with dexmethylphenidate hydrochloride extended-release capsules.
Who should not take dexmethylphenidate hydrochloride extendedrelease capsules?
Dexmethylphenidate hydrochloride extended-release capsules should
not be taken if you or your child:
• are very anxious, tense, or agitated
• have an eye problem called glaucoma
• have tics or Tourette’s syndrome, or a family history of Tourette’s
syndrome. Tics are hard to control repeated movements or sounds.
• are taking or have taken within the past 14 days an anti-depression
medicine called a monoamine oxidase inhibitor or MAOI.
What is the most important information I should know about dexmethylphenidate hydrochloride extended-release capsules?
The following have been reported with use of dexmethylphenidate hydrochloride and other stimulant medicines.
1. Heart-related problems:
• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
7
extended-release capsules treatment may be stopped if a problem is
found during these check-ups.
• If you or your child takes too much dexmethylphenidate hydrochloride extended-release capsules or overdoses, call your doctor or
poison control center right away, or get emergency treatment.
What are possible side effects of dexmethylphenidate hydrochloride
extended-release capsules?
See “What is the most important information I should know about
dexmethylphenidate hydrochloride extended-release capsules?” for
information on reported heart and mental problems.
Other serious side effects include:
• serious allergic reactions (symptoms can be difficulty breathing,
swelling of the face, neck and throat, rashes and hives, fever)
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• painful and prolonged erections (priapism) have occurred with
methylphenidate. If you or your child develop priapism seek medical
help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately.
• eyesight changes or blurred vision
Common side effects include:
• headache
• upset stomach
• trouble sleeping
• anxiety
• decreased appetite
• dry mouth
• dizziness
• nervousness
Talk to your doctor if you or your child has side effects that are bothersome
or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report
side effects to FDA at 1-800-FDA-1088.
How should I store dexmethylphenidate hydrochloride extended-release
capsules?
• Store dexmethylphenidate hydrochloride extended-release capsules in
a safe place at 20° to 25°C (68° to 77°F).
• Keep dexmethylphenidate hydrochloride extended-release capsules and all medicines out of the reach of children.
General information about dexmethylphenidate hydrochloride extendedrelease capsules
Medicines are sometimes prescribed for purposes other than those listed in
a Medication Guide. Do not use dexmethylphenidate hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not
give dexmethylphenidate hydrochloride extended-release capsules to other
people, even if they have the same condition. It may harm them and it is
against the law.
This Medication Guide summarizes the most important information about
dexmethylphenidate hydrochloride extended-release capsules. If you would
like more information, talk with your doctor. You can ask your doctor or
pharmacist for information about dexmethylphenidate hydrochloride
extended-release capsules that was written for healthcare professionals.
For more information about dexmethylphenidate hydrochloride extendedrelease capsules call Mylan Pharmaceuticals Inc. at 1-877-446-3679
(1-877-4-INFO-RX).
What are the ingredients in dexmethylphenidate hydrochloride extended-release capsules?
Active ingredient: dexmethylphenidate hydrochloride
Inactive ingredients: ammonio methacrylate copolymer type B, gelatin, hypromellose, methacrylic acid copolymer type A, sodium lauryl sulfate, sugar
spheres, talc, titanium dioxide and triethyl citrate. The 5 mg capsules also
contain FD&C Blue No. 2. The 10 mg, 15 mg, 30 mg and 40 mg capsules
also contain black iron oxide. The 10 mg and 30 mg capsules also contain
red iron oxide. The 10 mg, 15 mg, 30 mg and 40 mg capsules also contain
yellow iron oxide.
•
are allergic to anything in dexmethylphenidate hydrochloride extended-release capsules. See the end of this Medication Guide for a complete list of ingredients.
Dexmethylphenidate hydrochloride extended-release capsules should not
be used in children less than 6 years old because it has not been studied
in this age group.
Dexmethylphenidate hydrochloride extended-release capsules may not
be right for you or your child. Before starting dexmethylphenidate
hydrochloride extended-release capsules tell your or your child’s doctor about all health conditions (or a family history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or
depression
• tics or Tourette’s syndrome
• seizures or have had an abnormal brain wave test (EEG)
• circulation problems in fingers or toes
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Can dexmethylphenidate hydrochloride extended-release capsules be
taken with other medicines?
Tell your doctor about all of the medicines that you or your child takes
including prescription and nonprescription medicines, vitamins, and
herbal supplements. Dexmethylphenidate hydrochloride extended-release
capsules and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be
adjusted while taking dexmethylphenidate hydrochloride extended-release
capsules.
Your doctor will decide whether dexmethylphenidate hydrochloride extended-release capsules can be taken with other medicines.
Especially tell your doctor if you or your child takes:
• anti-depression medicines including MAOIs
• seizure medicines
• blood thinner medicines
• blood pressure medicines
• antacids
• cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.
Do not start any new medicine while taking dexmethylphenidate hydrochloride extended-release capsules without talking to your doctor first.
How should dexmethylphenidate hydrochloride extended-release capsules be taken?
• Take dexmethylphenidate hydrochloride extended-release capsules exactly as prescribed. Your doctor may adjust the dose until it
is right for you or your child.
• Take dexmethylphenidate hydrochloride extended-release capsules
once each day in the morning. Dexmethylphenidate hydrochloride
extended-release capsules are extended-release capsules. It releases
medicine into your body throughout the day.
• Dexmethylphenidate hydrochloride extended-release capsules can be
taken with or without food. Taking dexmethylphenidate hydrochloride
extended-release capsules with food may slow the time it takes for the
medicine to start working.
• Swallow dexmethylphenidate hydrochloride extended-release capsules
whole with water or other liquids. Do not chew, crush, or divide the
capsules or the beads in the capsule. If you or your child cannot
swallow the capsule, open it and sprinkle the small beads of medicine
over a spoonful of applesauce and swallow it right away without
chewing.
• From time to time, your doctor may stop dexmethylphenidate hydrochloride extended-release capsules treatment for a while to check
ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood
pressure while taking dexmethylphenidate hydrochloride extendedrelease capsules. Children should have their height and weight
checked often while taking dexmethylphenidate hydrochloride
extended-release capsules. Dexmethylphenidate hydrochloride
8
The imprinting ink for the 5 mg capsules contains the following: ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium
dioxide.
The imprinting ink for the 10 mg, 15 mg, 20 mg and 40 mg capsules contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.
The imprinting ink for the 30 mg capsules contains the following: ammonium hydroxide, black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C
Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No.
40 Aluminum Lake, propylene glycol and shellac glaze.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
DEXM:R18mmh
9
alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxyamphetamine are both active and each is subsequently oxidized to form 4-hydroxynorephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone,
which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric
acid. Although the enzymes involved in amphetamine metabolism have not been clearly
defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since
CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a
possibility.
Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine
and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of
CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more
metabolites. However, due to the probability of auto-inhibition and the lack of information on
the concentration of these metabolites relative to in vivo concentrations, no predications
regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other
drugs by CYP isozymes in vivo can be made.
With normal urine pHs approximately half of an administered dose of amphetamine is
recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30% to 40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine
has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow
rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic
pHs and high flow rates result in increased renal elimination with clearances greater than
glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of
amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the
remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal
dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that affect urinary pH are known to alter the elimination
of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to
drug interactions or genetic polymorphisms is more likely to be clinically significant when
renal elimination is decreased (see PRECAUTIONS).
DEXTROAMPHETAMINE SACCHARATE,
AMPHETAMINE ASPARTATE,
DEXTROAMPHETAMINE SULFATE
AND AMPHETAMINE SULFATE TABLETS
5 mg, 7.5 mg, 10 mg, 12.5 mg,
15 mg, 20 mg and 30 mg
AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF AMPHETAMINES
FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING
AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS
SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY.
MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR
ADVERSE EVENTS.
DESCRIPTION: A single-entity amphetamine product combining the neutral sulfate salts of
dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate
and d, l-amphetamine aspartate.
EACH TABLET CONTAINS
Dextroamphetamine
Saccharate
Amphetamine Aspartate
Monohydrate Equivalent
Dextroamphetamine
Sulfate, USP
Amphetamine Sulfate, USP
Total Amphetamine Base
Equivalence
5 mg
1.25 mg
7.5 mg
1.875 mg
10 mg 12.5 mg
2.5 mg 3.125 mg
15 mg
3.75 mg
20 mg
5 mg
30 mg
7.5 mg
1.25 mga 1.875 mgb 2.5 mgc 3.125 mgd 3.75 mge 5 mgf
7.5 mgg
1.25 mg
1.875 mg
2.5 mg 3.125 mg
3.75 mg
5 mg
7.5 mg
1.25 mg
3.13 mg
1.875 mg
4.7 mg
2.5 mg 3.125 mg
6.3 mg 7.8 mg
3.75 mg
9.4 mg
5 mg
7.5 mg
12.6 mg 18.8 mg
INDICATIONS AND USAGE: Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are indicated for the treatment of
Attention Deficit Hyperactivity Disorder (ADHD) and Narcolepsy.
Attention Deficit Hyperactivity Disorder (ADHD): A diagnosis of Attention Deficit Hyperactivity
Disorder (ADHD; DSM-IV®*) implies the presence of hyperactive-impulsive or inattentive
symptoms that caused impairment and were present before age 7 years. The symptoms must
cause clinically significant impairment, e.g., in social, academic, or occupational functioning,
and be present in two or more settings, e.g., school (or work) and at home. The symptoms must
not be better accounted for by another mental disorder. For the Inattentive Type, at least six of
the following symptoms must have persisted for at least 6 months: lack of attention to
details/careless mistakes; lack of sustained attention; poor listener; failure to follow through
on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Type requires both inattentive and
hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations: Specific etiology of this syndrome is unknown, and there
is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of
special psychological, educational, and social resources. Learning may or may not be
impaired. The diagnosis must be based upon a complete history and evaluation of the child
and not solely on the presence of the required number of DSM-IV®* characteristics.
Need for Comprehensive Treatment Program: Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are indicated
as an integral part of a total treatment program for ADHD that may include other measures
(psychological, educational, social) for patients with this syndrome. Drug treatment may not
be indicated for all children with this syndrome. Stimulants are not intended for use in the
child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the
decision to prescribe stimulant medication will depend upon the physician’s assessment of
the chronicity and severity of the child’s symptoms.
Long-Term Use: The effectiveness of dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets for long-term use has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets for extended periods should periodically re-evaluate the longterm usefulness of the drug for the individual patient.
a 1.25 mg of Amphetamine Aspartate Monohydrate equivalent to 1.17 mg Amphetamine
Aspartate (Anhydrous) as supplied
b 1.875 mg of Amphetamine Aspartate Monohydrate equivalent to 1.755 mg Amphetamine
c 2.5 mg of Amphetamine Aspartate Monohydrate equivalent to 2.34 mg Amphetamine Aspartate (Anhydrous) as supplied
d 3.125 mg of Amphetamine Aspartate Monohydrate equivalent to 2.925 mg Amphetamine
e 3.75 mg of Amphetamine Aspartate Monohydrate equivalent to 3.51 mg Amphetamine
f 5 mg of Amphetamine Aspartate Monohydrate equivalent to 4.6 mg Amphetamine Aspartate (Anhydrous) as supplied
g 7.5 mg of Amphetamine Aspartate Monohydrate equivalent to 7.03 mg Amphetamine Aspartate (Anhydrous) as supplied
Inactive Ingredients: Colloidal silicon dioxide, compressible sugar, magnesium stearate,
microcrystalline cellulose and pregelatinized starch (corn).
Colors: Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate
and amphetamine sulfate tablets 5 mg, 7.5 mg and 10 mg contain FD&C Blue No. 1 Aluminum
Lake as a color additive.
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets 12.5 mg, 15 mg, 20 mg, and 30 mg contain FD&C Blue No. 1
Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake as color additives.
CLINICAL PHARMACOLOGY: Pharmacodynamics: Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block
the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the
release of these monoamines into the extraneuronal space.
Pharmacokinetics: Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets contain d-amphetamine and l-amphetamine
salts in the ratio of 3:1. Following administration of a single dose 10 mg or 30 mg of dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets to healthy volunteers under fasted conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d-amphetamine and l-amphetamine. The mean elimination half-life (t1/2) for d-amphetamine was shorter than the t1/2 of
the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (Cmax, AUC0-inf) of
d- and l-amphetamine increased approximately 3-fold from 10 mg to 30 mg indicating doseproportional pharmacokinetics.
The effect of food on the bioavailability of dextroamphetamine saccharate, amphetamine
aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets has not been studied.
Metabolism and Excretion: Amphetamine is reported to be oxidized at the 4 position of the
benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form
CONTRAINDICATIONS: Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the
sympathomimetic amines, glaucoma.
Agitated states.
Patients with a history of drug abuse.
During or within 14 days following the administration of monoamine oxidase inhibitors
(hypertensive crises may result).
WARNINGS: Serious Cardiovascular Events: Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems: Children and Adolescents: Sudden
1
death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.
Although some structural heart problems alone may carry an increased risk of sudden death,
stimulant products generally should not be used in children or adolescents with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other
serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug (see CONTRAINDICATIONS).
Adults: Sudden deaths, stroke, and myocardial infarction have been reported in adults taking
stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases
is also unknown, adults have a greater likelihood than children of having serious structural
cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery
disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS).
Hypertension and Other Cardiovascular Conditions: Stimulant medications cause a modest
increase in average blood pressure (about 2 mmHg to 4 mmHg) and average heart rate (about
3 bpm to 6 bpm) (see ADVERSE REACTIONS), and individuals may have larger increases. While
the mean changes alone would not be expected to have short-term consequences, all patients
should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by
increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS).
Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications:
Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden
death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g.,
electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional
chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during
stimulant treatment should undergo a prompt cardiac evaluation.
Psychiatric Adverse Events: Preexisting Psychosis: Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting
psychotic disorder.
Bipolar Illness: Particular care should be taken in using stimulants to treat ADHD patients
with comorbid bipolar disorder because of concern for possible induction of mixed/manic
episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for
bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms: Treatment emergent psychotic or manic
symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents
without prior history of psychotic illness or mania can be caused by stimulants at usual doses.
If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple
short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (four patients
with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at
usual doses) of stimulant-treated patients compared to zero in placebo-treated patients.
Aggression: Aggressive behavior or hostility is often observed in children and adolescents
with ADHD, and has been reported in clinical trials and the postmarketing experience of some
medications indicated for the treatment of ADHD. Although there is no systematic evidence
that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD
should be monitored for the appearance of or worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth: Careful follow-up of weight and height in children ages 7
to 10 years who were randomized to either methylphenidate or non-medication treatment
groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the
year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth
in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound
during this period of development. Published data are inadequate to determine whether
chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they will likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted.
Seizures: There is some clinical evidence that stimulants may lower the convulsive threshold
in patients with prior history of seizure, in patients with prior EEG abnormalities in absence of
seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence
of seizures. In the presence of seizures, the drug should be discontinued.
Peripheral Vasculopathy, including Raynaud’s Phenomenon: Stimulants, including dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine
sulfate tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare
sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different
times and at therapeutic doses in all age groups throughout the course of treatment. Signs and
symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical
evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
Visual Disturbance: Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
PRECAUTIONS: General: The least amount of amphetamine feasible should be prescribed or
dispensed at one time in order to minimize the possibility of overdosage. Dextroamphetamine
saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate
tablets should be used with caution in patients who use other sympathomimetic drugs.
Tics: Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s
syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their
families should precede use of stimulant medications.
Information for Patients: Amphetamines may impair the ability of the patient to engage in
potentially hazardous activities such as operating machinery or vehicles; the patient should
therefore be cautioned accordingly.
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with amphetamine or dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide
is available for dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine
sulfate and amphetamine sulfate tablets.
The prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication
Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]
• Instruct patients beginning treatment with dextroamphetamine saccharate, amphetamine
aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets about the risk of
peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and
symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from
pale, to blue, to red.
• Instruct patients to report to their physician any new numbness, pain, skin color change,
or sensitivity to temperature in fingers or toes.
• Instruct patients to call their physician immediately with any signs of unexplained
wounds appearing on fingers or toes while taking dextroamphetamine saccharate,
amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain
patients.
Drug Interactions: Acidifying Agents: Gastrointestinal acidifying agents (guanethidine,
reserpine, glutamic acid hydrochloride, ascorbic acid, fruit juices, etc.) lower absorption of
amphetamines.
Urinary Acidifying Agents: (Ammonium chloride, sodium acid phosphate, etc.) Increase the
concentration of the ionized species of the amphetamine molecule, thereby increasing urinary
excretion. Both groups of agents lower blood levels and efficacy of amphetamines.
Adrenergic Blockers: Adrenergic blockers are inhibited by amphetamines.
Alkalinizing Agents: Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase
absorption of amphetamines. Coadministration of dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets and gastrointestinal alkalizing agents, such as antacids, should be avoided. Urinary alkalinizing agents
(acetazolamide, some thiazides) increase the concentration of the non-ionized species of the
amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase
blood levels and therefore potentiate the actions of amphetamines.
Antidepressants, Tricyclic: Amphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the
brain; cardiovascular effects can be potentiated.
MAO Inhibitors: MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the
release of norepinephrine and other monoamines from adrenergic nerve endings; this can
cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects
and malignant hyperpyrexia can occur, sometimes with fatal results.
Antihistamines: Amphetamines may counteract the sedative effect of antihistamines.
Antihypertensives: Amphetamines may antagonize the hypotensive effects of antihypertensives.
Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine receptors, thus
inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.
Ethosuximide: Amphetamines may delay intestinal absorption of ethosuximide.
Haloperidol: Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant
effects of amphetamines.
Lithium Carbonate: The anorectic and stimulatory effects of amphetamines may be inhibited
by lithium carbonate.
Meperidine: Amphetamines potentiate the analgesic effect of meperidine.
Methenamine Therapy: Urinary excretion of amphetamines is increased, and efficacy is
reduced, by acidifying agents used in methenamine therapy.
Norepinephrine: Amphetamines enhance the adrenergic effect of norepinephrine.
Phenobarbital: Amphetamines may delay intestinal absorption of phenobarbital; coadministration of phenobarbital may produce a synergistic anticonvulsant action.
Phenytoin: Amphetamines may delay intestinal absorption of phenytoin; coadministration of
phenytoin may produce a synergistic anticonvulsant action.
Propoxyphene: In cases of propoxyphene overdosage, amphetamine CNS stimulation is
2
Endocrine: Impotence, changes in libido, frequent or prolonged erections.
Skin: Alopecia.
Musculoskeletal: Rhabdomyolysis.
potentiated and fatal convulsions can occur.
Proton Pump Inhibitors: PPIs act on proton pumps by blocking acid production, thereby
reducing gastric acidity. When dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules (20 mg singledose) was administered concomitantly with the proton pump inhibitor, omeprazole (40 mg
once daily for 14 days), the median Tmax of d-amphetamine was decreased by 1.25 hours
(from 4 to 2.75 hours), and the median Tmax of l-amphetamine was decreased by 2.5 hours
(from 5.5 to 3 hours), compared to dextroamphetamine saccharate, amphetamine aspartate,
dextroamphetamine sulfate and amphetamine sulfate extended-release capsules administered alone. The AUC and Cmax of each moiety were unaffected. Therefore, coadministration of
dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets and proton pump inhibitors should be monitored for changes in
clinical effect.
Veratrum Alkaloids: Amphetamines inhibit the hypotensive effect of veratrum alkaloids.
Drug/Laboratory Test Interactions: Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No evidence of carcinogenicity was
found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice
and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in
female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5,
and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on
a mg/m2 body surface area basis.
Amphetamine, in the enantiomer ratio present in dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (immediaterelease) (d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus
test in vivo and was negative when tested in the E. coli component of the Ames test in vitro.
D, l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in
the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.
Amphetamine, in the enantiomer ratio present in dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (immediaterelease) (d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development
in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m2 body surface area basis).
Pregnancy: Teratogenic Effects. Pregnancy Category C: Amphetamine, in the enantiomer ratio
present in dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and
rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis. Fetal malformations
and death have been reported in mice following parenteral administration of d-amphetamine
doses of 50 mg/kg/day (approximately 6 times that of a human dose of 30 mg/day [child] on a
mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.
A number of studies in rodents indicate that prenatal or early postnatal exposure to
amphetamine (d- or d,l-), at doses similar to those used clinically, can result in long-term
neurochemical and behavioral alterations. Reported behavioral effects include learning and
memory deficits, altered locomotor activity, and changes in sexual function.
There are no adequate and well-controlled studies in pregnant women. There has been one
report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater
association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin
during the first trimester of pregnancy. Amphetamines should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Infants born to mothers dependent on amphetamines have an
increased risk of premature delivery and low birth weight. Also, these infants may experience
symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant
lassitude.
Usage in Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking
amphetamines should be advised to refrain from nursing.
Pediatric Use: Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age with
Attention Deficit Hyperactivity Disorder described under INDICATIONS AND USAGE.
Geriatric Use: Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine
sulfate and amphetamine sulfate tablets have not been studied in the geriatric population.
DRUG ABUSE AND DEPENDENCE: Dextroamphetamine saccharate, amphetamine aspartate,
dextroamphetamine sulfate and amphetamine sulfate tablets are a Schedule II controlled
substance.
Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have
increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with
amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and
personality changes. The most severe manifestation of chronic intoxication is psychosis, often
clinically indistinguishable from schizophrenia.
OVERDOSAGE: Individual patient response to amphetamines varies widely. Toxic symptoms
may occur idiosyncratically at low doses.
Symptoms: Manifestations of acute overdosage with amphetamines include restlessness,
tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic
states, hyperpyrexia and rhabdomyolysis.
Fatigue and depression usually follow the central stimulation.
Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory
collapse.
Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps.
Fatal poisoning is usually preceded by convulsions and coma.
Treatment: Consult with a Certified Poison Control Center for up to date guidance and advice.
Management of acute amphetamine intoxication is largely symptomatic and includes gastric
lavage, administration of activated charcoal, administration of a cathartic and sedation.
Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation
in this regard. Acidification of the urine increases amphetamine excretion, but is believed to
increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension
complicates amphetamine overdosage, administration of intravenous phentolamine has been
suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication.
DOSAGE AND ADMINISTRATION: Regardless of indication, amphetamines should be administered at the lowest effective dosage, and dosage should be individually adjusted according to
the therapeutic needs and response of the patient. Late evening doses should be avoided
because of the resulting insomnia.
Attention Deficit Hyperactivity Disorder: Not recommended for children under 3 years of age.
In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in
increments of 2.5 mg at weekly intervals until optimal response is obtained.
In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may
be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only
in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
Where possible, drug administration should be interrupted occasionally to determine if
there is a recurrence of behavioral symptoms sufficient to require continued therapy.
Narcolepsy: Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual
patient response.
Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6 to 12 is
5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal
response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily
dosage may be raised in increments of 10 mg at weekly intervals until optimal response is
obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should
be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
HOW SUPPLIED: Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets contain dextroamphetamine saccharate,
amphetamine aspartate, dextroamphetamine sulfate, USP and amphetamine sulfate, USP.
The 5 mg tablets contain 1.25 mg of dextroamphetamine saccharate, 1.25 mg of amphetamine aspartate monohydrate (equivalent to 1.17 mg of amphetamine aspartate anhydrous),
1.25 mg of dextroamphetamine sulfate, USP and 1.25 mg of amphetamine sulfate, USP. The
5 mg tablets are light blue, round, tablets debossed with M over A5 on one side of the tablet
and a quadrisect on the other side. They are available as follows:
ADVERSE REACTIONS: Cardiovascular: Palpitations, tachycardia, elevation of blood pressure,
sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy
associated with chronic amphetamine use.
Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression,
anger, logorrhea, dermatillomania.
Eye Disorders: Vision blurred, mydriasis.
Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.
Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis.
Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have
been reported.
NDC 0378-4541-01
The 7.5 mg tablets contain 1.875 mg of dextroamphetamine saccharate, 1.875 mg of
amphetamine aspartate monohydrate (equivalent to 1.755 mg of amphetamine aspartate
anhydrous), 1.875 mg of dextroamphetamine sulfate, USP and 1.875 mg of amphetamine sulfate, USP. The 7.5 mg tablets are blue, round, tablets debossed with M over A7 on one side of
the tablet and a quadrisect on the other side.
NDC 0378-4542-01
The 10 mg tablets contain 2.5 mg of dextroamphetamine saccharate, 2.5 mg of amphetamine
3
aspartate monohydrate (equivalent to 2.34 mg of amphetamine aspartate anhydrous), 2.5 mg of
dextroamphetamine sulfate, USP and 2.5 mg of amphetamine sulfate, USP. The 10 mg tablets
are dark blue, round, tablets debossed with M over A10 on one side of the tablet and a quadrisect on the other side.
1. Heart-Related Problems:
• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart
defects, high blood pressure, or a family history of these problems.
Your doctor should check you or your child carefully for heart problems
before starting dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.
Your doctor should check your or your child’s blood pressure and heart
rate regularly during treatment with dextroamphetamine saccharate,
amphetamine aspartate, dextroamphetamine sulfate and amphetamine
sulfate tablets.
Call your doctor right away if you or your child have any signs of
heart problems such as chest pain, shortness of breath, or fainting
while taking dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.
2. Mental (Psychiatric) Problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing things
that are not true, are suspicious) or new manic symptoms
Tell your doctor about any mental problems you or your child have, or
about a family history of suicide, bipolar illness, or depression.
Call your doctor right away if you or your child have any new or
worsening mental symptoms or problems while taking dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate
and amphetamine sulfate tablets, especially seeing or hearing things
that are not real, believing things that are not real, or are suspicious.
3. Circulation Problems in Fingers and Toes [Peripheral Vasculopathy,
Including Raynaud’s Phenomenon]:
• Fingers or toes may feel numb, cool, painful
• Fingers or toes may change color from pale, to blue, to red
Tell your doctor if you have or your child has numbness, pain, skin color
change, or sensitivity to temperature in your fingers or toes.
Call your doctor right away if you have or your child has any signs
of unexplained wounds appearing on fingers or toes while taking dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.
NDC 0378-4543-01
The 12.5 mg tablets contain 3.125 mg of dextroamphetamine saccharate, 3.125 mg of
amphetamine aspartate monohydrate (equivalent to 2.925 mg of amphetamine aspartate
anhydrous), 3.125 mg of dextroamphetamine sulfate, USP and 3.125 mg of amphetamine sulfate, USP. The 12.5 mg tablets are peach, round, tablets debossed with M over A12 on one side
of the tablet and a quadrisect on the other side.
NDC 0378-4544-01
The 15 mg tablets contain 3.75 mg of dextroamphetamine saccharate, 3.75 mg of amphetamine aspartate monohydrate (equivalent to 3.51 mg of amphetamine aspartate anhydrous), 3.75 mg of dextroamphetamine sulfate, USP and 3.75 mg of amphetamine sulfate,
USP. The 15 mg tablets are peach, round, tablets debossed with M over A15 on one side of the
tablet and a quadrisect on the other side.
NDC 0378-4545-01
The 20 mg tablets contain 5 mg of dextroamphetamine saccharate, 5 mg of amphetamine
aspartate monohydrate (equivalent to 4.6 mg of amphetamine aspartate anhydrous), 5 mg of
dextroamphetamine sulfate, USP and 5 mg of amphetamine sulfate, USP. The 20 mg tablets
are peach, round, tablets debossed with M over A20 on one side of the tablet and a quadrisect on the other side.
NDC 0378-4546-01
The 30 mg tablets contain 7.5 mg of dextroamphetamine saccharate, 7.5 mg of amphetamine aspartate monohydrate (equivalent to 7.03 mg of amphetamine aspartate anhydrous), 7.5 mg of dextroamphetamine sulfate, USP and 7.5 mg of amphetamine sulfate, USP.
The 30 mg tablets are peach, round, tablets debossed with M over A30 on one side of the
tablet and a quadrisect on the other side.
NDC 0378-4547-01
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant
closure.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
* The brands listed are trademarks of their respective owners.
What are dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets?
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are a central nervous system
stimulant prescription medicine. It is used for the treatment of AttentionDeficit Hyperactivity Disorder (ADHD). Dextroamphetamine saccharate,
amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets may help increase attention and decrease impulsiveness and
hyperactivity in patients with ADHD.
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets should be used as a part of a total
treatment program for ADHD that may include counseling or other therapies.
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are also used in the
treatment of a sleep disorder called narcolepsy.
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are a federally controlled substance (CII) because it can be abused or lead to dependence.
Keep dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets in a safe place
to prevent misuse and abuse. Selling or giving away dextroamphetamine
saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets may harm others, and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever
abused or been dependent on alcohol, prescription medicines or street drugs.
MEDICATION GUIDE
DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE
ASPARTATE, DEXTROAMPHETAMINE SULFATE
AND AMPHETAMINE SULFATE TABLETS
(dex” troe am fet’ a meen sac cha rate, am fet’ a meen a spar’ tate,
dex” troe am fet’ a meen sul’ fate, am fet’ a meen sul’ fate)
5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg and 30 mg
Read the Medication Guide that comes with dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets before you or your child starts taking it and each
time you get a refill. There may be new information. This Medication Guide
does not take the place of talking to your doctor about you or your child’s
treatment with dextroamphetamine saccharate, amphetamine aspartate,
dextroamphetamine sulfate and amphetamine sulfate tablets.
What is the most important information I should know about dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets?
The following have been reported with use of dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets and other stimulant medicines.
4
Who should not take dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets?
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets should not be taken
if you or your child:
• have heart disease or hardening of the arteries
• have moderate to severe high blood pressure
• have hyperthyroidism
• have an eye problem called glaucoma
• are very anxious, tense, or agitated
• have a history of drug abuse
• are taking or have taken within the past 14 days an anti-depression
medicine called a monoamine oxidase inhibitor or MAOI
• are sensitive to, allergic to, or had a reaction to other stimulant medicines
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are not recommended
for use in children less than 3 years old.
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets may not be right
for you or your child. Before starting dextroamphetamine saccharate,
sulfate tablets tell your or your child’s doctor about all health conditions (or a family history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette’s syndrome
• liver or kidney problems
• circulation problems in fingers and toes
• thyroid problems
• seizures or have had an abnormal brain wave test (EEG)
Tell your doctor if you or your child are pregnant, planning to become
pregnant, or breastfeeding.
Can dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets be taken with
other medicines?
Tell your doctor about all of the medicines that you or your child take
including prescription and nonprescription medicines, vitamins, and
herbal supplements. Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets and
some medicines may interact with each other and cause serious side
effects. Sometimes the doses of other medicines will need to be adjusted
while taking dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.
Your doctor will decide whether dextroamphetamine saccharate,
sulfate tablets can be taken with other medicines.
Especially tell your doctor if you or your child take:
• anti-depression medicines including MAOIs
• blood pressure medicines
• seizure medicines
• blood thinner medicines
• cold or allergy medicines that contain decongestants
• stomach acid medicines
Know the medicines that you or your child take. Keep a list of your medicines with you to show your doctor and pharmacist.
Do not start any new medicine while taking dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and
amphetamine sulfate tablets without talking to your doctor first.
How should dextroamphetamine saccharate, amphetamine aspartate,
dextroamphetamine sulfate and amphetamine sulfate tablets be taken?
• Take dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets exactly as
prescribed. Your doctor may adjust the dose until it is right for you or
your child.
• Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets are usually taken
two to three times a day. The first dose is usually taken when you first
wake in the morning. One or two more doses may be taken during the
day, 4 to 6 hours apart.
• Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets can be taken with
or without food.
• From time to time, your doctor may stop dextroamphetamine saccharate,
sulfate tablets treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.
Children should have their height and weight checked often while taking
dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets. Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate
and amphetamine sulfate tablets treatment may be stopped if a problem is found during these check-ups.
• If you or your child take too much dextroamphetamine saccharate,
amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets or overdoses, call your doctor or poison control
center right away, or get emergency treatment.
What are possible side effects of dextroamphetamine saccharate,
sulfate tablets?
See “What is the most important information I should know about dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets?” for information on
reported heart and mental problems.
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
Common side effects include:
• headache
• stomach ache
• trouble sleeping
• decreased appetite
• nervousness
• dizziness
Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets may affect your or
your child’s ability to drive or do other dangerous activities.
Talk to your doctor if you or your child have side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or
pharmacist for more information.
How should I store dextroamphetamine saccharate, amphetamine
aspartate, dextroamphetamine sulfate and amphetamine sulfate
tablets?
• Store dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets in a safe
place at room temperature, 20° to 25°C (68° to 77°F).
• Keep dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets and all
medicines out of the reach of children.
General information about dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate
tablets.
5
a Medication Guide. Do not use dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate
tablets for a condition for which it was not prescribed. Do not give dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine
sulfate and amphetamine sulfate tablets to other people, even if they have
the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine
sulfate and amphetamine sulfate tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about dextroamphetamine saccharate, amphetamine aspartate,
dextroamphetamine sulfate and amphetamine sulfate tablets that was
written for healthcare professionals. For additional information about dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine
sulfate and amphetamine sulfate tablets, please call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).
What are the ingredients in dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate
tablets?
Active Ingredients: dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, USP and amphetamine sulfate, USP
Inactive Ingredients: Colloidal silicon dioxide, compressible sugar, magnesium stearate, microcrystalline cellulose and pregelatinized starch
(corn). The 5 mg, 7.5 mg and 10 mg contain FD&C Blue No. 1 Aluminum
Lake as a color additive. The 12.5 mg, 15 mg, 20 mg, and 30 mg contain
FD&C Blue No. 1 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake as
color additives.
Administration.
REVISED MAY 2015
AMPHT:R2m
6
These highlights do not include all the information needed to use DONEPEZIL
HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information
for DONEPEZIL HYDROCHLORIDE TABLETS.
DONEPEZIL HYDROCHLORIDE tablets, for oral use
------------------------------ INDICATIONS AND USAGE -----------------------------Donepezil hydrochloride is an acetylcholinesterase inhibitor indicated for the
treatment of dementia of the Alzheimer’s type. Efficacy has been demonstrated in
patients with mild, moderate, and severe Alzheimer’s Disease (1)
---------------------------- DOSAGE AND ADMINISTRATION -------------------------• Mild to Moderate Alzheimer’s Disease - 5 mg or 10 mg administered once daily
(2.1)
• Moderate to Severe Alzheimer’s Disease - 10 mg or 23 mg administered once
daily (2.2)
-------------------------- DOSAGE FORMS AND STRENGTHS -------------------------• Tablets: 23 mg (3)
• Patients should be monitored closely for symptoms of active or occult gastro
intestinal (GI) bleeding, especially those at increased risk for developing ulcers (5.4)
• The use of donepezil hydrochloride in a dose of 23 mg once daily is associated
with weight loss (5.5)
• Cholinomimetics may cause bladder outflow obstructions (5.6)
• Cholinomimetics are believed to have some potential to cause generalized
convulsions (5.7)
• Cholinesterase inhibitors should be prescribed with care to patients with a history
of asthma or obstructive pulmonary disease (5.8)
-------------------------------- ADVERSE REACTIONS -------------------------------Most common adverse reactions in clinical studies of donepezil hydrochloride are
nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc.
at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------- DRUG INTERACTIONS --------------------------------• Cholinesterase inhibitors have the potential to interfere with the activity of
anticholinergic medications (7.1)
-------------------------------- CONTRAINDICATIONS -------------------------------Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives (4)
• A synergistic effect may be expected with concomitant administration of suc
--------------------------- WARNINGS AND PRECAUTIONS --------------------------• Cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle
--------------------------- USE IN SPECIFIC POPULATIONS -------------------------Pregnancy: Based on animal data, donepezil hydrochloride may cause fetal harm
(8.1)
• Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
relaxation during anesthesia (5.1)
atrioventricular nodes manifesting as bradycardia or heart block (5.2)
• Donepezil hydrochloride can cause vomiting. Patients should be observed closely
at initiation of treatment and after dose increases (5.3)
1
2
2.1 Dosing in Mild to Moderate Alzheimer’s Disease
2.2 Dosing in Moderate to Severe Alzheimer’s Disease
2.3 Administration Information
3
4CONTRAINDICATIONS
cinylcholine, similar neuromuscular blocking agents, or cholinergic agonists (7.2)
MX:DNPZH:R4ppt/MX:PL:DNPZH:R3p/MX:PL:DNPZH:R3pt
8
8.1Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Lower Weight Individuals
10OVERDOSAGE
11DESCRIPTION
5
5.1Anesthesia
5.2 Cardiovascular Conditions
5.3 Nausea and Vomiting
5.4 Peptic Ulcer Disease and GI Bleeding
5.5 Weight Loss
5.6 Genitourinary Conditions
5.7 Neurological Conditions: Seizures
5.8 Pulmonary Conditions
6
ADVERSE REACTIONS
16.1 Donepezil Hydrochloride Tablets
7
DRUG INTERACTIONS
7.1 Use with Anticholinergics
7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Mild to Moderate Alzheimer’s Disease
14.2 Moderate to Severe Alzheimer’s Disease
Page 1 of 9
1
Donepezil hydrochloride is indicated for the treatment of dementia of the Alzheimer’s type.
Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s
disease.
2
2.1 Dosing in Mild to Moderate Alzheimer’s Disease
The recommended starting dosage of donepezil hydrocholoride is 5 mg administered once per
day in the evening, just prior to retiring. The maximum recommended dosage of donepezil
hydrocholoride in patients with mild to moderate Alzheimer’s disease is 10 mg per day. A dose
of 10 mg should not be administered until patients have been on a daily dose of 5 mg for
4 to 6 weeks.
2.2 Dosing in Moderate to Severe Alzheimer’s Disease
The recommended starting dosage of donepezil hydrocholoride is 5 mg administered once per
day in the evening, just prior to retiring. The maximum recommended dosage of donepezil
hydrochloride in patients with moderate to severe Alzheimer’s disease is 23 mg per day. A dose
of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to
6 weeks. A dose of 23 mg per day should not be administered until patients have been on a daily
dose of 10 mg for at least 3 months.
2.3 Administration Information
Donepezil hydrochloride tablets should be taken in the evening, just prior to retiring. Donepezil
hydrochloride tablets can be taken with or without food.
The donepezil hydrochloride 23 mg tablet should not be split, crushed, or chewed.
3
Donepezil Hydrochloride Tablets are available containing 23 mg of donepezil hydrochloride, USP.
The 23 mg tablets are pink, film-coated, round, unscored tablets debossed with M on one side
of the tablet and D N on the other side.
4CONTRAINDICATIONS
Donepezil hydrochloride tablets are contraindicated in patients with known hypersensitivity to
donepezil hydrochloride or to piperidine derivatives.
5
5.1Anesthesia
Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholinetype muscle relaxation during anesthesia.
5.2 Cardiovascular Conditions
Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects
on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart
block in patients both with and without known underlying cardiac conduction abnormalities.
Syncopal episodes have been reported in association with the use of donepezil hydrochloride.
5.3 Nausea and Vomiting
Donepezil hydrochloride, as a predictable consequence of its pharmacological properties, has
been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear
more frequently with the 10 mg/day dose than with the 5 mg/day dose, and more frequently
with the 23 mg dose than with the 10 mg dose. Specifically, in a controlled trial that compared
a dose of 23 mg/day to 10 mg/day in patients who had been treated with donepezil 10 mg/day
for at least 3 months, the incidence of nausea in the 23 mg group was markedly greater than
in the patients who continued on 10 mg/day (11.8% vs. 3.4%, respectively), and the incidence
of vomiting in the 23 mg group was markedly greater than in the 10 mg group (9.2% vs. 2.5%,
respectively). The percent of patients who discontinued treatment due to vomiting in the 23 mg
group was markedly higher than in the 10 mg group (2.9% vs. 0.4%, respectively).
Although in most cases, these effects have been transient, sometimes lasting 1 to 3 weeks, and
have resolved during continued use of donepezil hydrochloride, patients should be observed
closely at the initiation of treatment and after dose increases.
5.4 Peptic Ulcer Disease and GI Bleeding
Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid
secretion due to increased cholinergic activity. Therefore, patients should be monitored closely
for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk
for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent
nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of donepezil hydrochloride in
a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence
of either peptic ulcer disease or gastrointestinal bleeding. Results of a controlled clinical study
with 23 mg/day showed an increase, relative to 10 mg/day, in the incidence of peptic ulcer
disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%).
5.5 Weight Loss
Weight loss was reported as an adverse reaction in 4.7% of patients assigned to donepezil
hydrochloride in a dose of 23 mg/day compared to 2.5% of patients assigned to 10 mg/day.
Compared to their baseline weights, 8.4% of patients taking 23 mg/day were found to have a
weight decrease of ≥ 7% by the end of the study, while 4.9% of patients taking 10 mg/day
were found to have weight loss of ≥ 7% at the end of the study.
5.6 Genitourinary Conditions
Although not observed in clinical trials of donepezil hydrochloride, cholinomimetics may cause
bladder outflow obstruction.
5.7 Neurological Conditions: Seizures
Cholinomimetics are believed to have some potential to cause generalized convulsions.
However, seizure activity also may be a manifestation of Alzheimer’s disease.
5.8 Pulmonary Conditions
Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with
care to patients with a history of asthma or obstructive pulmonary disease.
6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Cardiovascular Conditions [see Warnings and Precautions (5.2)]
• Nausea and Vomiting [see Warnings and Precautions (5.3)]
• Peptic Ulcer Disease and GI Bleeding [see Warnings and Precautions (5.4)]
• Weight Loss [see Warnings and Precautions (5.5)]
• Genitourinary Conditions [see Warnings and Precautions (5.6)]
• Neurological Conditions: Seizures [see Warnings and Precautions (5.7)]
• Pulmonary Conditions [see Warnings and Precautions (5.8)]
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Donepezil hydrochloride has been administered to over 1,700 individuals during clinical trials
worldwide. Approximately 1,200 of these patients have been treated for at least 3 months and
more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled
trials in the United States included approximately 900 patients. In regards to the highest dose
of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated
for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from
1 to 1,214 days.
Mild to Moderate Alzheimer’s Disease: Adverse Reactions Leading to Discontinuation: The
rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse
reactions for the donepezil hydrochloride 5 mg/day treatment groups were comparable to those
of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who
received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%.
The most common adverse reactions leading to discontinuation, defined as those occurring
in at least 2% of patients and at twice or more the incidence seen in placebo patients, are
shown in Table 1.
Table 1. M
ost Common Adverse Reactions Leading to Discontinuation
in Patients with Mild to Moderate Alzheimer’s Disease
Placebo
(n = 355)
%
5 mg/day
Donepezil
Hydrochloride
(n = 350)
%
10 mg/day
Donepezil
Hydrochloride
(n = 315)
%
1
1
3
Diarrhea
0
<1
3
Vomiting
<1
<1
2
Adverse Reaction
Nausea
Most Common Adverse Reactions: The most common adverse reactions, defined as those
occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo
rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include
nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse
reactions were often transient, resolving during continued donepezil hydrochloride treatment
without the need for dose modification.
There is evidence to suggest that the frequency of these common adverse reactions may be
affected by the rate of titration. An open-label study was conducted with 269 patients who
received placebo in the 15- and 30-week studies. These patients were titrated to a dose of
10 mg/day over a 6 week period. The rates of common adverse reactions were lower than those
seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were
comparable to those seen in patients on 5 mg/day.
See Table 2 for a comparison of the most common adverse reactions following 1 and 6 week
titration regimens.
Table 2. C omparison of Rates of Adverse Reactions in Mild to Moderate Patients
Titrated to 10 mg/day Over 1 and 6 Weeks
No titration
Adverse
Reaction
Nausea
Placebo
(n = 315)
%
6
1 week titration 6 week titration
5 mg/day
(n = 311)
%
5
10 mg/day
(n = 315)
%
19
10 mg/day
(n = 269)
%
6
Diarrhea
5
8
15
9
Insomnia
6
6
14
6
Fatigue
3
4
8
3
Vomiting
3
3
8
5
Muscle cramps
2
6
8
3
Anorexia
2
3
7
3
Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebocontrolled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which
the rate of occurrence was greater for patients treated with donepezil hydrochloride than with
Page 2 of 9
placebo. In general, adverse reactions occurred more frequently in female patients and with
advancing age.
Table 3. A dverse Reactions in Pooled Placebo-Controlled Clinical Trials in Mild to
Moderate Alzheimer’s Disease
Adverse Reaction
Placebo
Donepezil Hydrochloride
(n = 355)
(n = 747)
%
%
Percent of Patients with any Adverse
72
74
Reaction
Nausea
6
11
Diarrhea
5
10
Headache
9
10
Insomnia
6
9
Pain, various locations
8
9
Dizziness
6
8
Accident
6
7
Muscle Cramps
2
6
Fatigue
3
5
Vomiting
3
5
Anorexia
2
4
Ecchymosis
3
4
Abnormal Dreams
0
3
Depression
<1
3
Weight Loss
1
3
Arthritis
1
2
Frequent Urination
1
2
Somnolence
<1
2
Syncope
1
2
Severe Alzheimer’s Disease (Donepezil Hydrochloride 5 mg/day and 10 mg/day): Donepezil
hydrochloride has been administered to over 600 patients with severe Alzheimer’s disease
during clinical trials of at least 6 months duration, including three double-blind, placebocontrolled trials, two of which had an open label extension.
Adverse Reactions Leading to Discontinuation: The rates of discontinuation from controlled
clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride
patients were approximately 12% compared to 7% for placebo patients. The most common
adverse reactions leading to discontinuation, defined as those occurring in at least 2% of
donepezil hydrochloride patients and at twice or more the incidence seen in placebo, were
anorexia (2% vs. 1% placebo), nausea (2% vs. < 1% placebo), diarrhea (2% vs. 0% placebo),
and urinary tract infection (2% vs. 1% placebo).
Most Common Adverse Reactions: The most common adverse reactions, defined as those
occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at
twice or more the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic
effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse
reactions were often transient, resolving during continued donepezil hydrochloride treatment
without the need for dose modification.
Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebocontrolled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of
occurrence was greater for patients treated with donepezil hydrochloride than with placebo.
Table 4. A dverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s
Disease
Body System/Adverse Reaction
Placebo
(n = 392)
(n = 501)
%
%
73
81
Reaction
Accident
12
13
Infection
9
11
Diarrhea
4
10
Anorexia
4
8
Vomiting
4
8
Nausea
2
6
Insomnia
4
5
Ecchymosis
2
5
Headache
3
4
Hypertension
2
3
Pain
2
3
Back Pain
2
3
Eczema
2
3
Continued
Table 4. A dverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s
Disease
Body System/Adverse Reaction
Placebo
(n = 392)
(n = 501)
%
%
73
81
Reaction
Hallucinations
1
3
Hostility
2
3
Increase in Creatine Phosphokinase
1
3
Nervousness
2
3
Fever
1
2
Chest Pain
<1
2
Confusion
1
2
Dehydration
1
2
Depression
1
2
Dizziness
1
2
Emotional Lability
1
2
Hemorrhage
1
2
Hyperlipemia
<1
2
Personality Disorder
1
2
Somnolence
1
2
Syncope
1
2
Urinary Incontinence
1
2
Moderate to Severe Alzheimer’s Disease (Donepezil Hydrochloride 23 mg/day): Donepezil
hydrochloride 23 mg/day has been administered to over 1,300 individuals globally in clinical
trials. Approximately 1,050 of these patients have been treated for at least 3 months and more
than 950 patients have been treated for at least 6 months. The range of patient exposure was
from 1 to over 500 days.
Adverse Reactions Leading to Discontinuation: The rate of discontinuation from a controlled
clinical trial of donepezil hydrochloride 23 mg/day due to adverse reactions was higher (19%)
than for the 10 mg/day treatment group (8%). The most common adverse reactions leading to
discontinuation, defined as those occurring in at least 1% of patients and greater than those
occurring with 10 mg/day are shown in Table 5.
Table 5. M
ost Common Adverse Reactions Leading to Discontinuation in Patients with
Moderate to Severe Alzheimer’s Disease
Adverse Reaction
Vomiting
Diarrhea
Nausea
Dizziness
23 mg/day
(n = 963)
%
3
2
2
1
10 mg/day
(n = 471)
%
0
0
0
0
The majority of discontinuations due to adverse reactions in the 23 mg group occurred during
the first month of treatment.
Most Common Adverse Reactions with Donepezil Hydrochloride 23 mg/day: The most common
adverse reactions, defined as those occurring at a frequency of at least 5%, include nausea,
diarrhea, vomiting, and anorexia.
Table 6 lists adverse reactions that occurred in at least 2% of patients who received 23 mg/day
of donepezil hydrochloride and at a higher frequency than those receiving 10 mg/day of donepezil
hydrochloride in a controlled clinical trial that compared the two doses. In this study, there were no
important differences in the type of adverse reactions in patients taking donepezil hydrochloride
with or without memantine.
Table 6. A dverse Reactions in a Controlled Clinical Trial in Moderate to Severe
Alzheimer’s Disease
Adverse Reaction
23 mg/day
10 mg/day
Donepezil
Donepezil
Hydrochloride
Hydrochloride
(n = 963)
(n = 471)
%
%
Percent of Patients with any Adverse Reaction
74
64
Nausea
12
3
Vomiting
9
3
Diarrhea
8
5
Anorexia
5
2
Dizziness
5
3
Weight Loss
5
3
Continued
Page 3 of 9
Table 6. A dverse Reactions in a Controlled Clinical Trial in Moderate to Severe
Alzheimer’s Disease
Adverse Reaction
23 mg/day
10 mg/day
Donepezil
Donepezil
Hydrochloride
Hydrochloride
(n = 963)
(n = 471)
%
%
Percent of Patients with any Adverse Reaction
74
64
Headache
4
3
Insomnia
3
2
Urinary Incontinence
3
1
Asthenia
2
1
Contusion
2
0
Fatigue
2
1
Somnolence
2
1
The following adverse reactions have been identified during post-approval use of donepezil
hydrochloride. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations,
heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant
syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes.
7
DRUG INTERACTIONS
7.1 Use with Anticholinergics
Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere
with the activity of anticholinergic medications.
7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors
A synergistic effect may be expected when cholinesterase inhibitors are given concurrently
with succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists such as
bethanechol.
8
8.1Pregnancy
Teratogenic Effects: Pregnancy Category C: There are no adequate or well-controlled studies in
pregnant women. Donepezil hydrochloride should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis
did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 6 times the
maximum recommended human dose [MRHD] of 23 mg/day on a mg/m2 basis) and 10 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil
(1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an
increase in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose.
The no-effect dose of 3 mg/kg/day is approximately equal to the MRHD on a mg/m2 basis.
8.3 Nursing Mothers
It is not known whether donepezil is excreted in human milk. Caution should be exercised when
donepezil hydrochloride is administered to a nursing woman.
8.4 Pediatric Use
The safety and effectiveness of donepezil hydrochloride in pediatric patients have not been
established.
8.5 Geriatric Use
Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age. The
mean age of patients enrolled in the clinical studies with donepezil hydrochloride was 73 years;
80% of these patients were between 65 and 84 years old, and 49% of patients were at or above
the age of 75. The efficacy and safety data presented in the clinical trials section were obtained
from these patients. There were no clinically significant differences in most adverse reactions
reported by patient groups ≥ 65 years old and < 65 years old.
8.6 Lower Weight Individuals
In the controlled clinical trial, among patients in the donepezil hydrochloride 23 mg treatment
group, those patients weighing < 55 kg reported more nausea, vomiting, and decreased weight
than patients weighing 55 kg or more. There were more withdrawals due to adverse reactions
as well. This finding may be related to higher plasma exposure associated with lower weight.
10OVERDOSAGE
Because strategies for the management of overdose are continually evolving, it is advisable to
contact a Poison Control Center to determine the latest recommendations for the management
of an overdose of any drug.
As in any case of overdose, general supportive measures should be utilized. Overdosage with
cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea,
vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse,
and convulsions. Increasing muscle weakness is a possibility and may result in death if
respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as
an antidote for donepezil hydrochloride overdosage. Intravenous atropine sulfate titrated to
effect is recommended: an initial dose of 1 mg to 2 mg IV with subsequent doses based upon
clinical response. Atypical responses in blood pressure and heart rate have been reported
with other cholinomimetics when co-administered with quaternary anticholinergics such as
glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be
removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
Dose-related signs of toxicity in animals included reduced spontaneous movement, prone
position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation,
miosis, tremors, fasciculation, and lower body surface temperature.
11DESCRIPTION
Donepezil hydrochloride is a reversible inhibitor of the enzyme acetylcholinesterase, known
chemically as (±)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride.
Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020.
It has a molecular formula of C24H29NO3HCl and a molecular weight of 415.95. Donepezil
hydrochloride, USP is a white to off-white crystalline powder and is soluble in methylene
chloride, methanol and insoluble in n-Hexane and diisopropyl ether.
Donepezil hydrochloride tablets are available for oral administration in film-coated tablets
containing 23 mg of donepezil hydrochloride, USP (monohydrate).
Inactive ingredients in 23 mg tablets include ethylcellulose, hydroxypropyl cellulose, hypro
mellose, lactose monohydrate, magnesium stearate, polyethylene glycol, red iron oxide, sodium
alginate, titanium dioxide, triacetin, and yellow iron oxide.
USP Dissolution Test pending.
Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer’s
disease attribute some of them to a deficiency of cholinergic neurotransmission.
Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic
function. This is accomplished by increasing the concentration of acetylcholine through
reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that
donepezil alters the course of the underlying dementing process.
Pharmacokinetics of donepezil are linear over a dose range of 1 mg to 10 mg given once daily.
The rate and extent of absorption of donepezil hydrochloride tablets are not influenced by food.
Based on population pharmacokinetic analysis of plasma donepezil concentrations measured
in patients with Alzheimer’s disease, following oral dosing, peak plasma concentration is
achieved for donepezil hydrochloride 23 mg tablets in approximately 8 hours, compared with
3 hours for donepezil hydrochloride 10 mg tablets. Peak plasma concentrations were about
2-fold higher for donepezil hydrochloride 23 mg tablets than donepezil hydrochloride 10 mg
tablets.
The elimination half life of donepezil is about 70 hours, and the mean apparent plasma
clearance (Cl/F) is 0.13 to 0.19 L/hr/kg. Following multiple dose administration, donepezil
accumulates in plasma by 4- to 7-fold, and steady-state is reached within 15 days. The steadystate volume of distribution is 12 to 16 L/kg. Donepezil is approximately 96% bound to human
plasma proteins, mainly to albumins (about 75%) and alpha1 – acid glycoprotein (about 21%)
over the concentration range of 2 to 1000 ng/mL. Donepezil is both excreted in the urine intact
and extensively metabolized to four major metabolites, two of which are known to be active, and
a number of minor metabolites, not all of which have been identified. Donepezil is metabolized
by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration
of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered
dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%),
which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found
in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of
the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days,
while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine
as unchanged drug. Examination of the effect of CYP2D6 genotype in Alzheimer’s patients
showed differences in clearance values among CYP2D6 genotype subgroups. When compared
to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid
metabolizers had a 24% faster clearance.
Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of
donepezil hydrochloride was decreased by 20% relative to 10 healthy age- and sex-matched
subjects.
Renal Disease: In a study of 11 patients with moderate to severe renal impairment
(ClC < 18 mL/min/1.73 m2) the clearance of donepezil hydrochloride did not differ from
11 age- and sex-matched healthy subjects.
Age: No formal pharmacokinetic study was conducted to examine age-related differences in the
pharmacokinetics of donepezil hydrochloride. Population pharmacokinetic analysis suggested
that the clearance of donepezil in patients decreases with increasing age. When compared with
65-year old, subjects, 90-year old subjects have a 17% decrease in clearance, while 40-year
old subjects have a 33% increase in clearance. The effect of age on donepezil clearance may
not be clinically significant.
Gender and Race: No specific pharmacokinetic study was conducted to investigate the effects
of gender and race on the disposition of donepezil hydrochloride. However, retrospective
pharmacokinetic analysis and population pharmacokinetic analysis of plasma donepezil
concentrations measured in patients with Alzheimer’s disease indicates that gender and
race (Japanese and Caucasians) did not affect the clearance of donepezil hydrochloride to an
important degree.
Body Weight: There was a relationship noted between body weight and clearance. Over the
Page 4 of 9
range of body weight from 50 kg to 110 kg, clearance increased from 7.77 L/h to 14.04 L/h, with
a value of 10 L/hr for 70 kg individuals.
Drug Interactions: Effect of Donepezil Hydrochloride on the Metabolism of Other Drugs: No
in vivo clinical trials have investigated the effect of donepezil hydrochloride on the clearance of
drugs metabolized by CYP 3A4 (e.g., cisapride, terfenadine) or by CYP 2D6 (e.g., imipramine).
However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50 mM to
130 mM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates
little likelihood of interference. Based on in vitro studies, donepezil shows little or no evidence
of direct inhibition of CYP2B6, CYP2C8, and CYP2C19 at clinically relevant concentrations.
Whether donepezil hydrochloride has any potential for enzyme induction is not known. Formal
pharmacokinetic studies evaluated the potential of donepezil hydrochloride for interaction
with theophylline, cimetidine, warfarin, digoxin, and ketoconazole. No effects of donepezil
hydrochloride on the pharmacokinetics of these drugs were observed.
Effect of Other Drugs on the Metabolism of Donepezil Hydrochloride: Ketoconazole and
quinidine, strong inhibitors of CYP450 3A and 2D6, respectively, inhibit donepezil metabolism
in vitro. Whether there is a clinical effect of quinidine is not known. Population pharmacokinetic
analysis showed that in the presence of concomitant CYP2D6 inhibitors donepezil AUC was
increased by approximately 17% to 20% in Alzheimer’s disease patients taking donepezil
hydrochloride 10 and 23 mg. This represented an average effect of weak, moderate, and strong
CYP2D6 inhibitors. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg
q.d.) increased mean donepezil (5 mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The
clinical relevance of this increase in concentration is unknown.
Inducers of CYP 3A (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and pheno
barbital) could increase the rate of elimination of donepezil hydrochloride.
Formal pharmacokinetic studies demonstrated that the metabolism of donepezil hydrochloride
is not significantly affected by concurrent administration of digoxin or cimetidine.
An in vitro study showed that donepezil was not a substrate of P-glycoprotein.
Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed
in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin,
and warfarin. Donepezil hydrochloride at concentrations of 0.3 to 10 micrograms/mL did
not affect the binding of furosemide (5 micrograms/mL), digoxin (2 ng/mL), and warfarin
(3 micrograms/mL) to human albumin. Similarly, the binding of donepezil hydrochloride to
human albumin was not affected by furosemide, digoxin, and warfarin.
No evidence of carcinogenic potential was obtained in an 88-week carcinogenicity study of
donepezil conducted in mice at oral doses up to 180 mg/kg/day (approximately 40 times the
maximum recommended human dose [MRHD] of 23 mg/day on a mg/m2 basis), or in a 104-week
carcinogenicity study in rats at oral doses up to 30 mg/kg/day (approximately 13 times the MRHD
on a mg/m2 basis).
Donepezil was negative in a battery of genotoxicity assays (in vitro bacterial reverse mutation,
in vitro mouse lymphoma tk, in vitro chromosomal aberration, and in vivo mouse micronucleus).
Donepezil had no effect on fertility in rats at oral doses up to 10 mg/kg/day (approximately
4 times the MRHD on a mg/m2 basis) when administered to males and females prior to and
during mating and continuing in females through implantation.
In an acute dose neurotoxicity study in female rats, oral administration of donepezil and
memantine in combination resulted in increased incidence, severity, and distribution of
neurodegeneration compared with memantine alone. The no-effect levels of the combination
were associated with clinically relevant plasma donepezil and memantine levels.
The relevance of this finding to humans is unknown.
14 CLINICAL STUDIES
14.1 Mild to Moderate Alzheimer’s Disease
The effectiveness of donepezil hydrochloride as a treatment for mild to moderate Alzheimer’s
disease is demonstrated by the results of two randomized, double-blind, placebo-controlled
clinical investigations in patients with Alzheimer’s disease (diagnosed by NINCDS and DSM III-R
criteria, Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2).
The mean age of patients participating in donepezil hydrochloride trials was 73 years with a
range of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial
distribution was white 95%, black 3%, and other races 2%.
The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than
5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend
analyses of data from these clinical trials, that a daily dose of 10 mg of donepezil hydrochloride
might provide additional benefit for some patients. Accordingly, whether or not to employ a dose
of 10 mg is a matter of prescriber and patient preference.
Study Outcome Measures: In each study, the effectiveness of treatment with donepezil
hydrochloride was evaluated using a dual outcome assessment strategy.
The ability of donepezil hydrochloride to improve cognitive performance was assessed with
the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), a multi-item
instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease
patients. The ADAS-cog examines selected aspects of cognitive performance including elements
of memory, orientation, attention, reasoning, language, and praxis. The ADAS-cog scoring range
is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults
may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.
The patients recruited as participants in each study had mean scores on the ADAS-cog of
approximately 26 points, with a range from 4 to 61. Experience based on longitudinal studies
of ambulatory patients with mild to moderate Alzheimer’s disease suggest that scores on the
ADAS-cog increase (worsen) by 6 to 12 points per year. However, smaller changes may be
seen in patients with very mild or very advanced disease since the ADAS-cog is not uniformly
sensitive to change over the course of the disease. The annualized rate of decline in the placebo
patients participating in donepezil hydrochloride trials was approximately 2 to 4 points per year.
The ability of donepezil hydrochloride to produce an overall clinical effect was assessed using a
Clinician’s Interview-Based Impression of Change that required the use of caregiver information,
the CIBIC-plus. The CIBIC-plus is not a single instrument and is not a standardized instrument
like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats,
each different in terms of depth and structure.
As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it
was used and cannot be compared directly with the results of CIBIC-plus evaluations from other
clinical trials. The CIBIC-plus used in donepezil hydrochloride trials was a semi-structured
instrument that was intended to examine four major areas of patient function: General,
Cognitive, Behavioral, and Activities of Daily Living. It represents the assessment of a skilled
clinician based upon his/her observations at an interview with the patient, in combination with
information supplied by a caregiver familiar with the behavior of the patient over the interval
rated. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of
1, indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7,
indicating “markedly worse.” The CIBIC-plus has not been systematically compared directly to
assessments not using information from caregivers (CIBIC) or other global methods.
Thirty-Week Study: In a study of 30 weeks duration, 473 patients were randomized to receive single
daily doses of placebo, 5 mg/day or 10 mg/day of donepezil hydrochloride. The 30-week study was
divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind
placebo washout period. The study was designed to compare 5 mg/day or 10 mg/day fixed doses
of donepezil hydrochloride to placebo. However, to reduce the likelihood of cholinergic effects, the
10 mg/day treatment was started following an initial 7 day treatment with 5 mg/day doses.
Effects on the ADAS-cog: Figure 1 illustrates the time course for the change from baseline in
ADAS-cog scores for all three dose groups over the 30 weeks of the study. After 24 weeks of
treatment, the mean differences in the ADAS-cog change scores for donepezil hydrochloride
treated patients compared to the patients on placebo were 2.8 and 3.1 points for the 5 mg/day
and 10 mg/day treatments, respectively. These differences were statistically significant. While
the treatment effect size may appear to be slightly greater for the 10 mg/day treatment, there
was no statistically significant difference between the two active treatments.
Following 6 weeks of placebo washout, scores on the ADAS-cog for both the donepezil
hydrochloride treatment groups were indistinguishable from those patients who had received
only placebo for 30 weeks. This suggests that the beneficial effects of donepezil hydrochloride
abate over 6 weeks following discontinuation of treatment and do not represent a change
in the underlying disease. There was no evidence of a rebound effect 6 weeks after abrupt
discontinuation of therapy.
Figure 1. Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing
24 Weeks of Treatment.
Figure 2 illustrates the cumulative percentages of patients from each of the three treatment
groups who had attained the measure of improvement in ADAS-cog score shown on the X axis.
Three change scores (7-point and 4-point reductions from baseline or no change in score) have
been identified for illustrative purposes, and the percent of patients in each group achieving
that result is shown in the inset table.
The curves demonstrate that both patients assigned to placebo and donepezil hydrochloride
have a wide range of responses, but that the active treatment groups are more likely to show
greater improvements. A curve for an effective treatment would be shifted to the left of the
curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or
shifted to the right of the curve for placebo.
Page 5 of 9
Figure 2. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment
with Specified Changes from Baseline ADAS-cog Scores. The Percentages of Randomized
Patients who Completed the Study were: Placebo 80%, 5 mg/day 85%, and 10 mg/day 68%.
Effects on the CIBIC-plus: Figure 3 is a histogram of the frequency distribution of CIBIC-plus
scores attained by patients assigned to each of the three treatment groups who completed
24 weeks of treatment. The mean drug-placebo differences for these groups of patients were
0.35 points and 0.39 points for 5 mg/day and 10 mg/day of donepezil hydrochloride, respectively.
These differences were statistically significant. There was no statistically significant difference
between the two active treatments.
Figure 5. Cumulative Percentage of Patients with Specified Changes from Baseline ADAS-cog
Scores. The Percentages of Randomized Patients Within Each Treatment Group Who Completed
the Study Were: Placebo 93%, 5 mg/day 90%, and 10 mg/day 82%.
Effects on the CIBIC-plus: Figure 6 is a histogram of the frequency distribution of CIBIC-plus
scores attained by patients assigned to each of the three treatment groups who completed
12 weeks of treatment. The differences in mean scores for donepezil hydrochloride treated
patients compared to the patients on placebo at Week 12 were 0.36 and 0.38 points for the
5 mg/day and 10 mg/day treatment groups, respectively. These differences were statistically
significant.
Figure 3. Frequency Distribution of CIBIC-plus Scores at Week 24.
Fifteen-Week Study: In a study of 15 weeks duration, patients were randomized to receive single
daily doses of placebo or either 5 mg/day or 10 mg/day of donepezil hydrochloride for 12 weeks,
followed by a 3 week placebo washout period. As in the 30-week study, to avoid acute cholinergic
effects, the 10 mg/day treatment followed an initial 7 day treatment with 5 mg/day doses.
Effects on the ADAS-cog: Figure 4 illustrates the time course of the change from baseline in
ADAS-cog scores for all three dose groups over the 15 weeks of the study. After 12 weeks of
treatment, the differences in mean ADAS-cog change scores for the donepezil hydrochloride
treated patients compared to the patients on placebo were 2.7 and 3 points each, for the 5 and
10 mg/day donepezil hydrochloride treatment groups, respectively. These differences were
statistically significant. The effect size for the 10 mg/day group may appear to be slightly
larger than that for 5 mg/day. However, the differences between active treatments were not
statistically significant.
Figure 4. Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing
the 15-week Study.
Following 3 weeks of placebo washout, scores on the ADAS-cog for both the donepezil
hydrochloride treatment groups increased, indicating that discontinuation of donepezil
hydrochloride resulted in a loss of its treatment effect. The duration of this placebo washout
period was not sufficient to characterize the rate of loss of the treatment effect, but the 30-week
study (see above) demonstrated that treatment effects associated with the use of donepezil
hydrochloride abate within 6 weeks of treatment discontinuation.
Figure 5 illustrates the cumulative percentages of patients from each of the three treatment
groups who attained the measure of improvement in ADAS-cog score shown on the X axis. The
same three change scores (7-point and 4-point reductions from baseline or no change in score)
as selected for the 30-week study have been used for this illustration. The percentages of
patients achieving those results are shown in the inset table.
As observed in the 30-week study, the curves demonstrate that patients assigned to either
placebo or to donepezil hydrochloride have a wide range of responses, but that the donepezil
hydrochloride treated patients are more likely to show greater improvements in cognitive
performance.
In both studies, patient age, sex, and race were not found to predict the clinical outcome of
donepezil hydrochloride treatment.
14.2 Moderate to Severe Alzheimer’s Disease
The effectiveness of donepezil hydrochloride in the treatment of patients with moderate to
severe Alzheimer’s disease was established in studies employing doses of 10 mg/day and
23 mg/day. Results of a controlled clinical trial in moderate to severe Alzheimer’s Disease that
compared donepezil hydrochloride 23 mg once daily to 10 mg once daily suggest that a 23 mg
dose of donepezil hydrochloride provided additional benefit.
Swedish 6 Month Study (10 mg/day): The effectiveness of donepezil hydrochloride as a
treatment for severe Alzheimer’s disease is demonstrated by the results of a randomized, doubleblind, placebo-controlled clinical study conducted in Sweden (6 month study) in patients with
probable or possible Alzheimer’s disease diagnosed by NINCDS-ADRDA and DSM-IV criteria,
MMSE: range of 1 to 10. Two hundred and forty eight (248) patients with severe Alzheimer’s
disease were randomized to donepezil hydrochloride or placebo. For patients randomized to
donepezil hydrochloride, treatment was initiated at 5 mg once daily for 28 days and then
increased to 10 mg once daily. At the end of the 6 month treatment period, 90.5% of the
donepezil hydrochloride treated patients were receiving the 10 mg/day dose. The mean age of
patients was 84.9 years, with a range of 59 to 99. Approximately 77% of patients were women,
and 23% were men. Almost all patients were Caucasian. Probable Alzheimer’s disease was
diagnosed in the majority of the patients (83.6% of donepezil hydrochloride treated patients
and 84.2% of placebo treated patients).
Study Outcome Measures: The effectiveness of treatment with donepezil hydrochloride was
determined using a dual outcome assessment strategy that evaluated cognitive function using
an instrument designed for more impaired patients and overall function through caregiverrated assessment. This study showed that patients on donepezil hydrochloride experienced
significant improvement on both measures compared to placebo.
The ability of donepezil hydrochloride to improve cognitive performance was assessed with
the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated
for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB
evaluates selective aspects of cognitive performance, including elements of memory, language,
orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB
scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
Daily function was assessed using the Modified Alzheimer’s Disease Cooperative Study
Activities of Daily Living Inventory for Severe Alzheimer’s Disease (ADCS-ADL-severe). The
ADCS-ADL-severe is derived from the Alzheimer’s Disease Cooperative Study Activities of Daily
Living Inventory, which is a comprehensive battery of ADL questions used to measure the
functional capabilities of patients. Each ADL item is rated from the highest level of independent
Page 6 of 9
performance to complete loss. The ADCS-ADL-severe is a subset of 19 items, including ratings
of the patient’s ability to eat, dress, bathe, use the telephone, get around (or travel), and
perform other activities of daily living; it has been validated for the assessment of patients with
moderate to severe dementia. The ADCS-ADL-severe has a scoring range of 0 to 54, with the
lower scores indicating greater functional impairment. The investigator performs the inventory
by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning
of the patient.
Effects on the SIB: Figure 7 shows the time course for the change from baseline in SIB score for
the two treatment groups over the 6 months of the study. At 6 months of treatment, the mean
difference in the SIB change scores for donepezil hydrochloride treated patients compared
to patients on placebo was 5.9 points. Donepezil hydrochloride treatment was statistically
significantly superior to placebo.
Figure 7. Time Course of the Change from Baseline in SIB Score for Patients Completing 6 Months
of Treatment.
Figure 8 illustrates the cumulative percentages of patients from each of the two treatment
groups who attained the measure of improvement in SIB score shown on the X-axis. While
patients assigned both to donepezil hydrochloride and to placebo have a wide range of
responses, the curves show that the donepezil hydrochloride group is more likely to show a
greater improvement in cognitive performance.
Figure 8. Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment
with Particular Changes from Baseline in SIB Scores.
Figure 9. Time Course of the Change from Baseline in ADCS-ADL-Severe Score for Patients
Completing 6 Months of Treatment.
Effects on the ADCS-ADL-severe: Figure 9 illustrates the time course for the change from baseline
in ADCS-ADL-severe scores for patients in the two treatment groups over the 6 months of the
study. After 6 months of treatment, the mean difference in the ADCS-ADL-severe change scores
for donepezil hydrochloride treated patients compared to patients on placebo was 1.8 points.
Donepezil hydrochloride treatment was statistically significantly superior to placebo.
Figure 10 shows the cumulative percentages of patients from each treatment group with specified
changes from baseline ADCS-ADL-severe scores. While both patients assigned to donepezil
hydrochloride and placebo have a wide range of responses, the curves demonstrate that the
donepezil hydrochloride group is more likely to show a smaller decline or an improvement.
Figure 10. Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment
with Particular Changes from Baseline in ADCS-ADL-Severe Scores.
Japanese 24-Week Study (10 mg/day): In a study of 24 weeks duration conducted in Japan, 325
patients with severe Alzheimer’s disease were randomized to doses of 5 mg/day or 10 mg/day of
donepezil, administered once daily, or placebo. Patients randomized to treatment with donepezil
were to achieve their assigned doses by titration, beginning at 3 mg/day, and extending over
a maximum of 6 weeks. Two hundred and forty eight (248) patients completed the study, with
similar proportions of patients completing the study in each treatment group. The primary efficacy
measures for this study were the SIB and CIBIC-plus.
At 24 weeks of treatment, statistically significant treatment differences were observed between
the 10 mg/day dose of donepezil and placebo on both the SIB and CIBIC-plus. The 5 mg/day
dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not
on the CIBIC-plus.
Study of 23 mg/day: The effectiveness of donepezil hydrochloride 23 mg/day as a treatment for
moderate to severe Alzheimer’s disease has been demonstrated by the results of a randomized,
double-blind, controlled clinical investigation in patients with moderate to severe Alzheimer’s
disease. The controlled clinical study was conducted globally in patients with probable
Alzheimer’s disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 0 to 20.
Patients were required to have been on a stable dose of donepezil hydrochloride 10 mg/day for
at least 3 months prior to screening. One thousand four hundred and thirty four (1,434) patients
with moderate to severe Alzheimer’s disease were randomized to 23 mg/day or 10 mg/day. The
mean age of patients was 73.8 years, with a range of 47 to 90. Approximately 63% of patients
were women, and 37% were men. Approximately 36% of the patients were taking memantine
throughout the study.
Study Outcome Measures: The effectiveness of treatment with 23 mg/day was determined using
a dual outcome assessment strategy that evaluated cognitive function using an instrument
designed for more impaired patients and overall function through caregiver-rated assessment.
The ability of 23 mg/day to improve cognitive performance was assessed with the Severe
Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the
evaluation of cognitive function in patients with moderate to severe dementia. The SIB
evaluates selective aspects of cognitive performance, including elements of memory, language,
orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB
scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
The ability of 23 mg/day to produce an overall clinical effect was assessed using a Clinician’s
Interview-Based Impression of Change that incorporated the use of caregiver information, the
CIBIC-plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines
four major areas of patient function: General, Cognitive, Behavioral, and Activities of Daily
Living. It represents the assessment of a skilled clinician based upon his/her observations at
an interview with the patient, in combination with information supplied by a caregiver familiar
with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a sevenpoint categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score
of 4, indicating “no change” to a score of 7, indicating “markedly worse.”
Effects on the SIB: Figure 11 shows the time course for the change from baseline in SIB score
for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the LS
mean difference in the SIB change scores for 23 mg/day-treated patients compared to patients
treated with 10 mg was 2.2 units (p = 0.0001). The dose of 23 mg/day was statistically
significantly superior to the dose of 10 mg/day.
Figure 11. Time-course of the Change from Baseline in SIB Score for Patients Completing 24
Weeks of Treatment.
Page 7 of 9
Figure 12 illustrates the cumulative percentages of patients from each of the two treatment
groups who attained the measure of improvement in SIB score shown on the X-axis. While
patients assigned both to 23 mg/day and to 10 mg/day have a wide range of responses, the
curves show that the 23 mg-group is more likely to show a greater improvement in cognitive
performance. When such curves are shifted to the left, this indicates a greater percentage of
patients responding to treatment on the SIB.
Figure 12. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment
with Specified Changes from Baseline SIB Scores.
Effects on the CIBIC-plus: Figure 13 is a histogram of the frequency distribution of CIBICplus scores attained by patients at the end of 24 weeks of treatment. The mean difference
between the 23 mg/day and 10 mg/day treatment groups was 0.06 units. This difference was
not statistically significant.
16.1 Donepezil Hydrochloride Tablets
Donepezil Hydrochloride Tablets are available containing 23 mg of donepezil hydrochloride, USP.
The 23 mg tablets are pink, film-coated, round, unscored tablets debossed with M on one side
of the tablet and D N on the other side. They are available as follows:
NDC 0378-1025-93
NDC 0378-1025-77
NDC 0378-1025-05
Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.]
Instruct patients and caregivers to take donepezil hydrochloride only once per day, as prescribed.
Instruct patients and caregivers that donepezil hydrochloride can be taken with or without food.
Donepezil hydrochloride 23 mg tablets should be swallowed whole without the tablets being
split, crushed, or chewed.
Advise patients and caregivers that donepezil hydrochloride may cause nausea, diarrhea,
insomnia, vomiting, muscle cramps, fatigue, and decreased appetite.
PATIENT INFORMATION
DONEPEZIL HYDROCHLORIDE TABLETS
23 mg
(doe nep' e zil hye'' droe klor' ide)
Read the Patient Information that comes with donepezil hydrochloride
tablets before the patient starts taking it and each time you get a refill.
There may be new information. This leaflet does not take the place of talking
with the doctor about Alzheimer’s disease or treatment for it. If you have
questions, ask the doctor or pharmacist.
What is donepezil hydrochloride?
Donepezil hydrochloride tablets come as film-coated tablets in a dosage
strength of 23 mg.
Donepezil hydrochloride is a prescription medicine to treat mild, moderate,
and severe Alzheimer’s disease. Donepezil hydrochloride can help with
mental function and with doing daily tasks. Donepezil hydrochloride does
not work the same in all people. Some people may:
• Seem much better
• Get better in small ways or stay the same
• Get worse over time but slower than expected
• Not change and then get worse as expected
Donepezil hydrochloride tablets do not cure Alzheimer’s disease. All patients
with Alzheimer’s disease get worse over time, even if they take donepezil
hydrochloride tablets.
Donepezil hydrochloride tablets have not been approved as a treatment for
any medical condition in children.
Who should not take donepezil hydrochloride tablets?
The patient should not take donepezil hydrochloride tablets if allergic to any
of the ingredients in donepezil hydrochloride tablets or to medicines that
contain piperidines. Ask the patient’s doctor if you are not sure. See the end
of this leaflet for a list of ingredients in donepezil hydrochloride tablets.
What should I tell the doctor before the patient takes donepezil
hydrochloride tablets?
Tell the doctor about all the patient’s present or past health problems.
Include:
• Any heart problems including problems with irregular, slow, or fast
heartbeats
• Asthma or lung problems
• A seizure
• Stomach ulcers
• Difficulty passing urine
• Liver or kidney problems
• Trouble swallowing tablets
• Present pregnancy or plans to become pregnant. It is not known if
donepezil hydrochloride can harm an unborn baby.
• Present breast-feeding. It is not known if donepezil hydrochloride passes
into breast milk. Donepezil hydrochloride tablets are not for women who
are breast-feeding.
Tell the doctor about all the medicines the patient takes, including
prescription and non-prescription medicines, vitamins, and herbal products.
Donepezil hydrochloride tablets and other medicines may affect each other.
Be particularly sure to tell the doctor if the patient takes aspirin or medicines
called nonsteroidal anti-inflammatory drugs (NSAIDs). There are many
NSAID medicines, both prescription and non-prescription. Ask the doctor or
pharmacist if you are not sure if any of the patient’s medicines are NSAIDs.
Taking NSAIDs and donepezil hydrochloride tablets together may make the
patient more likely to get stomach ulcers.
Donepezil hydrochloride tablets taken with certain medicines used for
anesthesia may cause side effects. Tell the responsible doctor or dentist
that the patient takes donepezil hydrochloride tablets before the patient has:
• surgery
• medical procedures
• dental surgery or procedures.
Know the medicines that the patient takes. Keep a list of all the patient’s
medicines. Show it to the doctor or pharmacist before the patient starts a
new medicine.
How should the patient take donepezil hydrochloride tablets?
• Give donepezil hydrochloride tablets exactly as prescribed by the doctor.
Do not stop donepezil hydrochloride tablets or change the dose yourself.
Talk with the doctor first.
Page 8 of 9
• Give donepezil hydrochloride tablets one time each day. Donepezil hydro What are the ingredients in donepezil hydrochloride tablets?
chloride tablets can be taken with or without food.
Active Ingredient: donepezil hydrochloride, USP
without the tablets being split, crushed, or chewed.
lactose monohydrate, magnesium stearate, polyethylene glycol, red iron
oxide, sodium alginate, titanium dioxide, triacetin and yellow iron oxide.
• Donepezil hydrochloride 23 mg tablets should be swallowed whole Inactive Ingredients: ethylcellulose, hydroxypropyl cellulose, hypromellose,
• If you miss giving the patient a dose of donepezil hydrochloride tablets,
•
•
just wait. Give only the next dose at the usual time. Do not give 2 doses
at the same time.
If donepezil hydrochloride tablets are missed for 7 days or more, talk with
the doctor before starting again.
If the patient takes too much donepezil hydrochloride at one time, call the
doctor or poison control center, or go to the emergency room right away.
What are the possible side effects of donepezil hydrochloride tablets?
Donepezil hydrochloride tablets may cause the following serious side
effects:
• slow heartbeat and fainting. This happens more often in people with
heart problems. Call the doctor right away if the patient faints while
taking donepezil hydrochloride tablets.
• more stomach acid. This raises the chance of ulcers and bleeding,
especially when taking 23 mg donepezil hydrochloride tablets. The risk
is higher for patients who had ulcers, or take aspirin or other NSAIDs.
• worsening of lung problems in people with asthma or other lung disease.
• seizures.
• difficulty passing urine.
Call the doctor right away if the patient has:
• fainting.
• heartburn or stomach pain that is new or won’t go away.
• nausea or vomiting, blood in the vomit, dark vomit that looks like coffee
grounds.
• bowel movements or stools that look like black tar.
• new or worse asthma or breathing problems.
• seizures.
• difficulty passing urine.
The most common side effects of donepezil hydrochloride tablets are:
• nausea
• diarrhea
• not sleeping well
• vomiting
• muscle cramps
• feeling tired
• not wanting to eat
These side effects may get better after the patient takes donepezil
hydrochloride tablets for a while. This is not a complete list of side
effects with donepezil hydrochloride tablets. For more information, ask
the doctor or pharmacist.
Manufactured for:
Hyderabad—500 034, India
75057547MX:DNPZH:R4ppt
How should donepezil hydrochloride tablets be stored?
Store donepezil hydrochloride tablets at 20º to 25ºC (68º to 77ºF).
Keep donepezil hydrochloride tablets and all medicines out of the reach
of children.
General information about donepezil hydrochloride tablets
Medicines are sometimes prescribed for conditions that are not mentioned
in this Patient Information Leaflet. Do not use donepezil hydrochloride
tablets for a condition for which it was not prescribed. Do not give donepezil
hydrochloride tablets to people other than the patient, even if they have the
same symptoms as the patient, as it may harm them.
This leaflet summarizes the most important information about donepezil
hydrochloride tablets. If you would like more information talk with the
patient’s doctor. You can ask your pharmacist or doctor for information about
donepezil hydrochloride tablets that is written for health professionals. For
more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679
(1-877-4-INFO-RX).
Page 9 of 9
These highlights do not include all the information needed to use Fentanyl Transdermal
System safely and effectively. See full prescribing information for Fentanyl Transdermal
System.
FENTANYL transdermal system, for transdermal administration, CII
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION;
ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4
INTERACTION, and EXPOSURE TO HEAT
• Fentanyl transdermal system exposes users to risks of addiction, abuse, and misuse, which
can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor
regularly for development of these behaviors or conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2)
• Accidental exposure to fentanyl transdermal system, especially in children, can result in
fatal overdose of fentanyl. (5.3)
• Prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid
use is required for a prolonged period in a pregnant woman, advise the patient of the risk
of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.4)
• Initiation of CYP 3A4 inhibitors (or discontinuation of CYP 3A4 inducers) can result in a fatal
overdose of fentanyl from fentanyl transdermal system. (5.10)
• Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources. Temperature dependent increases in fentanyl release from the
system may result in overdose and death. (5.11)
-------------------------------------- RECENT MAJOR CHANGES -------------------------------------Boxed Warning
04/2014
Indications and Usage (1)
04/2014
Dosage and Administration (2)
04/2014
Warnings and Precautions (5)
04/2014
------------------------------------ INDICATIONS AND USAGE ----------------------------------• Fentanyl transdermal system is indicated for the management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for
which alternative treatment options are inadequate. (1)
• Patients considered opioid-tolerant are those who are taking, for one week or longer, at least
60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral
hydromorphone daily, or an equianalgesic dose of another opioid. (1)
Limitations of use:
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended
doses, and because of the greater risks of overdose and death with extended-release opioid
formulations, reserve fentanyl transdermal system for use in patients for whom alternative
treatment options (i.e., non-opioid analgesics or immediate-release opioids) are ineffective,
not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1)
----------------------------------- DOSAGE AND ADMINISTRATION -----------------------------• For use in opioid-tolerant patients only.
• Initial dose selection: consult conversion instructions. (2.1)
• Each transdermal system is intended to be worn for 72 hours. (2.2)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION: ACCIDENTAL EXPOSURE;
NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME
P450 3A4 INTERACTION; and EXPOSURE TO HEAT
Boxed Warning
2.1 Initial Dosing
2.2 Titration and Maintenance of Therapy
2.3 Administration of Fentanyl Transdermal System
2.4 Disposal Instructions
2.5 Discontinuation of Fentanyl Transdermal System
4 CONTRAINDICATIONS
5.1 Addiction, Abuse, and Misuse
5.2 Life-Threatening Respiratory Depression
5.3 Accidental Exposure
5.4 Neonatal Opioid Withdrawal Syndrome
5.5 Interactions with Central Nervous System Depressants
5.6 Use in Elderly, Cachectic, and Debilitated Patients
5.7 Chronic Pulmonary Disease
5.8 Head Injuries and Increased Intracranial Pressure
5.9 Hypotensive Effects
• Adhere to instructions concerning administration and disposal of fentanyl transdermal system. (2.4)
• Reduce the dose with hepatic, and renal impairment. (2.1)
------------------------------- DOSAGE FORMS AND STRENGTHS -------------------------------Transdermal system: 12 mcg/hr, 25 mcg/hr, 37.5 mcg/hr, 50 mcg/hr, 62.5 mcg/hr, 75 mcg/hr, 87.5
mcg/hr, 100 mcg/hr. (3)
------------------------------------- CONTRAINDICATIONS -------------------------------------• Opioid non-tolerant patients. (4)
• Acute or intermittent pain, postoperative pain, mild pain. (4)
• Respiratory compromise, acute or severe asthma. (4)
• Paralytic ileus. (4)
• Known hypersensitivity to fentanyl or any of the components of the transdermal system. (4)
--------------------------------- WARNINGS AND PRECAUTIONS -------------------------------• Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory
depression, and death. If co-administration is required, consider dose reduction of one or
both drugs because of pharmacological effects. (5.5)
• Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor
closely because of increased risk for life-threatening respiratory depression. (5.6, 5.7)
• Hypotensive effects: Monitor during dose initiation and titration. (5.9)
• Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of fentanyl transdermal system in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.8)
• Bradycardia. Administer with caution to patients with bradyarrhythmias. (5.13)
-------------------------------------- ADVERSE REACTIONS ------------------------------------Most common adverse reactions (≥ 5%) are nausea, vomiting, somnolence, dizziness, insomnia,
constipation, hyperhidrosis, fatigue, feeling cold, anorexia, headache, and diarrhea. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-4463679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------------- DRUG INTERACTIONS -----------------------------------• Mixed agonist/antagonist and partial agonist opioid analgesics: Avoid use with fentanyl
transdermal system because they may reduce analgesic effect of fentanyl transdermal system
or precipitate withdrawal symptoms. (5.1, 7.4)
• Monoamine oxidase inhibitors (MAOIs): Avoid fentanyl transdermal system in patients taking
MAOIs or within 14 days of stopping such treatment. (7.3)
----------------------------------- USE IN SPECIFIC POPULATIONS ----------------------------• Pregnancy: Based on animal data, may cause fetal harm. (8.1)
• Nursing Mothers: Breast-feeding is not advised in mothers treated with fentanyl transdermal
system. (8.3)
• Pediatric Use: Safety and efficacy in pediatric patients below the age of 2 years have not
been established. To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl transdermal system. (8.4)
• Geriatric Use: Administer fentanyl transdermal system with caution, and in reduced dosages
in elderly patients. (8.5)
• Hepatic or Renal Impairment: Administer fentanyl transdermal system with caution. Monitor
for signs of fentanyl toxicity and reduce dosage, if necessary. (8.6, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
5.10 Interactions with CYP3A4 Inhibitors and Inducers
5.11 Application of External Heat
5.12 Patients with Fever
5.13 Cardiac Disease
5.16 Use in Pancreatic/Biliary Tract Disease
5.17 Avoidance of Withdrawal
5.18 Driving and Operating Machinery
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Central Nervous System Depressants
7.2 Drugs Affecting Cytochrome P450 3A4 Isoenzymes
7.3 MAO Inhibitors
7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid
Analgesics
7.5 Anticholinergics
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
Revised: MAY 2014
FTS:R22/MG:FTS:R8
9
10
11
12
13
14
16
17
9.1 Controlled Substance
9.2 Abuse
9.3 Dependence
OVERDOSAGE
10.1 Clinical Presentation
10.2 Treatment of Overdose
DESCRIPTION
NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of
Fertility
CLINICAL STUDIES
[*Sections or subsections omitted from the full prescribing information are not listed]
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WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY
DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME;
CYTOCHROME P450 3A4 INTERACTION; and EXPOSURE TO HEAT
Addiction, Abuse, and Misuse
Fentanyl transdermal system exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s
risk prior to prescribing fentanyl transdermal system, and monitor all patients regularly
for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of fentanyl
transdermal system, even when used as recommended. Monitor for respiratory depression,
especially during initiation of fentanyl transdermal system or following a dose increase.
Because of the risk of respiratory depression, fentanyl transdermal system is contraindicated for use as an as-needed analgesic, in non-opioid tolerant patients, in acute pain, and
in postoperative pain [see Contraindications (4) and Warnings and Precautions (5.2)].
Accidental Exposure
Deaths due to a fatal overdose of fentanyl have occurred when children and adults were
accidentally exposed to fentanyl transdermal system. Strict adherence to the recommended
handling and disposal instructions is of the utmost importance to prevent accidental exposure [see Warnings and Precautions (5.3)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and
requires management according to protocols developed by neonatology experts. If opioid
use is required for a prolonged period in a pregnant woman, advise the patient of the risk
of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)].
Cytochrome P450 3A4 Interaction
The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase
or prolong adverse drug effects and may cause potentially fatal respiratory depression. In
addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result
in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.10)
and Clinical Pharmacology (12.3)].
Exposure To Heat
Exposure of the fentanyl transdermal system application site and surrounding area to direct
external heat sources, such as heating pads or electric blankets, heat or tanning lamps,
sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl and death [see Warnings and Precautions (5.11)]. Patients wearing fentanyl transdermal systems who develop fever or
increased core body temperature due to strenuous exertion are also at risk for increased
fentanyl exposure and may require an adjustment in the dose of fentanyl transdermal system to avoid overdose and death [see Warnings and Precautions (5.12)].
1
Fentanyl transdermal system is indicated for the management of pain in opioid-tolerant patients,
severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Patients considered opioid-tolerant are those who are taking, for one week or longer, at least
60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.
Limitations of Use
•
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended
doses, and because of the greater risks of overdose and death with extended-release
opioid formulations, reserve fentanyl transdermal system for use in patients for whom alternative treatment options (i.e., non-opioid analgesics or immediate-release opioids) are
ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
2
2.1 Initial Dosing
Fentanyl transdermal system should be prescribed only by healthcare professionals who are
knowledgeable in the use of potent opioids for the management of chronic pain.
Due to the risk of respiratory depression, fentanyl transdermal system is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when
beginning fentanyl transdermal system therapy. As fentanyl transdermal system is only for use in opioid-tolerant patients, do not begin any patient on fentanyl transdermal system as the first opioid.
Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily,
or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an
equianalgesic dose of another opioid for a week or longer.
Initiate the dosing regimen for each patient individually, taking into account the patient's prior
analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings
and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the
first 24 to 72 hours of initiating therapy with fentanyl transdermal system when serum concentrations from the initial patch will peak [see Warnings and Precautions (5.2)].
The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose.
Discontinue all other around-the-clock opioid drugs when fentanyl transdermal system therapy is
initiated.
While there are useful tables of opioid equivalents readily available, there is substantial interpatient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour fentanyl requirements and provide rescue medication
(i.e., immediate-release opioid) than to overestimate the 24-hour fentanyl requirements which
could result in adverse reactions. In a fentanyl transdermal system clinical trial, patients were
converted from their prior opioid to fentanyl transdermal system using Table 1 as a guide for the
initial fentanyl transdermal system dose.
Consider the following when using the information in Table 1:
• This is not a table of equianalgesic doses.
• The conversion doses in this table are only for the conversion from one of the listed oral or
parenteral opioid analgesics to fentanyl transdermal system.
• The table cannot be used to convert from fentanyl transdermal system to another opioid.
Doing so will result in an overestimation of the dose of the new opioid and may result in
fatal overdose.
To convert patients from oral or parenteral opioids to fentanyl transdermal system, use Table 1. Do
not use Table 1 to convert from fentanyl transdermal system to other therapies because this
conversion to fentanyl transdermal system is conservative and will overestimate the dose of
the new agent.
Table 11: DOSE CONVERSION TO FENTANYL TRANSDERMAL SYSTEM
Current Analgesic
Daily Dosage (mg/day)
Oral morphine
60 to 134
135 to 224
225 to 314
315 to 404
Intramuscular or
10 to 22
23 to 37
38 to 52
53 to 67
Intravenous morphine
Oral oxycodone
30 to 67
67.5 to 112
112.5 to 157 157.5 to 202
Oral codeine
150 to 447
Oral hydromorphone
8 to 17
17.1 to 28
28.1 to 39
39.1 to 51
Intravenous hydromorphone 1.5 to 3.4
3.5 to 5.6
5.7 to 7.9
8 to 10
Intramuscular meperidine
75 to 165
166 to 278
279 to 390
391 to 503
Oral methadone
20 to 44
45 to 74
75 to 104
105 to 134
fl
fl
fl
fl
Recommended Fentanyl
25 mcg/hour
50 mcg/hour 75 mcg/hour 100 mcg/hour
Transdermal System Dose
Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the conversion
methodology outlined above with Table 2.
1 Table 1 should not be used to convert from fentanyl transdermal system to other therapies because this
conversion to fentanyl transdermal system is conservative. Use of Table 1 for conversion to other analgesic
therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible
[see Dosage and Administration (2.3)].
Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the
following methodology:
1. Calculate the previous 24-hour analgesic requirement.
2. Convert this amount to the equianalgesic oral morphine dose using a reliable reference.
Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to
each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose
and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after
the initial dose and every 6 days thereafter) until analgesic efficacy is attained.
3. Do not use Table 2 to convert from fentanyl transdermal system to other therapies because
this conversion to fentanyl transdermal system is conservative and will overestimate the dose of
the new agent.
Table 21: RECOMMENDED INITIAL FENTANYL TRANSDERMAL SYSTEM DOSE BASED UPON DAILY
ORAL MORPHINE DOSE
Oral 24 hour
Fentanyl Transdermal System
Morphine
Dose
(mg/day)
(mcg/hour)
60 to 134
25
135 to 224
50
225 to 314
75
315 to 404
100
405 to 494
125
495 to 584
150
585 to 674
175
675 to 764
200
765 to 854
225
855 to 944
250
945 to 1034
275
1035 to 1124
300
NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal system.
1 Table 2 should not be used to convert from fentanyl transdermal system to other therapies because this
conversion to fentanyl transdermal system is conservative. Use of Table 2 for conversion to other analgesic
therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible
[see Dosage and Administration (2.5)].
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For delivery rates in excess of 100 mcg/hour, multiple systems may be used.
For patients that may be more sensitive to the effects of opioids, additional intermediate
strengths may be considered during conversion from prior opioids or titrating the dose of the
fentanyl transdermal system. For example, rather than converting or titrating to a 50 mcg/hr
system, a 37.5 mcg/hr system is available. Similarly a 62.5 mcg/hr system is available for
use as an intermediate strength between the 50 mcg/hr and the 75 mcg/hr system, and an
87.5 mcg/hr system is available as an intermediate strength between the 75 mcg/hr system
and the 100 mcg/hr system.
The additional intermediate strengths, 32.5 mcg/hr, 62.5 mcg/hr and 87.5 mcg/hr, were not
used in the clinical studies.
Hepatic Impairment: Avoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of
the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.14),
Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Renal Impairment: Avoid the use of fentanyl transdermal system in patients with severe renal
impairment. In patients with mild to moderate renal impairment, start with one half of the usual
dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory
depression, including at each dosage increase [see Warnings and Precautions (5.15), Use in
Specific Populations (8.7) and Clinical Pharmacology (12.3)].
2.2 Titration and Maintenance of Therapy
Individually titrate fentanyl transdermal system to a dose that provides adequate analgesia and
minimizes adverse reactions. Continually reevaluate patients receiving fentanyl transdermal
system to assess the maintenance of pain control and the relative incidence of adverse reactions,
as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient,
and the caregiver/family during periods of changing analgesic requirements, including initial
titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.
The dosing interval for fentanyl transdermal system is 72 hours. Do not increase the fentanyl
transdermal system dose for the first time until at least 3 days after the initial application.
Titrate the dose based on the daily dose of supplemental opioid analgesics required by the patient
on the second or third day of the initial application.
It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose [see Clinical Pharmacology (12.3)]. Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made.
Base dosage increments on the daily dosage of supplementary opioids, using the ratio of
45 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal system
dose.
If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be
reduced. Adjust the dose to obtain an appropriate balance between management of pain and
opioid-related adverse reactions.
A small proportion of adult patients may not achieve adequate analgesia using a 72-hour dosing
interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate
pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal
system dose should be evaluated before changing dosing intervals in order to maintain patients
on a 72-hour regimen.
Dosing intervals less than every 72 hours were not studied in children and adolescents and are
not recommended.
2.3 Administration of Fentanyl Transdermal System
Fentanyl transdermal system patches are for transdermal use, only.
Proper handling of fentanyl transdermal system is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to fentanyl
transdermal system [see Warnings and Precautions (5.3)].
Application and Handling Instructions
•
Patients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children
and persons with cognitive impairment, adhesion should be monitored and the upper back
is the preferred location to minimize the potential of inappropriate patch removal. Hair at
the application site may be clipped (not shaved) prior to system application. If the site of
fentanyl transdermal system application must be cleansed prior to application of the
patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents
that might irritate the skin or alter its characteristics. Allow the skin to dry completely
prior to patch application.
•
Patients should apply fentanyl transdermal system immediately upon removal from the
sealed package. The patch must not be altered (i.e., cut) in any way prior to application.
Fentanyl transdermal system should not be used if the pouch seal is broken or if the patch
is cut or damaged.
•
The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.
•
Each fentanyl transdermal system patch may be worn continuously for 72 hours. The next
patch is applied to a different skin site after removal of the previous transdermal system.
•
If problems with adhesion of the fentanyl transdermal system patch occur, the edges of
the patch may be taped with first aid tape. If problems with adhesion persist, the patch
may be overlayed with a transparent adhesive film dressing (i.e., BIOCLUSIVE® or Askina®Derm).
•
If the patch falls off before 72 hours, dispose of it by folding in half and flushing down
the toilet. A new patch may be applied to a different skin site.
•
Patients (or caregivers who apply fentanyl transdermal system) should wash their hands
immediately with soap and water after applying fentanyl transdermal system.
•
Contact with unwashed or unclothed application sites can result in secondary exposure
to fentanyl transdermal system and should be avoided. Examples of accidental exposure
include transfer of a fentanyl transdermal system patch from an adult’s body to a child
while hugging, sharing the same bed as the patient, accidental sitting on a patch and
possible accidental exposure of a caregiver’s skin to the medication in the patch while
applying or removing the patch.
•
Instruct patients, family members, and caregivers to keep patches in a secure location
out of the reach of children and of others for whom fentanyl transdermal system was not
prescribed.
Avoidance of Heat: Instruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric
blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water
beds, while wearing the system [see Warnings and Precautions (5. 11)].
2.4 Disposal Instructions
Failure to properly dispose of fentanyl transdermal system has resulted in accidental exposures
and deaths [see Warnings and Precautions (5.3)].
Patients should dispose of used patches immediately upon removal by folding the adhesive side
of the patch to itself, then flushing down the toilet.
Unused patches should be removed from their pouches, the protective liners removed, the
patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed
down the toilet.
Patients should dispose of any patches remaining from a prescription as soon as they are no
longer needed.
2.5 Discontinuation of Fentanyl Transdermal System
Significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after
the patch is removed [see Clinical Pharmacology (12.3)].
To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose
of the new analgesic based upon the patient’s report of pain until adequate analgesia has been
attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Withdrawal symptoms are possible in some patients after conversion or
dose adjustment [see Warnings and Precautions (5.17)].
Do not use Tables 1 and 2 to convert from fentanyl transdermal system to other therapies to
avoid overestimating the dose of the new agent resulting in overdose of the new analgesic and
possibly death.
When discontinuing fentanyl transdermal system and not converting to another opioid, use a gradual downward titration, such as halving the dose every 6 days, in order to reduce the possibility of
withdrawal symptoms [see Warnings and Precautions (5.17)]. It is not known at what dose level
fentanyl transdermal system may be discontinued without producing the signs and symptoms of
opioid withdrawal.
3
Fentanyl transdermal system is available as:
•
Fentanyl Transdermal System 12 mcg/hour* (system size 3.13 cm2).
•
Fentanyl Transdermal System 25 mcg/hour (system size 6.25 cm2).
•
Fentanyl Transdermal System 37.5 mcg/hour (system size 9.38 cm²).
•
•
•
•
•
Fentanyl Transdermal System 100 mcg/hour (system size 25 cm2).
*This lowest dosage is designated as 12 mcg/hour (however, the actual dosage is 12.5 mcg/hour) to distinguish
it from a 125 mcg/hour dosage that could be prescribed by multiple patches.
4
CONTRAINDICATIONS
Fentanyl transdermal system is contraindicated in the following patients and situations:
•
in patients who are not opioid-tolerant.
•
in the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time.
•
in the management of post-operative pain, including use after out-patient or day surgeries,
(i.e., tonsillectomies).
•
in the management of mild pain.
•
in patients with significant respiratory compromise, especially if adequate monitoring
and resuscitative equipment are not readily available.
•
in patients who have acute or severe bronchial asthma.
•
in patients who have or are suspected of having paralytic ileus.
•
in patients with known hypersensitivity to fentanyl or any components of the transdermal
system. Severe hypersensitivity reactions, including anaphylaxis have been observed with
fentanyl transdermal system [see Adverse Reactions (6.2)].
5
5.1 Addiction, Abuse, and Misuse
Fentanyl transdermal system contains fentanyl, an opioid agonist and a Schedule II controlled
substance. As an opioid, fentanyl transdermal system exposes users to the risks of addiction,
abuse, and misuse [see Drug Abuse and Dependence (9)]. As modified-release products such
as fentanyl transdermal system deliver the opioid over an extended period of time, there is a
greater risk for overdose and death due to the larger amount of fentanyl present.
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Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed fentanyl transdermal system and in those who obtain the drug illicitly. Addiction can
occur at recommended doses and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing fentanyl
transdermal system, and monitor all patients receiving fentanyl transdermal system for the development of these behaviors or conditions. Risks are increased in patients with a personal or
family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness
(i.e., major depression). The potential for these risks should not, however, prevent the prescribing
of fentanyl transdermal system for the proper management of pain in any given patient. Patients
at increased risk may be prescribed modified-release opioid formulations such as fentanyl transdermal system, but use in such patients necessitates intensive counseling about the risks and
proper use of fentanyl transdermal system along with intensive monitoring for signs of addiction,
abuse, and misuse.
Abuse or misuse of fentanyl transdermal system by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death [see
Overdosage (10)].
Opioid agonists such as fentanyl transdermal system are sought by drug abusers and people
with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing fentanyl transdermal system. Strategies to reduce these risks include
prescribing the drug in the smallest appropriate quantity and advising the patient on the proper
disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent
and detect abuse or diversion of this product.
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids,
even when used as recommended. Respiratory depression from opioid use, if not immediately
recognized and treated, may lead to respiratory arrest and death. Management of respiratory
depression may include close observation, supportive measures, and use of opioid antagonists,
depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention
from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Fentanyl transdermal system is indicated only in opioid tolerant patients because of the risk for
respiratory depression and death. While serious, life-threatening, or fatal respiratory depression
can occur at any time during the use of fentanyl transdermal system, the risk is greatest during
the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with fentanyl transdermal system.
To reduce the risk of respiratory depression, proper dosing and titration of fentanyl transdermal
system are essential [see Dosage and Administration (2)]. Overestimating the fentanyl transdermal system dose when converting patients from another opioid product can result in fatal overdose
with the first dose.
Accidental exposure to fentanyl transdermal system, especially in children, can result in respiratory depression and death due to an overdose of fentanyl.
5.3 Accidental Exposure
A considerable amount of active fentanyl remains in fentanyl transdermal system even after use
as directed. Death and other serious medical problems have occurred when children and adults
were accidentally exposed to fentanyl transdermal system. Accidental or deliberate application
or ingestion by a child or adolescent will cause respiratory depression that can result in death.
Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways
other than indicated may cause choking or overdose that could result in death. Improper disposal
of fentanyl transdermal system in the trash has resulted in accidental exposures and deaths.
Advise patients about strict adherence to the recommended handling and disposal instructions
in order to prevent accidental exposure to fentanyl transdermal system [see Dosage and Administration (2.4), (2.5)].
5.4 Neonatal Opioid Withdrawal Syndrome
Prolonged use of fentanyl transdermal system during pregnancy can result in withdrawal signs
in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in
adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged
period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep
pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid
used, duration of use, timing and amount of last maternal use, and rate of elimination of the
drug by the newborn.
5.5 Interactions with Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, and death may result if fentanyl
transdermal system is used concomitantly with alcohol or other central nervous system (CNS)
depressants (i.e., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of fentanyl transdermal system in a patient taking a CNS depressant,
assess the duration use of the CNS depressant and the patient’s response, including the degree
of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of
alcohol or illicit drugs that cause CNS depression. If the decision to begin fentanyl transdermal
system is made, reduce the starting dose, monitor patients for signs of sedation and respiratory
depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.1)].
5.6 Use in Elderly, Cachectic, and Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated
patients as they may have altered pharmacokinetics or altered clearance compared to younger,
healthier patients. Monitor such patients closely, particularly when initiating and titrating fentanyl
transdermal system and when fentanyl transdermal system is given concomitantly with other
drugs that depress respiration [see Warnings and Precautions (5.2)].
5.7 Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting
respiratory depression for respiratory depression, particularly when initiating therapy with fentanyl
transdermal system, as in these patients, even usual therapeutic doses of fentanyl transdermal
system may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)].
Consider the use of alternative non-opioid analgesics in these patients if possible.
5.8 Head Injuries and Increased Intracranial Pressure
Avoid use of fentanyl transdermal system in patients who may be particularly susceptible to the
intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure,
impaired consciousness, or coma [see Warnings and Precautions (5.2)]. In addition, opioids may
obscure the clinical course of patients with head injury. Monitor patients with brain tumors who
may be susceptible to the intracranial effects of CO2 retention for signs of sedation and respiratory
depression, particularly when initiating therapy with fentanyl transdermal system, as fentanyl
transdermal system may reduce respiratory drive and CO2 retention can further increase intracranial
pressure.
5.9 Hypotensive Effects
Fentanyl transdermal system may cause severe hypotension including orthostatic hypotension and
syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain
blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (i.e., phenothiazines or general anesthetics) [see Drug Interactions (7.1)]. Monitor these patients for signs of hypotension after initiating or titrating the dose
of fentanyl transdermal system.
5.10 Interactions with CYP3A4 Inhibitors and Inducers
Since the CYP3A4 isoenzyme plays a major role in the metabolism of fentanyl transdermal system,
drugs that alter CYP3A4 activity may cause changes in clearance of fentanyl which could lead to
changes in fentanyl plasma concentrations.
The concomitant use of fentanyl transdermal system with a CYP3A4 inhibitors (such as ritonavir,
ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse
drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients
receiving fentanyl transdermal system and any CYP3A4 inhibitor for signs of sedation and respiratory depression for an extended period of time, and make dosage adjustments as needed.
CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism
of fentanyl and, therefore, may cause increased clearance of the drug which could lead to a decrease in fentanyl plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to fentanyl.
If co-administration is necessary, caution is advised when initiating fentanyl transdermal system
treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate
these patients at frequent intervals and consider dose adjustments until stable drug effects are
achieved [see Drug Interactions (7.2), and Clinical Pharmacology (12.3)].
5.11 Application of External Heat
Exposure to heat may increase fentanyl absorption and there have been reports of overdose and
death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult
subjects has shown that the application of heat over the fentanyl transdermal system increased
fentanyl exposure [see Clinical Pharmacology (12.3)].
Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources [see Dosage and Administration (2.3)].
5.12 Patients with Fever
Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase
by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Monitor patients wearing fentanyl transdermal systems who develop fever closely for
opioid side effects and reduce the fentanyl transdermal system dose if necessary. Warn patients
to avoid strenuous exertion that leads to increased core body temperature while wearing fentanyl
transdermal system to avoid the risk of potential overdose and death.
5.13 Cardiac Disease
Fentanyl transdermal system may produce bradycardia. Monitor patients with bradyarrhythmias
closely for changes in heart rate, particularly when initiating therapy with fentanyl transdermal
system.
A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has
shown that systemic fentanyl exposure increased in these patients. Because of the long halflife of fentanyl when administered as fentanyl transdermal system and hepatic metabolism of
fentanyl, avoid use of fentanyl transdermal system in patients with severe hepatic impairment.
Insufficient information exists to make precise dosing recommendations regarding the use of
fentanyl transdermal system in patients with impaired hepatic function. Therefore, to avoid
starting patients with mild to moderate hepatic impairment on too high of a dose, start with
one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation
and respiratory depression, including at each dosage increase [see Dosing and Administration
(2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance.
Page 4 of 12
Because of the long half-life of fentanyl when administered as fentanyl transdermal system,
avoid the use of fentanyl transdermal system in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl
transdermal system in patients with impaired renal function. Therefore, to avoid starting patients
with mild to moderate renal impairment on too high of a dose, start with one half of the usual
dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory
depression, including at each dosage increase [see Dosing and Administration (2.2), Use in
Specific Populations (8.7) and Clinical Pharmacology (12.3)].
5.16 Use in Pancreatic/Biliary Tract Disease
Fentanyl transdermal system may cause spasm of the sphincter of Oddi. Monitor patients with
biliary tract disease, including acute pancreatitis for worsened symptoms. Fentanyl transdermal
system may cause increases in the serum amylase concentration.
5.17 Avoidance of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or
partial agonist (buprenorphine) analgesics in patients who have received or are receiving a
course of therapy with an opioid agonist analgesic, including fentanyl transdermal system. In
these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
5.18 Driving and Operating Machinery
Strong opioid analgesics impair the mental or physical abilities required for the performance of
potentially dangerous tasks, such as driving a car or operating machinery. Warn patients not to
drive or operate dangerous machinery unless they are tolerant to the effects of the fentanyl
transdermal system.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
•
Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
•
Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
•
Accidental Exposure [see Warnings and Precautions (5.3)]
•
Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
•
Interactions with Central Nervous System Depressants [see Warnings and Precautions (5.5)]
•
Hypotensive Effects [see Warnings and Precautions (5.9)]
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
The safety of fentanyl transdermal system was evaluated in 216 patients who took at least one
dose of fentanyl transdermal system in a multicenter, double-blind, randomized, placebo-controlled clinical trial of fentanyl transdermal system. This trial examined patients over 40 years
of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and
waiting for joint replacement.
The most common adverse reactions (≥ 5%) in a double-blind, randomized, placebo-controlled
clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions (≥ 5%) reported in clinical trials in patients with chronic malignant or nonmalignant
pain were headache and diarrhea. Adverse reactions reported for ≥ 1% of fentanyl transdermal
system-treated patients and with an incidence greater than placebo-treated patients are shown
in Table 3.
The most common adverse reactions that were associated with discontinuation in patients with
pain (causing discontinuation in ≥ 1% of patients) were depression, dizziness, somnolence,
headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.
Table 3. Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Patients and With an Incidence Greater Than Placebo-treated Patients in 1 DoubleBlind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal System
Placebo
System/Organ Class
%
%
Adverse Reaction
(N = 216)
(N = 200)
Cardiac disorders
Palpitations
4
1
Ear and labyrinth disorders
Vertigo
2
1
Gastrointestinal disorders
Nausea
41
17
Vomiting
26
3
Constipation
9
1
Abdominal pain upper
3
2
Dry mouth
2
0
General disorders and administration site conditions
Fatigue
6
3
Feeling cold
6
2
Malaise
4
1
Asthenia
2
0
Edema peripheral
1
1
Metabolism and nutrition disorders
Anorexia
5
0
Musculoskeletal and connective tissue disorders
Muscle spasms
4
2
continued
Table 3. Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Patients and With an Incidence Greater Than Placebo-treated Patients in 1 DoubleBlind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal System
Placebo
System/Organ Class
%
%
Adverse Reaction
(N = 216)
(N = 200)
Nervous system disorders
Somnolence
19
3
Dizziness
10
4
Psychiatric disorders
Insomnia
10
7
Depression
1
0
Skin and subcutaneous tissue disorders
Hyperhidrosis
6
1
Pruritus
3
2
Rash
2
1
Adverse reactions not reported in Table 1 that were reported by ≥ 1% fentanyl transdermal systemtreated adult and pediatric patients (N = 1,854) in 11 controlled and uncontrolled clinical trials of
fentanyl transdermal system used for the treatment of chronic malignant or nonmalignant pain are
shown in Table 4.
Table 4. Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Patients in 11 Clinical Trials of Fentanyl Transdermal System
System/Organ Class
%
Adverse Reaction
(N = 1,854)
Diarrhea
10
Abdominal pain
3
Immune system disorders
Hypersensitivity
1
Headache
12
Tremor
3
Paresthesia
2
Anxiety
3
Confusional state
2
Hallucination
1
Renal and urinary disorders
Urinary retention
1
Erythema
1
The following adverse reactions occurred in adult and pediatric patients with an overall frequency
of < 1% and are listed in descending frequency within each System/Organ Class:
Cardiac disorders: cyanosis
Eye disorders: miosis
Gastrointestinal disorders: subileus
General disorders and administration site conditions: application site reaction, influenzalike illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitis
Musculoskeletal and connective tissue disorders: muscle twitching
Nervous system disorders: hypoesthesia
Psychiatric disorders: disorientation, euphoric mood
Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction
Respiratory, thoracic and mediastinal disorders: respiratory depression
Skin and subcutaneous tissue disorders: eczema, dermatitis allergic, dermatitis contact
Pediatrics: The safety of fentanyl transdermal system was evaluated in three open-label trials in
289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Adverse reactions
reported by ≥ 1% fentanyl transdermal system-treated pediatric patients are shown in Table 5.
Table 5. Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Pediatric Patients in 3 Clinical Trials of Fentanyl Transdermal System
System/Organ Class
%
Adverse Reaction
(N = 289)
Vomiting
34
Nausea
24
Constipation
13
Diarrhea
13
Abdominal pain
9
4
Dry mouth
2
General disorders and administration site conditions
Edema peripheral
5
Fatigue
2
Application site reaction
1
continued
Page 5 of 12
Table 5. Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Pediatric Patients in 3 Clinical Trials of Fentanyl Transdermal System
System/Organ Class
%
Adverse Reaction
(N = 289)
Asthenia
1
Immune system disorders
Hypersensitivity
3
Anorexia
4
Musculoskeletal and connective tissue disorders
Muscle spasms
2
Headache
16
Somnolence
5
Dizziness
2
Tremor
2
Hypoesthesia
1
Insomnia
6
Anxiety
4
Depression
2
Hallucination
2
Renal and urinary disorders
Urinary retention
3
Respiratory, thoracic and mediastinal disorders
Respiratory depression
1
Pruritus
13
Rash
6
Hyperhidrosis
3
Erythema
3
The following adverse reactions have been identified during post-approval use of fentanyl transdermal system. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency.
Cardiac Disorders: tachycardia, bradycardia
Eye Disorders: vision blurred
Gastrointestinal Disorders: ileus, dyspepsia
General Disorders and Administration Site Conditions: pyrexia
Immune System Disorders: anaphylactic shock, anaphylactic reaction, anaphylactoid reaction
Investigations: weight decreased
Nervous System Disorders: convulsions (including clonic convulsions and grand mal convulsion),
amnesia, depressed level of consciousness, loss of consciousness
Psychiatric Disorders: agitation
Respiratory, Thoracic, and Mediastinal Disorders: respiratory distress, apnea, bradypnea, hypoventilation, dyspnea
Vascular Disorders: hypotension, hypertension
7
DRUG INTERACTIONS
7.1 Central Nervous System Depressants
The concomitant use of fentanyl transdermal system with other CNS depressants, including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, can
increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients
receiving CNS depressants and fentanyl transdermal system for signs of respiratory depression,
sedation and hypotension.
When combined therapy with any of the above medications is considered, the dose of one or both
agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions
(5.5)].
7.2 Drugs Affecting Cytochrome P450 3A4 Isoenzymes
Inhibitors of CYP3A4: Because the CYP3A4 isoenzyme plays a major role in the metabolism of
fentanyl, drugs that inhibit CYP3A4 activity may cause decreased clearance of fentanyl which
could lead to an increase in fentanyl plasma concentrations and result in increased or prolonged
opioid effects. These effects could be more pronounced with concomitant use of 3A4 inhibitors.
If coadministration with fentanyl transdermal system is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable
drug effects are achieved [see Clinical Pharmacology (12.3)].
Inducers of CYP3A4: CYP450 3A4 inducers may induce the metabolism of fentanyl and, therefore, may cause increased clearance of the drug which could lead to a decrease in fentanyl
plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in
a patient who had developed physical dependence to fentanyl. If co-administration with fentanyl
transdermal system is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl
plasma concentration will increase which could increase or prolong both the therapeutic and adverse
effects, and may cause serious respiratory depression [see Clinical Pharmacology (12.3)].
7.3 MAO Inhibitors
Avoid use of fentanyl transdermal system in the patient who would require the concomitant ad-
ministration of a monoamine oxidase (MAO) inhibitor, or within 14 days of stopping such treatment because severe and unpredictable potentiation by MAO inhibitors has been reported with
opioid analgesics.
7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist
(buprenorphine) analgesics may reduce the analgesic effect of fentanyl transdermal system or may
precipitate withdrawal symptoms. Avoid the use of agonist/antagonist and partial agonist analgesics in patients receiving fentanyl transdermal system.
7.5 Anticholinergics
Anticholinergics or other medications with anticholinergic activity when used concurrently with
opioid analgesics may result in increased risk of urinary retention and/or severe constipation,
which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastrointestinal motility when fentanyl transdermal system is used concurrently with anticholinergic
drugs.
8
8.1 Pregnancy
Clinical Considerations
Fetal/neonatal adverse reactions: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid
withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures,
and manage accordingly [see Warnings and Precautions (5.4)].
Teratogenic Effects
Pregnancy C: There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse,
and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or
500 mcg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted micro
osmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis).
In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female
rats from gestation day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in
mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity
noted.
Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg)
via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease
in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity.
Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on
embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose
administered by a 100 mcg/hr patch on a mg/m2 basis).
Nonteratogenic Effects
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient
respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence
syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were
no more frequent than expected in most studies of infants born to women treated acutely during
labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat
model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment
(0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased
survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated
alterations in some physical landmarks of development (delayed incisor eruption and eye opening)
and transient behavioral development (decreased locomotor activity at day 28 which recovered
by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis.
Opioids cross the placenta and may produce respiratory depression in neonates. Fentanyl transdermal system is not for use in women during and immediately prior to labor, when shorter acting
analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong
labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical
dilatation, which tends to shorten labor.
8.3 Nursing Mothers
Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended
for use in nursing women because of the possibility of effects in their infants.
8.4 Pediatric Use
The safety of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of
25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at
least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl
transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine
or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials.
The safety and effectiveness of fentanyl transdermal system in children under 2 years of age have
not been established.
To guard against excessive exposure to fentanyl transdermal system by young children, advise caregivers to strictly adhere to recommended fentanyl transdermal system application and disposal
Page 6 of 12
instructions [see Dosage and Administration (2.4), (2.5) and Warnings and Precautions (5.3)].
8.5 Geriatric Use
Clinical studies of fentanyl transdermal system did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced
clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the
active substance than younger patients. A study conducted with the fentanyl transdermal system
patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly
from young adult subjects, although peak serum concentrations tended to be lower and mean
half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology (12.3)].
Monitor geriatric patients closely for signs of sedation and respiratory depression, particularly
when initiating therapy with fentanyl transdermal system and when given in conjunction with
other drugs that depress respiration [see Warnings and Precautions (5.2), (5.6)].
The effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system has
not been fully evaluated. A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because there is in vitro and in vivo evidence of extensive hepatic contribution to the elimination
of fentanyl transdermal system, hepatic impairment would be expected to have significant effects
on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.1), Warnings
and Precautions (5.14) and Clinical Pharmacology 12.3)].
The effect of renal impairment on the pharmacokinetics of fentanyl transdermal system has not
been fully evaluated. A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level
had low fentanyl clearance. Because there is in vivo evidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant
effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosing and Administration (2.1),
Warnings and Precautions (5.15) and Clinical Pharmacology (12.3)].
9
Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance with a high
potential for abuse similar to other opioids including morphine, hydromorphone, methadone,
oxycodone, and oxymorphone. Fentanyl transdermal system can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
The high drug content in extended-release formulations adds to the risk of adverse outcomes
from abuse and misuse.
9.2 Abuse
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since
use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even
once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited
to, the following examples: the use of a prescription or over-the-counter drug to get “high”, or the
use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop
after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to
drug use than to other activities and obligations, increased tolerance, and sometimes a physical
withdrawal.
“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and
reluctance to provide prior medical records or contact information for other treating physician(s).
“Doctor shopping” to obtain additional prescriptions is common among drug abusers and people
suffering from untreated addiction. Preoccupation with achieving pain relief can be appropriate
behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. Fentanyl transdermal system, like other opioids, can
be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of
prescribing information, including quantity, frequency, and renewal requests, as required by
state law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy,
and proper dispensing and storage are appropriate measures that help to limit abuse of opioid
drugs.
Risks Specific to the Abuse of Fentanyl Transdermal System: Fentanyl transdermal system is
intended for transdermal use only. Abuse of fentanyl transdermal system poses a risk of overdose
and death. This risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants [see Warnings and Precautions (5.5), and
Drug Interactions (7.1)]. Intentional compromise of the transdermal delivery system may result
in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result
in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the
transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting
fentanyl extracted from the transdermal system.
9.3 Dependence
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the
need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence
of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration
of drugs with opioid antagonist activity, i.e., naloxone, nalmefene, mixed agonist/antagonist
analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical
dependence may not occur to a clinically significant degree until after several days to weeks of
continued opioid usage.
Fentanyl transdermal system should not be abruptly discontinued [see Dosage and Administration
(2.5)]. If fentanyl transdermal system is abruptly discontinued in a physically-dependent patient,
an abstinence syndrome may occur. Some or all of the following can characterize this syndrome:
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other
signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood
pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and
may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations
(8.2, 8.3)].
10 OVERDOSAGE
10.1 Clinical Presentation
Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils,
and sometimes bradycardia, hypotension and death. The pharmacokinetic characteristics of
fentanyl transdermal system must also be taken into account when treating the overdose. Even
in the face of improvement, continued medical monitoring is required because of the possibility
of extended effects. Deaths due to overdose have been reported with abuse and misuse of fentanyl transdermal system.
10.2 Treatment of Overdose
Give primary attention to the reestablishment of a patent airway and institution of assisted or
controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the
management of circulatory shock and pulmonary edema accompanying overdose as indicated.
Cardiac arrest or arrhythmias will require advanced life support techniques. Remove all fentanyl
transdermal system systems.
The pure opioid antagonists, such as naloxone, are specific antidotes to respiratory depression
from opioid overdose. Since the duration of reversal is expected to be less than the duration of
action of fentanyl, carefully monitor the patient until spontaneous respiration is reliably reestablished. After fentanyl transdermal system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20 to 27 hours. Therefore, management of an overdose
must be monitored accordingly, at least 72 to 96 hours beyond the overdose.
Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent
on any opioid agonist including fentanyl transdermal system, an abrupt or complete reversal of
opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal
syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist
for details of their proper use.
11 DESCRIPTION
Fentanyl transdermal system is a transdermal system containing fentanyl. The chemical name
is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:
The molecular weight of fentanyl base is 336.5, and the molecular formula is C22H28N2O. The
n-octanol: water partition coefficient is 860:1. The pKa is 8.4.
System Components and Structure: The amount of fentanyl released from each system per hour
is proportional to the surface area (25 mcg/hr per 6.25 cm2). The composition per unit area of
all system sizes is identical.
Dose*
Size
Fentanyl Content
(mcg/hr)
(cm2)
(mg)
12**
3.13
1.28
25
6.25
2.55
37.5
9.38
3.83
50
12.5
5.10
62.5
15.63
6.38
75
18.75
7.65
87.5
21.88
8.93
100
25
10.20
*Nominal delivery rate per hour
**Nominal delivery rate is 12.5 mcg/hr
Fentanyl transdermal system is a transparent rectangular patch with rounded corners comprising
a protective liner and two functional layers. Proceeding from the outer surface toward the surface
Page 7 of 12
adhering to skin, these layers are:
1) a backing layer of polyolefin film; 2) a drug-in-adhesive layer containing fentanyl as the active
ingredient and silicone adhesive and dimethicone NF as inactive ingredients. Before use, a protective liner covering the adhesive layer is removed and discarded.
Fentanyl transdermal systems are packaged with additional pieces of protective film above and
below the system within each pouch. These are discarded at the time of use.
Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor.
These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.
Central Nervous System Effects: Fentanyl exerts its principal pharmacologic effects on the central nervous system. Central nervous system effects increase with increasing serum fentanyl
concentrations.
In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly
occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the
pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting directly by
stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more
common in ambulatory than in recumbent patients, as is postural syncope.
Ventilatory Effects: In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl
transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by
respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies,
the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were
not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced
clinically significant hypoventilation and death with fentanyl transdermal system.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations,
especially for patients who have an underlying pulmonary condition or who receive concomitant
opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal
system is contraindicated in patients who are not tolerant to opioid therapy.
Gastrointestinal Tract and Other Smooth Muscle: Opioids increase the tone and decrease the
propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may
experience worsening rather than relief of pain.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be
variable, in some cases producing urinary urgency, in others, difficulty in urination.
Cardiovascular Effects: Fentanyl may cause orthostatic hypotension and fainting. Fentanyl may
infrequently produce bradycardia. The incidence of bradycardia in clinical trials with fentanyl
transdermal system was less than 1%.
Histamine assays and skin wheal testing in clinical studies indicate that clinically significant
histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically
significant histamine release in dosages up to 50 mcg/kg.
Absorption: Fentanyl transdermal system is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl
moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion
of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over
the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.
While there is variation in dose delivered among patients, the nominal flux of the systems
(12.5 mcg, 25 mcg, 37.5 mcg, 50 mcg, 62.5 mcg, 75 mcg, 87.5 mcg, and 100 mcg of fentanyl
per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.
Following fentanyl transdermal system application, the skin under the system absorbs fentanyl,
and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to
the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl
transdermal system application, generally leveling off between 12 and 24 hours and remaining
relatively constant, with some fluctuation, for the remainder of the 72-hour application period.
Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial
application (see Table 6). Serum fentanyl concentrations achieved are proportional to the fentanyl
transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to
rise for the first two system applications. By the end of the second 72-hour application, a steadystate serum concentration is reached and is maintained during subsequent applications of a patch
of the same size (see Figure 1). Patients reach and maintain a steady-state serum concentration
that is determined by individual variation in skin permeability and body clearance of fentanyl.
The kinetics of fentanyl in normal subjects following application of a 25 mcg/hr fentanyl transdermal system were bioequivalent with or without either BIOCLUSIVE® or Askina®Derm overlay
(polyurethane film dressing).
After system removal, serum fentanyl concentrations decline gradually, falling about 50% in
approximately 20 to 27 hours. Continued absorption of fentanyl from the skin accounts for a
slower disappearance of the drug from the serum than is seen after an IV infusion, where the
apparent half-life is approximately 7 (range 3 to 12) hours.
A clinical pharmacology study conducted in healthy adult subjects has shown that the application
of heat over the fentanyl transdermal system increased mean overall fentanyl exposure by 120%
and average maximum fentanyl level by 61%.
Table 6: FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION
OF FENTANYL TRANSDERMAL SYSTEM
Mean (SD) Time to
Mean (SD)
Maximal Concentration Maximal Concentration
Tmax
Cmax
(hr)
(ng/mL)
Fentanyl Transdermal System 12 mcg/hr
28.8 (13.7)
0.38 (0.13)*
31.7 (16.5)
0.85 (0.26)**
32.8 (15.6)
1.72 (0.53)**
35.8 (14.1)
2.32 (0.86)**
29.9 (13.3)
3.36 (1.28)**
*Cmax values dose normalized from 4 x 12.5 mcg/hr: Study 2003-038 in healthy volunteers
**Cmax values: Study C-2002-048 dose proportionality study in healthy volunteers
NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so
that serum concentrations fall 50%, on average, in approximately 20 to 27 hours.
Figure 1 Serum Fentanyl Concentrations
Following Single and Multiple Applications of Fentanyl Transdermal System 100 mcg/hr
FENTANYL TRANSDERMAL SYSTEM 100 mcg/hr (1x) (n=36)
FENTANYL TRANSDERMAL SYSTEM 100 mcg/hr (4x) (n=34)
Table 7: RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS
Clearance
Volume of Distribution
Half-Life
t1/2
(L/hr)
VSS
Range
(L/kg)
(hr)
[70 kg]
Range
Range
Surgical Patients
27 to 75
3 to 8
3 to 12
Hepatically Impaired Patients
3 to 80+
0.8 to 8+
4 to 12+
Renally Impaired Patients
30 to 78
–
–
+Estimated
NOTE: Information on volume of distribution and half-life not available for renally impaired patients.
Distribution: Fentanyl plasma protein binding capacity decreases with increasing ionization of
the drug. Alterations in pH may affect its distribution between plasma and the central nervous
system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the
blood. The average volume of distribution for fentanyl is 6 L/kg (range 3 to 8; N = 8).
Metabolism: Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to
norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.
Excretion: Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for
unbound fractions of fentanyl in plasma are estimated to be between 13% and 21%.
Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a
human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from
the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.
Specific Populations
Geriatric Use: Data from intravenous studies with fentanyl suggest that the elderly patients may
have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ
significantly from young adult subjects, although peak serum concentrations tended to be lower
and mean half-life values were prolonged to approximately 34 hours. In this study, a single fentanyl transdermal system 100 mcg/hour patch was applied to a skin site on the upper outer arm
in a group of healthy elderly Caucasians ≥ 65 years old (n = 21, mean age 71 years) and worn
for 72 hours. The mean Cmax and AUC∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject
variability in AUC∞ was higher in elderly subjects than in healthy adult subjects 18 to 45 years
(58% and 37%, respectively). The mean half-life value was longer in subjects ≥ 65 years old
than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions
(5.6) and Use in Specific Populations (8.5)].
Pediatric Use: In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients,
Page 8 of 12
the pharmacokinetic parameters were similar to that of adults. However, these findings have
been taken into consideration in determining the dosing recommendations for opioid-tolerant
pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see
Dosing and Administration (2.1)].
Hepatic Impairment: Information on the effect of hepatic impairment on the pharmacokinetics
of fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system
delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n = 8), Cmax and AUC in the patients with cirrhosis
(n = 9) increased 35% and 73%, respectively.
Because there is in vitro and in vivo evidence of extensive hepatic contribution to the elimination
of fentanyl transdermal system, hepatic impairment would be expected to have significant effects
on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.1), Warnings
and Precautions (5.14), and Use in Specific Populations (8.6)].
Renal Impairment: Information on the effect of renal impairment on the pharmacokinetics of
fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of
25 mcg/kg fentanyl was evaluated in patients (n = 8) undergoing kidney transplantation. An
inverse relationship between blood urea nitrogen level and fentanyl clearance was found.
Because there is in vivo evidence of renal contribution to the elimination of fentanyl transdermal
system, renal impairment would be expected to have significant effects on the pharmacokinetics
of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with
severe renal impairment [see Dosing and Administration (2.1), Warnings and Precautions (5.15)
and Use in Specific Populations (8.7)].
Drug-Drug Interactions
CYP3A4 Inhibitors: Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was
investigated in eleven healthy volunteers in a randomized crossover study. Subjects received
oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid
on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a
single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52% to
420%) increase in fentanyl AUC0-∞. The concomitant use of transdermal fentanyl with all CYP3A4
inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,
fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially
fatal respiratory depression. Carefully monitor patients receiving fentanyl transdermal system
and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and
adjust the dosage if warranted [see Boxed Warning and Warnings and Precautions (5.10), and
Drug Interactions (7.2)].
CYP3A4 Inducers: Co-administration with agents that induce CYP3A4 activity may reduce the
efficacy of fentanyl transdermal system.
13 NON-CLINICAL TOXICOLOGY
Carcinogenesis: In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 mcg /kg/day in
males or 100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained
via the 100 mcg/hr patch based on AUC0-24h comparison).
Mutagenesis: There was no evidence of mutagenicity in the Ames Salmonella mutagenicity
assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in vitro assays.
Impairment of Fertility: The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were
treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28
days prior to mating; female rats were not treated. In the female fertility study, female rats were
treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14
days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility
parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day
to either the male or the female alone produced no effects on fertility (this dose is approximately
1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In a
separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when
given in intravenous doses of 0.3 times the human dose for a period of 12 days.
14 CLINICAL STUDIES
Fentanyl transdermal system as therapy for pain due to cancer has been studied in 153 patients.
In this patient population, fentanyl transdermal system has been administered in doses of
25 mcg/hr to 600 mcg/hr. Individual patients have used fentanyl transdermal system continuously for up to 866 days. At one month after initiation of fentanyl transdermal system therapy,
patients generally reported lower pain intensity scores as compared to a prestudy analgesic regimen of oral morphine.
The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used
fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months,
and 10% used fentanyl transdermal system for more than 1 year.
In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 289
patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use
varied; 20% of pediatric patients were treated ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60
days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal
system for at least 4 months and 9 patients for more than 9 months.
Fentanyl transdermal system is supplied in cartons containing 5 individually packaged systems.
See chart for information regarding individual systems.
Fentanyl Transdermal System Dose
System Size
Fentanyl Content
NDC
(mcg/hr)
(cm2)
(mg)
Number
Fentanyl Transdermal System – 12*
3.13
1.28
0378-9119-98
Fentanyl Transdermal System – 25
6.25
2.55
0378-9121-98
Fentanyl Transdermal System – 37.5
9.38
3.83
0378-9125-98
12.5
5.10
0378-9122-98
15.63
6.38
0378-9126-98
18.75
7.65
0378-9123-98
21.88
8.93
0378-9127-98
25
10.20
0378-9124-98
*This lowest dosage is designated as 12 mcg/hr (however, the actual dosage is 12.5 mcg/hr) to distinguish
it from a 125 mcg/hr dosage that could be prescribed by using multiple patches.
Store in original unopened pouch. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions
for Use).
Addiction, Abuse, and Misuse: Inform patients that the use of fentanyl transdermal system,
even when taken as recommended, can result in addiction, abuse, and misuse, which can lead
to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share fentanyl
transdermal system with others and to take steps to protect fentanyl transdermal system from
theft or misuse.
Life-Threatening Respiratory Depression: Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl transdermal system or when the dose is increased, and that it can occur even at recommended doses
[see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression
and to seek medical attention if breathing difficulties develop.
Accidental Exposure: Inform patients to keep fentanyl transdermal system in a secure place
out of the reach of children due to the high risk of respiratory depression or death. [see Warnings
and Precautions (5.3)]. Fentanyl transdermal system can be accidentally transferred to children.
Instruct patients to take special precautions to avoid accidental contact when holding or caring
for children.
Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person,
to immediately take the patch off, wash the exposed area with water and seek medical attention
for the accidentally exposed individual as accidental exposure may lead to death or other serious
medical problems.
Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that
prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings
Interactions with Alcohol and other CNS Depressants: Inform patients that potentially serious
additive effects may occur if fentanyl transdermal system is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a healthcare provider.
Important Administration Instructions: Advise patients never to change the dose of fentanyl
transdermal system or the number of patches applied to the skin unless instructed to do so by
the prescribing healthcare professional.
When no longer needed, advise patients how to safely taper fentanyl transdermal system and
not to stop it abruptly to avoid the risk of precipitating withdrawal symptoms.
Warnings About Heat: Warn patients of the potential for temperature-dependent increases in
fentanyl release from the patch that could result in an overdose of fentanyl. Instruct patients to
contact their healthcare provider if they develop a high fever. Instruct patients to:
• avoid strenuous exertion that can increase body temperature while wearing the patch
• avoid exposing the fentanyl transdermal system application site and surrounding area to
direct external heat sources including heating pads, electric blankets, sunbathing, heat or
tanning lamps, saunas, hot tubs or hot baths, and heated water beds.
Driving or Operating Heavy Machinery: Fentanyl transdermal system may impair mental and/or
physical ability required for the performance of potentially hazardous tasks (i.e., driving, operating machinery). Instruct patients to refrain from any potentially dangerous activity when starting on fentanyl transdermal system or when their dose is being adjusted, until it is established
that they have not been adversely affected.
Pregnancy: Advise women of childbearing potential who become, or are planning to become
pregnant, to consult a healthcare provider prior to initiating or continuing therapy with fentanyl
transdermal system.
Additive Effects of Alcohol and other CNS Depressants: Instruct patients not to use alcohol or
other CNS depressants (i.e., sleep medications, tranquilizers) while using fentanyl transdermal
system because dangerous additive effects may occur, resulting in serious injury or death.
Constipation: Advise patients of the potential for severe constipation.
Disposal: Instruct patients to refer to the Instructions for Use for proper disposal of fentanyl
transdermal system. To properly dispose of a used patch, instruct patients to remove it, fold so
that the adhesive side of the patch adheres to itself, and immediately flush down the toilet. Unused patches should be removed from their pouches, the protective liners removed, the patches
folded so that the adhesive side of the patch adheres to itself, and immediately flushed down
the toilet.
Instruct patients to dispose of any patches remaining from a prescription as soon as they are
no longer needed.
Page 9 of 12
Medication Guide
Issue: 4/2014
Fentanyl Transdermal System, CII
(fen’ ta nil)
Fentanyl Transdermal System is:
•
A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-theclock, long-term treatment with an opioid, in people who are already regularly using opioid pain medicine, when other pain treatments such as
non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
•
A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as
prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
•
Not for use to treat pain that is not around-the-clock.
Important information about Fentanyl Transdermal System:
•
Get emergency help right away if you use too much fentanyl transdermal system (overdose). When you first start taking fentanyl transdermal
system, when your dose is changed, or if you take too much (overdose), serious or life threatening breathing problems that can lead to death may
occur.
•
Never give anyone else your fentanyl transdermal system. They could die from using it. Store fentanyl transdermal system away from children
and in a safe place to prevent stealing or abuse. Selling or giving away fentanyl transdermal system is against the law.
•
If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with water, and get emergency
help right away because an accidental exposure to fentanyl transdermal system can lead to death or other serious medical problems.
•
Proper disposal of fentanyl transdermal system after use and for unused patches when no longer needed: Fold the sticky sides of the patch together
and flush down the toilet. Do not put patches in a trash can.
Do not use Fentanyl Transdermal System if you have:
•
severe asthma, trouble breathing, or other lung problems.
•
a bowel blockage or have narrowing of the stomach or intestines.
Before applying Fentanyl Transdermal System, tell your healthcare provider if you have a history of:
•
head injury, seizures
•
liver, kidney, thyroid problems
•
problems urinating
•
pancreas or gallbladder problems
•
abuse of street or prescription drugs, alcohol addiction, or mental health problems.
Tell your healthcare provider if you:
•
have a fever
•
are pregnant or planning to become pregnant. Prolonged use of fentanyl transdermal system during pregnancy can cause withdrawal
symptoms in your newborn baby that could be life-threatening if not recognized and treated.
•
are breastfeeding. Fentanyl transdermal system passes into breast milk and may harm your baby.
•
are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl transdermal system with certain
other medicines can cause serious side effects that could lead to death.
When using Fentanyl Transdermal System:
•
Do not change your dose. Apply fentanyl transdermal system exactly as prescribed by your healthcare provider.
•
See the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system.
•
Do not apply more than 1 patch at the same time unless your healthcare provider tells you to.
•
You should wear the fentanyl transdermal system patch continuously for 3 days, unless advised otherwise by your healthcare provider.
•
Call your healthcare provider if the dose you are using does not control your pain.
•
Do not stop using fentanyl transdermal system without talking to your healthcare provider.
While using Fentanyl Transdermal System DO NOT:
•
Take hot baths or sunbathe, use hot tubs, saunas, heating pads, electric blankets, heated waterbeds, or tanning lamps, or engage in
exercise that increases your body temperature. These can cause an overdose that can lead to death.
•
Drive or operate heavy machinery, until you know how fentanyl transdermal system affects you. Fentanyl transdermal system can make you
sleepy, dizzy, or lightheaded.
•
Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with
fentanyl transdermal system may cause you to overdose and die.
The possible side effects of Fentanyl Transdermal System are:
•
constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, itching, redness, or rash where the patch is applied.
Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
•
trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness
when changing positions, or you are feeling faint.
These are not all the possible side effects of fentanyl transdermal system. Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. www.mylan.com or call 1-877-446-3679
REVISED MAY 2014
MG:FTS:R8
Page 10 of 12
Instructions for Use
Fentanyl Transdermal System CII
(fen’ ta nil)
Instructions for Applying a fentanyl transdermal system
Be sure that you read, understand, and follow these Instructions for Use
before you use fentanyl transdermal system. Talk to your healthcare
provider or pharmacist if you have any questions.
Parts of the fentanyl transdermal system:
Before applying fentanyl transdermal system
• Each fentanyl transdermal system is sealed in its own protective pouch. Do
not remove a fentanyl transdermal system from the pouch until you are
ready to use it.
• Do not use a fentanyl transdermal system if the pouch seal is broken
or the patch is cut, damaged or changed in any way.
• Fentanyl transdermal systems are available in 8 different doses and patch
sizes. Make sure you have the right dose patch or patches that have been
prescribed for you.
Applying a fentanyl transdermal system
1. Skin areas where the fentanyl transdermal system may be applied:
For adults:
• Put the patch on the chest, back, flank (sides of the waist), or upper
arm in a place where there is no hair (See Figures A-D).
Figure A
Figure B
Figure C
Figure D
For children (and adults with mental impairment):
• Put the patch on the upper back (See Figure B). This will lower the
chances that the child will remove the
Figure E
patch and put it in their mouth.
For adults and children
• Do not put a fentanyl transdermal system
on skin that is very oily, burned, broken out,
cut, irritated, or damaged in any way.
• Avoid sensitive areas or those that move
around a lot. If there is hair, do not shave
(shaving irritates the skin). Instead, clip
hair as close to the skin as possible (See
Figure E).
• Talk to your healthcare provider if you have questions about skin application sites.
2. Prepare to apply a fentanyl transdermal system:
• Choose the time of day that is best for you to apply fentanyl transdermal
system. Change it at about the same time of day (3 days or 72 hours
after you apply the patch) or as directed by your healthcare provider.
• Do not wear more than one fentanyl transdermal system at a time unless
your healthcare provider tells you to do so. Before applying a new fentanyl transdermal system, remove the patch you have been wearing.
• Clean the skin area with clear water only.
Figure F
Pat skin completely dry. Do not use anything on the skin such as soaps, lotions,
oils, or alcohol before the patch is applied.
3. Open the pouch: Tear at notch and remove
the fentanyl transdermal system. Each fentanyl transdermal system is packaged with
additional pieces of protective film above
Figure G
and below the patch and is sealed in its own
protective pouch. Do not remove the fentanyl
transdermal system from the pouch until you
are ready to use it (See Figure F). The additional pieces of protective film are discarded
at time of use (See Figure G).
4. Peel: Peel off both parts of the protective
liner from the patch. Each fentanyl transdermal system has a clear plastic liner that
Figure H
can be peeled off in two pieces. This covers
the sticky side of the patch. Carefully peel
this liner off. Throw the clear plastic liner
away. Touch the sticky side of the fentanyl
transdermal system as little as possible
(See Figure H).
5. Press: Press the patch onto the chosen skin
Figure I
site with the palm of your hand and hold
there for at least 30 seconds (See Figure
I). Make sure it sticks well, especially at the
edges.
• Fentanyl transdermal system may not
stick to all patients. You need to check the
patches often to make sure that they are
sticking well to the skin.
• If the patch falls off right away after applying, throw it away and put a new one
on at a different skin site. See the section
below called “Disposing of a fentanyl transdermal system”.
• If you have a problem with the patch not sticking
° Apply first aid tape only to the edges of the patch.
° If you continue to have problems with the patch sticking, you may cover
the patch with BIOCLUSIVE® or Askina®Derm. These are special seethrough adhesive dressings. Never cover a fentanyl transdermal system with any other bandage or tape. Remove the liner from the
BIOCLUSIVE® or Askina®Derm dressing and place it carefully over the
fentanyl transdermal system, smoothing it over the patch and your skin.
• If your patch falls off later, but before 3 days (72 hours) of use, dispose of properly. See the section below “Disposing of a fentanyl
transdermal system”. Apply a new fentanyl transdermal system on
at a different skin site. Be sure to let your healthcare provider know
that this has happened, and do not replace the new patch until 3 days
(72 hours) after you put it on (or as directed by your healthcare
provider).
6. Wash your hands when you have finished applying a fentanyl transdermal
system.
7. Remove a fentanyl transdermal system after wearing it for 3 days (72 hours).
See the section below “Disposing of a fentanyl transdermal system”. Choose
Page 11 of 12
a different skin site to apply a new fentanyl transdermal system. Repeat
Steps 2 through 6 above when applying a new fentanyl transdermal system.
Do not apply the new patch to the same place as the last one.
Water and fentanyl transdermal system
• You can bathe, swim or shower while you are wearing a fentanyl transdermal
system. If the patch falls off before 3 days (72 hours) after application, dispose
of properly. See the section below “Disposing of a fentanyl transdermal system”. Apply a new fentanyl transdermal system on at a different skin site. Be
sure to let your healthcare provider know that this has happened, and do not
replace the new patch until 3 days (72 hours) after you put it on (or as directed
by your healthcare provider).
Disposing of a fentanyl transdermal system
• Fold the used fentanyl transdermal system
Figure J
in half so that the sticky side sticks to itself
(See Figure J). Flush the used fentanyl
transdermal system down the toilet right
away (See Figure K). A used fentanyl transdermal system can be very dangerous for
or lead to death in babies, children, pets,
and adults who have not been prescribed
fentanyl transdermal system.
Figure K
• Throw away any fentanyl transdermal systems that are left over from your prescription
as soon as they are no longer needed. Remove the leftover patches from their protective pouch and remove the protective liner.
Fold the patches in half with the sticky
sides together, and flush the patches down
the toilet. Do not flush the pouch or the protective liner down the toilet. These items can
be thrown away in a trashcan.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
BIOCLUSIVE® is a registered trademark of Systagenix Wound Management, Inc.
Askina®Derm is a registered trademark of BBraun Melsungen AG
For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679
(1-877-4-INFO-RX).
REVISED MAY 2014
FTS:R22
Page 12 of 12
-------------------------------- ADVERSE REACTIONS -------------------------------Most common adverse reactions (incidence > 3%) are dizziness, diarrhea, nervousness, tremor, hypoglycemia and flatulence (6.1).
These highlights do not include all the information needed to use GLIPIZIDE
EXTENDED-RELEASE TABLETS safely and effectively. See full prescribing information for GLIPIZIDE EXTENDED-RELEASE TABLETS.
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc.
at 1-877-446-3679 (1-877-4-INFO-RX) or FDA 1-800-FDA-1088 or
GLIPIZIDE extended-release tablets, for oral use
-------------------------------- DRUG INTERACTIONS -------------------------------•
Miconazole: Monitor patients closely. Severe hypoglycemia can occur when glipizide extended-release tablets and oral miconazole are used concomitantly
(7.1, 12.3).
•
Fluconazole: Monitor patients closely. An increase in glipizide extended release
tablets AUC was seen after fluconazole administration (7.2, 12.3).
--------------------------- DOSAGE AND ADMINISTRATION --------------------------Colesevelam: Glipizide extended-release tablets should be administered at
•
Recommended starting dose is 5 mg once daily. Dose adjustment can be made •
least 4 hours prior to colesevelam (7.3, 12.3).
based on the patient’s glycemic control. Maximum recommended dose is 20 mg
once daily (2.1).
-------------------------- USE IN SPECIFIC POPULATIONS --------------------------•
Administer with breakfast or the first meal of the day (2.1).
•
Pregnancy: Based on animal data, may case fetal harm (8.1).
•
For combination therapy with other blood-glucose-lowering agents, initiate the •
Nursing Mothers: Discontinue glipizide extended-release tablets or nursing takagent in the lowest recommended dose, and observe patients for hypoglycemia
ing into consideration the importance of glipizide extended-release tablets to
(2.2).
the mother (8.3).
Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with glipizide
-------------------------- DOSAGE FORMS AND STRENGTHS -------------------------- •
extended-release tablets. Use caution in dose selection and titration, and monTablets: 2.5 mg, 5 mg and 10 mg (3).
itor closely (8.5, 8.6).
-------------------------------- CONTRAINDICATIONS -------------------------------SEE 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
•
Known hypersensitivity to glipizide or any of the product’s ingredients (4)
•
Hypersensitivity to sulfonamide derivatives (4)
REVISED NOVEMBER 2015
--------------------------- WARNINGS AND PRECAUTIONS --------------------------GLIPER:R3ppt/PL:GLIPER:R3p/PL:GLIPER:R3pt
•
Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and
instructions, particularly in at-risk populations (e.g., elderly, renally impaired)
and when used with other anti-diabetic medications (5.1).
•
Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD)
deficient. Consider a non-sulfonylurea alternative (5.2).
•
Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform
patient of risks, benefits and treatment alternatives (5.3).
•
Macrovascular Outcomes: No clinical studies have established conclusive evidence of macrovascular risk reduction with glipizide extended-release tablets
or any other anti-diabetic drug (5.4).
------------------------------ INDICATIONS AND USAGE -----------------------------Glipizide extended-release tablets are a sulfonylurea indicated as an adjunct to diet
and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis
1
1.1 Limitations of Use
2
2.1 Recommended Dosing
2.2 Use with Other Glucose Lowering Agent
3
4
CONTRAINDICATIONS
5
5.1 Hypoglycemia
5.2 Hemolytic Anemia
5.3 Increased Risk of Cardiovascular Mortality with Sulfonylureas
5.4 Macrovascular Outcomes
5.5 Gastrointestinal Obstruction
6
7
ADVERSE REACTIONS
DRUG INTERACTIONS
7.1 Miconazole
7.2 Fluconazole
7.3 Colesevelam
8
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
13
15
REFERENCES
16
17
1
(1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of
patients treated with diet alone. A significant increase in total mortality was not observed, but
the use of tolbutamide was discontinued based on the increase in cardiovascular mortality,
thus limiting the opportunity for the study to show an increase in overall mortality. Despite
controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks
and advantages of glipizide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it
is prudent from a safety standpoint to consider that this warning may also apply to other oral
hypoglycemic drugs in this class, in view of their close similarities in mode of action and
chemical structure.
5.4 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk
reduction with glipizide extended-release tablets or any other anti-diabetic drug.
5.5 Gastrointestinal Obstruction
There have been reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug with this non-dissolvable extended release formulation. Avoid use of glipizide extended-release tablets in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).
1
Glipizide extended-release tablets are indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.
1.1 Limitations of Use
Glipizide extended-release tablets are not recommended for the treatment of type 1 diabetes
mellitus or diabetic ketoacidosis.
2
2.1 Recommended Dosing
Glipizide extended-release tablets should be administered orally with breakfast or the first
main meal of the day.
The recommended starting dose of glipizide extended-release tablets is 5 mg once daily. Start
patients at increased risk for hypoglycemia (e.g. the elderly or patients with hepatic insufficiency) at 2.5 mg [see Use in Specific Population (8.5, 8.6)].
Dosage adjustment can be made based on the patient’s glycemic control. The maximum recommended dose is 20 mg once daily.
Patients receiving immediate release glipizide may be switched to glipizide extended-release
tablets once daily at the nearest equivalent total daily dose.
2.2 Use with Other Glucose Lowering Agents
When adding glipizide extended-release tablets to other anti-diabetic drugs, initiate glipizide
extended-release tablets at 5 mg once daily. Start patients at increased risk for hypoglycemia
at a lower dose.
When colesevelam is coadministered with glipizide extended-release, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, glipizide extended-release
tablets should be administered at least 4 hours prior to colesevelam.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in more detail below and elsewhere in
the labeling:
•
Hypoglycemia [see Warnings and Precautions (5.1)]
•
Hemolytic anemia [see Warnings and Precautions (5.2)]
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical trials, 580 patients from 31 to 87 years of age received glipizide extended-release
tablets in doses from 5 mg to 60 mg in both controlled and open trials. The dosages above
20 mg are not recommended dosages. In these trials, approximately 180 patients were treated with glipizide extended-release tablets for at least 6 months.
Table 1 summarizes the incidence of adverse reactions, other than hypoglycemia, that were
reported in pooled double-blind, placebo-controlled trials in ≥ 3% of glipizide extendedrelease tablets-treated patients and more commonly than in patients who received placebo.
Table 1: Incidence (%) of Adverse Reactions Reported in ≥ 3% of Patients Treated in
Placebo-Controlled Clinical Trials and More Commonly in Patients Treated with Glipizide
Extended-Release Tablets (Excluding Hypoglycemia)
Glipizide Extended-Release
Tablets (%)
Placebo (%)
(N = 278)
(N = 69)
Adverse Effect
Dizziness
6.8
5.8
Diarrhea
5.4
0.0
Nervousness
3.6
2.9
Tremor
3.6
0.0
Flatulence
3.2
1.4
3
Glipizide extended-release tablets:
•
The 2.5 mg tablets are light blue, film-coated, round, unscored tablets with M over GP2
imprinted in black ink on one side of the tablet and blank on the other side.
•
The 5 mg tablets are white, film-coated, round, unscored tablets with M over GP5
•
The 10 mg tablets are white, film-coated, round, unscored tablets with M over GP10
4
CONTRAINDICATIONS
Glipizide extended-release tablets are contraindicated in patients with:
•
Known hypersensitivity to glipizide or any of the product’s ingredients.
•
Hypersensitivity to sulfonamide derivatives.
5
5.1 Hypoglycemia
All sulfonylurea drugs, including glipizide extended-release tablets, are capable of producing
severe hypoglycemia [see Adverse Reactions (6)]. Concomitant use of glipizide extendedrelease tablets with other anti-diabetic medication can increase the risk of hypoglycemia. A
lower dose of glipizide extended-release tablets may be required to minimize the risk of hypoglycemia when combining it with other anti-diabetic medications.
Educate patients to recognize and manage hypoglycemia. When initiating and increasing glipizide extended-release tablets in patients who may be predisposed to hypoglycemia (e.g., the
elderly, patients with renal impairment, patients on other anti-diabetic medications) start at
2.5 mg. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic
impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe
or prolonged exercise, or when alcohol is ingested.
The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia.
Early warning symptoms of hypoglycemia may be different or less pronounced in patients with
autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking
medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain
function or death.
5.2 Hemolytic Anemia
Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including glipizide extended-release tablets, can lead to hemolytic anemia.
Avoid use of glipizide extended-release tablets in patients with G6PD deficiency. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known
G6PD deficiency.
5.3 Increased Risk of Cardiovascular Mortality with Sulfonylureas
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of
glucose-lowering drugs in preventing or delaying vascular complications in patients with type
2 diabetes mellitus. The study involved 823 patients who were randomly assigned to one of
four treatment groups.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide
Hypoglycemia: Of the 580 patients that received glipizide extended-release tablets in clinical
trials, 3.4% had hypoglycemia documented by a blood-glucose measurement < 60 mg/dL
and/or symptoms believed to be associated with hypoglycemia and 2.6% of patients discontinued for this reason. Hypoglycemia was not reported for any placebo patients.
Gastrointestinal Reactions: In clinical trials, the incidence of gastrointestinal (GI) side
effects (nausea, vomiting, constipation, dyspepsia), occurred in less than 3% of glipizide
extended-release tablets-treated patients and were more common in glipizide extendedrelease tablets-treated patients than those receiving placebo.
Dermatologic Reactions: In clinical trials, allergic skin reactions, i.e., urticaria occurred in
less than 1.5% of treated patients and were more common in glipizide extended-release
tablets treated patients than those receiving placebo. These may be transient and may disappear despite continued use of glipizide extended-release tablets; if skin reactions persist,
the drug should be discontinued.
Laboratory Tests: Mild to moderate elevations of ALT, LDH, alkaline phosphatase, BUN and
creatinine have been noted. The relationship of these abnormalities to glipizide is uncertain.
The following adverse reactions have been identified during post approval use of glipizide
extended-release tablets. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
•
Abdominal pain
•
Cholestatic and hepatocellular forms of liver injury accompanied by jaundice
•
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia [see Warnings and
Precautions (5.2)], aplastic anemia, pancytopenia
•
Hepatic porphyria and disulfiram-like reactions
•
Hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion
•
Rash
•
There have been reports of gastrointestinal irritation and gastrointestinal bleeding with
use of another drug with this non-dissolvable extended release formulation.
2
7
DRUG INTERACTIONS
7.1 Miconazole
Monitor patients closely for hypoglycemia when glipizide extended-release tablets are coadministered with miconazole. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported [see Clinical Pharmacology (12.3)].
7.2 Fluconazole
Monitor patients closely for hypoglycemia when glipizide extended-release tablets are coadministered with fluconazole. Concomitant treatment with fluconazole increases plasma
concentrations of glipizide, which may lead to hypoglycemia [see Clinical Pharmacology
(12.3)].
7.3 Colesevelam
Glipizide extended-release tablets should be administered at least 4 hours prior to the administration of colesevelam. Colesevelam can reduce the maximum plasma concentration and
total exposure of glipizide when the two are coadministered [see Clinical Pharmacology
(12.3)].
dioxide. The 2.5 mg tablet strength also contains FD&C Blue No. 2 Aluminum Lake. The 5 mg
and 10 mg tablet strengths also contain yellow iron oxide.
The black imprinting ink contains black iron oxide, hypromellose and propylene glycol.
System Components and Performance: Glipizide extended-release tablets are similar in
appearance to a conventional tablet. It consists, however, of an osmotically active drug core
surrounded by a semipermeable membrane. The core itself is divided into two layers: an
“active” layer containing the drug, and a “push” layer containing pharmacologically inert (but
osmotically active) components. The membrane surrounding the tablet is permeable to water
but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the
tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, resulting
in the release of drug through a small, laser-drilled orifice in the membrane on the drug side
of the tablet.
The function of the glipizide extended-release tablets depends upon the existence of an
osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. The biologically inert components of the tablet remain intact during GI transit and are eliminated in
the feces as an insoluble shell.
8
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat
reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly
noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal
and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide.
There are no adequate and well controlled studies in pregnant women. Glipizide extendedrelease tablets should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date.
8.3 Nursing Mothers
It is not known whether glipizide is excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the
mother.
8.4 Pediatric Use
Safety and effectiveness in children have not been established.
8.5 Geriatric Use
There were no overall differences in effectiveness or safety between younger and older
patients, but greater sensitivity of some individuals cannot be ruled out. Elderly patients are
particularly susceptible to the hypoglycemic action of anti-diabetic agents. Hypoglycemia may
be difficult to recognize in these patients. Therefore, dosing should be conservative to avoid
hypoglycemia [see Dosage and Administration (2.1), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
There is no information regarding the effects of hepatic impairment on the disposition of glipizide. However, since glipizide is highly protein bound and hepatic biotransformation is the
predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic impairment. If hypoglycemia occurs in such
patients, it may be prolonged and appropriate management should be instituted [see Dosage
and Administration (2.1), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Glipizide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Sulfonylureas
bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to
closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
The insulinotropic response to a meal is enhanced with glipizide extended-release tablets
administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In two randomized, double-blind,
dose-response studies comprising a total of 347 patients, there was no significant increase
in fasting insulin in all glipizide extended-release tablets-treated patients combined compared to placebo, although minor elevations were observed at some doses.
In studies of glipizide extended-release tablets in subjects with type 2 diabete mellitus, once
daily administration produced reductions in hemoglobin A1c, fasting plasma glucose and
postprandial glucose. The relationship between dose and reduction in hemoglobin A1c was not
established, however subjects treated with 20 mg had a greater reduction in fasting plasma
glucose compared to subjects treated with 5 mg.
Absorption: The absolute bioavailability of glipizide was 100% after single oral doses in
patients with type 2 diabetes mellitus. Beginning 2 to 3 hours after administration of glipizide extended-release tablets, plasma drug concentrations gradually rise reaching maximum
concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of glipizide extended-release tablets, plasma glipizide concentrations are maintained throughout the
24 hour dosing interval with less peak to trough fluctuation than that observed with twice
daily dosing of immediate release glipizide.
The mean relative bioavailability of glipizide in 21 males with type 2 diabetes mellitus after
administration of 20 mg glipizide extended-release tablets, compared to immediate release
Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with glipizide extended-release
tablets in 21 males with type 2 diabetes mellitus and patients younger than 65 years. No
accumulation of drug was observed in patients with type 2 diabetes mellitus during chronic
dosing with glipizide extended-release tablets.
Administration of glipizide extended-release tablets with food has no effect on the 2 to 3 hour
lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects,
the administration of glipizide extended-release tablets immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean C max value, which was significant, but
the effect on the AUC was not significant. There was no change in glucose response between
the fed and fasting state. Markedly reduced GI retention times of the glipizide extendedrelease tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations.
In a multiple dose study in 26 males with type 2 diabetes mellitus, the pharmacokinetics of
glipizide were linear with glipizide extended-release tablets in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects,
four 5 mg, two 10 mg, and one 20 mg glipizide extended-release tablets were bioequivalent.
In a separate single dose study in 36 healthy subjects, four 2.5 mg glipizide extended-release
tablets were bioequivalent to one 10 mg glipizide extended-release tablet.
Distribution: The mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type 2 diabetes mellitus. Glipizide is 98% to 99% bound to
serum proteins, primarily to albumin.
Metabolism: The major metabolites of glipizide are products of aromatic hydroxylation and
have no hypoglycemic activity. A minor metabolite, an acetylamino-ethyl benzene derivative,
which accounts for less than 2% of a dose, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound.
Elimination: Glipizide is eliminated primarily by hepatic biotransformation: less than 10%
of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is
excreted as biotransformation products in urine (80%) and feces (10%). The mean total
body clearance of glipizide was approximately 3 liters per hour after single intravenous
doses in patients with type 2 diabetes mellitus. The mean terminal elimination half-life of
glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus.
Specific Populations: Pediatric: Studies characterizing the pharmacokinetics of glipizide in
10 OVERDOSAGE
Overdosage of sulfonylureas including glipizide can produce severe hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated
with oral glucose. Severe hypoglycemic reactions with coma, seizure, or other neurological
impairment are medical emergencies requiring immediate treatment. The patient should be
treated with glucagon or intravenous glucose. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma may be prolonged in persons with liver disease. Because of the
extensive protein binding of glipizide, dialysis is unlikely to be of benefit.
11 DESCRIPTION
Glipizide extended-release tablets are an oral blood-glucose-lowering drug of the sulfonylurea
class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea. The molecular formula is C21H27N5O4S; the molecular
weight is 445.54; the structural formula is shown below:
Glipizide, USP is a white to almost white, odorless powder with a pKa of 5.9. It is insoluble in
water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide.
Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulation are: colloidal silicon dioxide, cellulose acetate, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polyethylene oxide,
polyvinyl alcohol, red iron oxide, sodium chloride, sodium stearyl fumarate, talc and titanium
3
Advise patients with diabetes to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.
pediatric patients have not been performed.
Geriatric: There were no differences in the pharmacokinetics of glipizide after single dose
administration to older diabetic subjects compared to younger healthy subjects [see Use in
Specific Populations (8.5)].
Renal Impairment: The pharmacokinetics of glipizide has not been evaluated in patients with
varying degree of renal impairment. Limited data indicates that glipizide biotransformation
products may remain in circulation for a longer time in subjects with renal impairment than
that seen in subjects with normal renal function.
Hepatic Impairment: The pharmacokinetics of glipizide has not been evaluated in patients
with hepatic impairment.
Drug-drug Interactions: Miconazole: A potential interaction between oral miconazole and oral
glipizide leading to severe hypoglycemia has been reported. Whether this interaction also
occurs with the intravenous, topical, or vaginal preparations of miconazole is not known [see
Fluconazole: Concomitant treatment with fluconazole increases plasma concentrations of
glipizide. The effect of concomitant administration of Diflucan® (fluconazole) and glipizide
tablets have been demonstrated in a placebo controlled crossover study in healthy volunteers.
All subjects received glipizide tablets alone and following treatment with 100 mg of Diflucan®
as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after
fluconazole administration was 56.9% (range: 35% to 81%) [see Drug Interactions (7.2)].
Colesevelam: Colesevelam can reduce the maximum plasma concentration and total exposure
of glipizide when the two are coadministered. In studies assessing the effect of colesevelam
on the pharmacokinetics of glipizide extended-release tablets in healthy volunteers, reductions in glipizide AUC0-∞ and Cmax of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide extended-release tablets. When glipizide extended-release tablets were administered 4 hours prior to colesevelam, there was no significant
change in glipizide AUC0-∞ or Cmax, -4% and 0%, respectively [see Drug Interactions (7.3)].
PATIENT INFORMATION LEAFLET
Glipizide Extended-Release Tablets
(glip’ i zide)
2.5 mg, 5 mg and 10 mg
What are glipizide extended-release tablets?
• Glipizide extended-release tablets are a prescription medicine you
take by mouth used along with diet and exercise to lower blood sugar
in adults with type 2 diabetes mellitus.
• Glipizide extended-release tablets are not for people with type 1 diabetes or people with diabetic ketoacidosis.
It is not known if glipizide extended-release tablets are safe and effective in children under 18 years of age.
Who should not take glipizide extended-release tablets?
Do not use glipizide extended-release tablets if you:
• have a condition called diabetic ketoacidosis
• have ever had an allergic reaction to glipizide or any of the other
ingredients in glipizide extended-release tablets. See the end of this
Patient Information for a complete list of ingredients in glipizide
extended-release tablets.
A twenty month study in rats and an eighteen month study in mice at doses up to 75 times
the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and
in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up
to 75 times the human dose showed no effects on fertility.
15
1.
What should I tell my doctor before taking glipizide extended-release
tablets?
Before you take glipizide extended-release tablets, tell your healthcare provider if you:
• Have ever had a condition called diabetic ketoacidosis
• Have kidney or liver problems
• Have had a blockage or narrowing of your intestines due to illness or
past surgery
• Have chronic (continuing) diarrhea
• Have glucose-6-phosphate dehydrogenase (G6PD) deficiency. This
condition usually runs in families. People with G6PD deficiency who
take glipizide extended-release tablets may develop hemolytic anemia (fast breakdown of red blood cells).
• Are pregnant or might be pregnant. It is not known if glipizide extended-release tablets will harm your unborn baby. If you are pregnant,
talk to you healthcare provider about the best way to control your
blood sugar while you are pregnant. You should not take glipizide
extended-release tablets during the last month of pregnancy.
• Are breastfeeding or plan to breastfeed. It is not known if glipizide
passes into your breast milk. You and your healthcare provider should
decide if you will take glipizide extended-release tablets or breastfeed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Glipizide extended-release tablets may affect the way other medicines
work, and other medicines may affect how glipizide extended-release
tablets work.
Some medicines can affect how well glipizide extended-release tablets
work or may affect your blood sugar level. Know the medicines you take.
Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
REFERENCES
Diabetes, 19, SUPP. 2: 747–830, 1970
16 HOW SUPPLIED/STORAGE AND HANDLING:
Glipizide Extended-Release Tablets are available containing 2.5 mg, 5 mg or 10 mg of glipizide, USP.
The 2.5 mg tablets are light blue, film-coated, round, unscored tablets with M over GP2
imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0340-93
The 5 mg tablets are white, film-coated, round, unscored tablets with M over GP5 imprinted
in black ink on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0342-01
NDC 0378-0342-10
The 10 mg tablets are white, film-coated, round, unscored tablets with M over GP10 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-0431-01
NDC 0378-0431-10
Recommended Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from moisture and humidity.
Inform patients of the potential adverse reactions of glipizide extended-release tablets including hypoglycemia. Explain the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development to patients and responsible family members. Also
inform patients about the importance of adhering to dietary instructions, of a regular exercise
program, and of regular testing of glycemic control.
Inform patients that glipizide extended-release tablets should be swallowed whole. Inform
patients that they should not chew, divide or crush tablets and they may occasionally notice
in their stool something that looks like a tablet. In the glipizide extended-release tablets, the
medication is contained within a non-dissolvable shell that has been specially designed to
slowly release the drug so the body can absorb it.
How should I take glipizide extended-release tablets?
• Take glipizide extended-release tablets exactly as your healthcare
provider tells you to take it.
• Your healthcare provider will tell you how many glipizide extendedrelease tablets to take and when to take it.
• Take glipizide extended-release tablets by mouth, one time each day
with breakfast or your first meal of the day.
4
• Each glipizide extended-release tablet will release the medicine slowly over 24 hours. This is why you take it only one time each day.
• Swallow the glipizide extended-release tablet whole. Do not break,
crush, dissolve, chew, or cut the tablet in half. This will damage the
tablet and release too much medicine into your body at one time.
• When you take glipizide extended-release tablets you may see something in your stool that looks like a tablet. This is the empty shell from
the tablet. It is normal for the empty shell to pass with your bowel
movement after medicine has been absorbed by your body.
General information about the safe and effective use of glipizide
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use glipizide extended-release
tablets for a condition for which it was not prescribed. Do not give glipizide extended-release tablets to other people, even if they have the same
symptoms you have. It may harm them. This Patient Information summarizes the most important information about glipizide extended-release
tablets. If you would like more information, talk with your healthcare
provider. You can ask your pharmacist or healthcare provider for information about glipizide extended-release tablets that is written for
healthcare professionals.
• It is important to take glipizide extended-release tablets every day to
help keep your blood sugar level under good control. Your healthcare
provider may change your dose depending on your blood sugar test
results. If your blood sugar level is not under control, call your healthcare provider. Do not change your dose unless your healthcare
provider tells you to.
• If you take too many glipizide extended-release tablets, call your
healthcare provider or go to the nearest emergency room right away.
Your healthcare provider may tell you to take glipizide extendedrelease tablets with other diabetes medicines. Low blood sugar can
happen more often when glipizide extended-release tablets are taken
with other diabetes medicines. See “What are the possible side
effects of glipizide extended-release tablets?”
• Check your blood sugar as your healthcare provider tells you to.
• Stay on your prescribed diet and exercise program while taking glipizide extended-release tablets.
What are the ingredients in glipizide extended-release tablets?
Active ingredient: glipizide, USP
Inactive ingredients: colloidal silicon dioxide, cellulose acetate, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polyethylene oxide,
polyvinyl alcohol, red iron oxide, sodium chloride, sodium stearyl
fumarate, talc and titanium dioxide. The 2.5 mg tablet strength also contains FD&C Blue No. 2 Aluminum Lake. The 5 mg and 10 mg tablet
strengths also contain yellow iron oxide. The black imprinting ink contains black iron oxide, hypromellose and propylene glycol.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
What should I avoid while taking glipizide extended-release tablets?
• Do not drink alcohol while taking glipizide extended-release tablets.
It can increase your chances of getting serious side effects.
• Do not drive, operate machinery, or do other dangerous activities until
you know how glipizide extended-release tablets affect you.
What are the possible side effects of glipizide extended-release
tablets?
Glipizide extended-release tablets can cause serious side effects,
including:
• Low blood sugar. Glipizide extended-release tablets may cause low
blood sugar. Signs and symptoms of low blood sugar may include:
• a cold clammy feeling • hunger
• unusual sweating
• fast heartbeat
• dizziness
• headache
• weakness
• blurred vision
• trembling
• slurred speech
• shakiness
• tingling in the
lips or hands
If you have signs or symptoms of low blood sugar, eat or drink something
with sugar in it right away. If you do not feel better or your blood sugar
level does not go up, call your healthcare provider or go to the nearest
emergency room.
The most common side effects of glipizide extended-release tablets
include: dizziness, diarrhea, nervousness, tremor, and gas.
These are not all the possible side effects of glipizide extended-release
tablets. For more information, ask your healthcare provider or pharmacist.
REVISED NOVEMBER 2015
GLIPER:R3ppt
How to store glipizide extended-release tablets?
• Store glipizide extended-release tablets at 20° to 25°C (68° to 77°F).
Protect from moisture and humidity.
• Store glipizide extended-release tablets in a dry place, in its original
container.
Keep glipizide extended-release tablets and all medicines out of
reach of children.
5
These highlights do not include all the information needed to use linezolid tablets safely
and effectively. See full prescribing information for linezolid tablets.
LINEZOLID tablets, for oral use
----------------------------------- INDICATIONS AND USAGE ----------------------------------Linezolid tablets are an oxazolidinone-class antibacterial indicated in adults and children for
the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia (1.1); Community-acquired pneumonia (1.1); Complicated skin and skin
structure infections, including diabetic foot infections, without concomitant osteomyelitis
(1.2); Uncomplicated skin and skin structure infections (1.2); Vancomycin-resistant Enterococcus faecium infections (1.3)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid tablets and other antibacterial drugs, linezolid tablets should be used only to treat or
prevent infections that are proven or strongly suspected to be caused by bacteria. (1.4)
-------------------------------- DOSAGE AND ADMINISTRATION -------------------------------Dosage, Route, and Frequency of Administration
Infection
Pediatric Patients
Adults and Adolescents Duration (days)
Nosocomial pneumonia
Community-acquired pneumonia,
10 mg/kg intravenous or
600 mg intravenous or
including concurrent bacteremia
10 to 14
oral every 8 hours
oral every 12 hours
Complicated skin and skin
structure infections
Vancomycin-resistant Enterococcus
10 mg/kg intravenous or
600 mg intravenous or
faecium infections, including
14 to 28
oral every 8 hours
oral every 12 hours
concurrent bacteremia
Uncomplicated skin and skin
less than 5 yrs: 10 mg/kg oral Adults: 400 mg oral
every 8 hours 5
every 12 hours
10 to 14
to 11 yrs: 10 mg/kg
Adolescents: 600 mg
oral every 12 hours
oral every 12 hours
------------------------------------- CONTRAINDICATIONS ------------------------------------• Known hypersensitivity to linezolid or any of the other product components. (4.1); Patients
taking any monoamine oxidase inhibitors (MAOI) or within 2 weeks of taking an MAOI. (4.2)
-------------------------------- WARNINGS AND PRECAUTIONS -------------------------------• Myelosuppression: Monitor complete blood counts weekly. Consider discontinuation in
patients who develop or have worsening myelosuppression. (5.1)
• Peripheral and optic neuropathy: Reported primarily in patients treated for longer than
28 days. If patients experience symptoms of visual impairment, prompt ophthalmic evaluation is recommended. (5.2)
• Serotonin syndrome: Patients taking serotonergic antidepressants should receive linezolid
only if no other therapies are available. Discontinue serotonergic antidepressants and
monitor patients for signs and symptoms of both serotonin syndrome and antidepressant
discontinuation. (5.3)
• A mortality imbalance was seen in an investigational study in linezolid-treated patients
with catheter-related bloodstream infections. (5.4)
• Clostridium difficile associated diarrhea: Evaluate if diarrhea occurs. (5.5)
• Potential interactions producing elevation of blood pressure: monitor blood pressure (5.6)
• Hypoglycemia: Postmarketing cases of symptomatic hypoglycemia have been reported in
patients with diabetes mellitus receiving insulin or oral hypoglycemic agents. (5.9)
------------------------------------- ADVERSE REACTIONS ------------------------------------Most common adverse reactions (> 5% of adult and/or pediatric patients treated with linezolid) include: diarrhea, vomiting, headache, nausea, and anemia. (6)
------------------------------------- DRUG INTERACTIONS ------------------------------------Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic
agents. (4.2, 5.3, 5.6, 7, 12.3)
See 17 for PATIENT COUNSELING INFORMATION
JUNE 2015
LINZ:R1
------------------------------- DOSAGE FORMS AND STRENGTHS -----------------------------• Tablet: 600 mg linezolid. (3)
1.1 Pneumonia
1.2 Skin and Skin Structure Infections
1.3 Vancomycin-resistant Enterococcus faecium Infections
1.4 Usage
2.1 General Dosage and Administration
4 CONTRAINDICATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12.4 Microbiology
5.1 Myelosuppression
5.2 Peripheral and Optic Neuropathy
5.4 Mortality Imbalance in an Investigational Study in Patients with Catheter-Related
Bloodstream Infections, Including Those with Catheter-Site Infections
5.5 Clostridium difficile Associated Diarrhea
5.6 Potential Interactions Producing Elevation of Blood Pressure
5.7 Lactic Acidosis
5.8 Convulsions
5.9 Hypoglycemia
5.10 Development of Drug-Resistant Bacteria
6 ADVERSE REACTIONS
14 CLINICAL STUDIES
14.1 Adults
14.2 Pediatric Patients
15 REFERENCES
16.2 Tablets
16.4 Storage
7 DRUG INTERACTIONS
7.2 Adrenergic and Serotonergic Agents
Page 1 of 9
FULL PRESCRIBING INFORMATION:
1
Linezolid tablets are indicated for the treatment of infections caused by susceptible strains of
the designated microorganisms in the specific conditions listed below. Linezolid tablets are
not indicated for the treatment of Gram-negative infections. It is critical that specific Gramnegative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Warnings and Precautions (5.4)].
1.1 Pneumonia
Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies (14)].
Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with
concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [see
Clinical Studies (14)].
1.2 Skin and Skin Structure Infections
Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant
isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid tablets have not been
studied in the treatment of decubitus ulcers [see Clinical Studies (14)].
Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes [see Clinical Studies (14)].
1.3 Vancomycin-resistant Enterococcus faecium Infections
Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent
bacteremia [see Clinical Studies (14)].
1.4 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid tablets and other antibacterial drugs, linezolid tablets should be used only to treat or
prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
When culture and susceptibility information are available, they should be considered in
selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology
and susceptibility patterns may contribute to the empiric selection of therapy.
The safety and efficacy of linezolid tablets given for longer than 28 days have not been evaluated in controlled clinical trials.
2
2.1 General Dosage and Administration
The recommended dosage for linezolid for the treatment of infections is described in Table 1.
Table 1. Dosage Guidelines for Linezolid
Dosage and Route of Administration
Infection*
Recommended
Adults and
Duration
Pediatric Patients†
(Birth through
Adolescents
of Treatment
11 Years of Age)
(12 Years and Older)
(consecutive days)
Community-acquired
pneumonia, including
10 mg/kg intravenously
600 mg intravenously
10 to 14
or oral‡ every 8 hours
Complicated skin and
skin structure infections
Vancomycin-resistant Enterococcus
10 mg/kg intravenously
600 mg intravenously
faecium infections, including
14 to 28
Uncomplicated skin and
less than 5 yrs: 10 mg/kg
Adults: 400 mg oral‡
skin structure infections
oral‡ every 8 hours
every 12 hours
10 to 14
5 to 11 yrs: 10 mg/kg oral‡ Adolescents: 600 mg oral‡
every 12 hours
every 12 hours
*
†
‡
Due to the designated pathogens [see Indications and Usage (1)]
Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than
34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term
neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every
12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a
sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of
life [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].
Oral dosing using linezolid tablets [see How Supplied/Storage and Handling (16)].
No dose adjustment is necessary when switching from intravenous to oral administration.
3
Linezolid 600 mg tablet: A yellow, film-coated, oval, unscored tablet debossed with MYLAN on
one side of the tablet and L77 on the other side.
4
CONTRAINDICATIONS
Linezolid tablets are contraindicated for use in patients who have known hypersensitivity to
linezolid or any of the other product components.
Linezolid should not be used in patients taking any medicinal product which inhibits
monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking any
such medicinal product.
5
5.1 Myelosuppression
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has
been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment
levels. Complete blood counts should be monitored weekly in patients who receive linezolid,
particularly in those who receive linezolid for longer than 2 weeks, those with pre-existing
myelosuppression, those receiving concomitant drugs that produce bone marrow suppression,
or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or
have worsening myelosuppression.
5.2 Peripheral and Optic Neuropathy
Peripheral and optic neuropathies have been reported in patients treated with linezolid, primarily in those patients treated for longer than the maximum recommended duration of
28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated
for extended periods beyond the maximum recommended duration. Visual blurring has been
reported in some patients treated with linezolid for less than 28 days. Peripheral and optic
neuropathy has also been reported in children.
If patients experience symptoms of visual impairment, such as changes in visual acuity,
changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is
recommended. Visual function should be monitored in all patients taking linezolid for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of
length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of
linezolid in these patients should be weighed against the potential risks.
Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.
Unless clinically appropriate and patients are carefully observed for signs and/or symptoms
of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid
should not be administered to patients with carcinoid syndrome and/or patients taking any of
the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin
5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone [see Drug Interactions
(7) and Clinical Pharmacology (12.3)].
In some cases, a patient already receiving a serotonergic antidepressant or buspirone may
require urgent treatment with linezolid. If alternatives to linezolid are not available and the
potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions,
the serotonergic antidepressant should be stopped promptly and linezolid administered. The
patient should be monitored for 2 weeks (5 weeks if fluoxetine was taken) or until 24 hours
after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or
NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The
patient should also be monitored for discontinuation symptoms of the antidepressant (see
package insert of the specified agent(s) for a description of the associated discontinuation
symptoms).
5.4 Mortality Imbalance in an Investigational Study in Patients with Catheter-Related
Bloodstream Infections, Including Those with Catheter-Site Infections
An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16%); odds ratio 1.426,
95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance
occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens,
mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.
Linezolid is not approved and should not be used for the treatment of patients with catheterrelated bloodstream infections or catheter-site infections.
Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for
the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy
be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Indications and Usage (1)].
5.5 Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal
colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections
can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
Careful medical history is necessary since CDAD has been reported to occur over 2 months
after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may
need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
5.6 Potential Interactions Producing Elevation of Blood Pressure
Unless patients are monitored for potential increases in blood pressure, linezolid should not be
administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis
Page 2 of 9
and/or patients taking any of the following types of medications: directly and indirectly acting
sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) [see Drug Interactions (7)
and Clinical Pharmacology (12.3)].
5.7 Lactic Acidosis
Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or
vomiting, unexplained acidosis, or a low bicarbonate level while receiving linezolid should
receive immediate medical evaluation.
5.8 Convulsions
Convulsions have been reported in patients when treated with linezolid. In some of these
cases, a history of seizures or risk factors for seizures was reported.
5.9 Hypoglycemia
Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a
reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a
causal relationship between linezolid and hypoglycemia has not been established, diabetic
patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.
If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.
5.10 Development of Drug-Resistant Bacteria
Prescribing linezolid in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of
the development of drug-resistant bacteria.
6
ADVERSE REACTIONS
Adults: The safety of linezolid was evaluated in 2,046 adult patients enrolled in seven Phase
3 comparator-controlled clinical trials, who were treated for up to 28 days.
Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4%
of linezolid-treated and 19.6% of comparator-treated patients experienced at least one drugrelated adverse event. For all other indications, 20.4% of linezolid-treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event.
Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported
in at least 1% of adult patients in these trials by dose of linezolid.
Table 2. Incidence (%) of Treatment–Emergent Adverse Reactions Occurring in > 1% of
Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials
ADVERSE REACTIONS
Uncomplicated Skin and Skin Structure Infections
All Other Indications
Linezolid 400 mg by Clarithromycin 250 mg Linezolid 600 mg All Other
mouth every 12 hours by mouth every 12 hours every 12 hours Comparators*
(n = 548)
(n = 537)
(n = 1,498)
(n = 1,464)
Headache
8.8
8.4
5.7
4.4
Diarrhea
8.2
6.1
8.3
6.4
Nausea
5.1
4.5
6.6
4.6
Vomiting
2
1.5
4.3
2.3
Dizziness
2.6
3
1.8
1.5
Rash
1.1
1.1
2.3
2.6
Anemia
0.4
0
2.1
1.4
Taste alteration
1.8
2
1
0.3
Vaginal moniliasis
1.8
1.3
1.1
0.5
Oral moniliasis
0.5
0
1.7
1
Abnormal liver function tests
0.4
0.2
1.6
0.8
Fungal infection
1.5
0.2
0.3
0.2
Tongue discoloration
1.3
0
0.3
0
Localized abdominal pain
1.3
0.6
1.2
0.8
Generalized abdominal pain
0.9
0.4
1.2
1
*
Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously
every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.
Of the patients treated for uSSSIs, 3.5% of linezolid-treated and 2.4% of comparator-treated
patients discontinued treatment due to drug-related adverse events. For all other indications,
discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and
1.7% of comparator-treated patients. The most common reported drug-related adverse events
leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.
Pediatric Patients: The safety of linezolid was evaluated in 215 pediatric patients ranging in
age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of
these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in
two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In the study
of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who
were randomized 2 to 1 (linezolid: vancomycin), mortality was 6% (13/215) in the linezolid arm
and 3% (3/101) in the vancomycin arm. However, given the severe underlying illness in the
patient population, no causality could be established.
Of the pediatric patients treated for uSSSIs, 19.2% of linezolid-treated and 14.1% of comparator-treated patients experienced at least one drug-related adverse event. For all other
indications, 18.8% of linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.
Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported
in more than 1% of pediatric patients (and more than one patient) in either treatment group
in the comparator-controlled Phase 3 trials.
Table 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in > 1% of
Pediatric Patients (and > 1 Patient) in Either Treatment Group in Comparator-Controlled
Clinical Trials
ADVERSE REACTIONS
Uncomplicated Skin and
All Other Indications†
Skin Structure Infections*
Linezolid
Cefadroxil
Linezolid
Vancomycin
(n = 248)
(n = 251)
(n = 215)
(n = 101)
Diarrhea
7.8
8
10.8
12.1
Vomiting
2.9
6.4
9.4
9.1
Headache
6.5
4
0.9
0
Anemia
0
0
5.6
7.1
Thrombocytopenia
0
0
4.7
2
Nausea
3.7
3.2
1.9
0
Generalized abdominal pain
2.4
2.8
0.9
2
Localized abdominal pain
2.4
2.8
0.5
1
Loose stools
1.6
0.8
2.3
3
Eosinophilia
0.4
0.8
1.9
1
Puruitus at non-application site
0.8
0.4
1.4
2
Vertigo
1.2
0.4
0
0
*
†
Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil
15 mg/kg by mouth every 12 hours. Patients 12 years or older received linezolid 600 mg by mouth every
12 hours or cefadroxil 500 mg by mouth every 12 hours.
Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every
8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal
clearance.
Of the pediatric patients treated for uSSSIs, 1.6% of linezolid-treated and 2.4% of comparatortreated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients.
Laboratory Abnormalities: Linezolid has been associated with thrombocytopenia when used in
doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparatorcontrolled trials, the percentage of adult patients who developed a substantially low platelet
count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range
among studies: 0.3 to 10%) with linezolid and 1.5% (range among studies: 0.4 to 7%) with a
comparator. In a study of hospitalized pediatric patients ranging in age from birth through
11 years, the percentage of patients who developed a substantially low platelet count (defined
as less than 75% of lower limit of normal and/or baseline) was 12.9% with linezolid and
13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through
17 years, the percentage of patients who developed a substantially low platelet count was
0% with linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of
linezolid appears to be dependent on duration of therapy (generally greater than 2 weeks of
treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical
trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for linezolid; the role of linezolid in these
events cannot be determined [see Warning and Precautions (5.1)].
Changes seen in other laboratory parameters, without regard to drug relationship, revealed no
substantial differences between linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The
incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7.
Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormal*
Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
Laboratory Assay
Skin Structure Infections
Linezolid
Clarithromycin
Linezolid
All Other
400 mg every 250 mg every 600 mg every Comparators†
12 hours
12 hours
12 hours
Hemoglobin (g/dL)
0.9
0
7.1
6.6
Platelet count (x 10 3/mm 3 )
0.7
0.8
3
1.8
WBC (x 10 3/mm 3 )
0.2
0.6
2.2
1.3
Neutrophils (x 10 3/mm 3 )
0
0.2
1.1
1.2
*
†
< 75% (< 50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; < 75%
(< 50% for neutrophils) of LLN and of baseline for values abnormal at baseline.
Page 3 of 9
Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal*
Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
Laboratory Assay
Skin Structure Infections
Linezolid
Clarithromycin
Linezolid
All Other
400 mg every
250 mg every 600 mg every Comparators†
12 hours
12 hours
12 hours
AST (U/L)
1.7
1.3
5
6.8
ALT (U/L)
1.7
1.7
9.6
9.3
LDH (U/L)
0.2
0.2
1.8
1.5
Alkaline phosphatase (U/L)
0.2
0.2
3.5
3.1
Lipase (U/L)
2.8
2.6
4.3
4.2
Amylase (U/L)
0.2
0.2
2.4
2
Total bilirubin (mg/dL)
0.2
0
0.9
1.1
BUN (mg/dL)
0.2
0
2.1
1.5
Creatinine (mg/dL)
0.2
0
0.2
0.6
*
†
> 2 x Upper Limit of Normal (ULN) for values normal at baseline; > 2 x ULN and > 2 x baseline for values
abnormal at baseline.
Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
Laboratory Assay
All Other Indications‡
Skin Structure Infections†
Linezolid
Cefadroxil
Linezolid
Vancomycin
Hemoglobin (g/dL)
0
0
15.7
12.4
Platelet count (x 10 3/mm 3 )
0
0.4
12.9
13.4
WBC (x 10 3/mm 3 )
0.8
0.8
12.4
10.3
1.2
0.8
5.9
4.3
Neutrophils (x 10 3/mm 3 )
*
†
‡
< 75% (< 50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; < 75% (< 50%
for neutrophils) of LLN and < 75% (< 50% for neutrophils, < 90% for hemoglobin if baseline < LLN) of baseline for values abnormal at baseline.
Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg
by mouth every 12 hours. Patients 12 years or older received linezolid 600 mg by mouth every 12 hours or
cefadroxil 500 mg by mouth every 12 hours.
Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously by mouth every 8 hours
or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.
Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal*
Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid
Laboratory Assay
All Other Indications‡
Skin Structure Infections†
Linezolid
Cefadroxil
Linezolid
Vancomycin
ALT (U/L)
0
0
10.1
12.5
Lipase (U/L)
0.4
1.2
—
—
Amylase (U/L)
—
—
0.6
1.3
Total bilirubin (mg/dL)
—
—
6.3
5.2
Creatinine (mg/dL)
0.4
0
2.4
1
*
†
‡
> 2 x Upper Limit of Normal (ULN) for values normal at baseline; > 2 x ULN and > 2 (> 1.5 for total bilirubin) x baseline for values abnormal at baseline.
Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil
15 mg/kg by mouth every 12 hours. Patients 12 years or older received linezolid 600 mg by mouth every
12 hours or cefadroxil 500 mg by mouth every 12 hours.
Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously/by mouth every 8 hours
or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.
The following adverse reactions have been identified during postapproval use of linezolid. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has
been reported during postmarketing use of linezolid [see Warnings and Precautions (5.1)].
Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have
been reported in patients treated with linezolid [see Warnings and Precautions (5.2)]. Lactic
acidosis has been reported with the use of linezolid [see Warnings and Precautions (5.7)].
Although these reports have primarily been in patients treated for longer than the maximum
recommended duration of 28 days, these events have also been reported in patients receiving
shorter courses of therapy. Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake
inhibitors (SSRIs) and linezolid [see Warnings and Precautions (5.3)]. Convulsions have been
reported with the use of linezolid [see Warnings and Precautions (5.8)]. Anaphylaxis,
angioedema, and bullous skin disorders such as those described as Stevens-Johnson syndrome have been reported. Superficial tooth discoloration and tongue discoloration have been
reported with the use of linezolid. The tooth discoloration was removable with professional
dental cleaning (manual descaling) in cases with known outcome. Hypoglycemia, including
symptomatic episodes, has been reported [see Warnings and Precautions (5.9)].
7
DRUG INTERACTIONS
Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [see Contraindications
7.2 Adrenergic and Serotonergic Agents
Linezolid has the potential for interaction with adrenergic and serotonergic agents [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.3)].
8
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C: Linezolid was not teratogenic in mice, rats, or
rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits)
the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were
seen (see Non-teratogenic Effects). There are no adequate and well-controlled studies in pregnant women. Linezolid should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Non-teratogenic Effects: In mice, embryo and fetal toxicities were seen only at doses that
caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day
(6.5-fold the estimated human exposure level based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an
increased incidence of costal cartilage fusion.
In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to
approximately equivalent to the estimated human exposure, respectively, based on AUCs). The
effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a
finding often seen in association with decreased fetal body weights. Slight maternal toxicity,
in the form of reduced body weight gain, was seen at 50 mg/kg/day.
In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at a dose of
15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).
When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of
pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to
reproductive age, when mated, showed an increase in preimplantation loss.
8.3 Nursing Mothers
Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk
were similar to those in maternal plasma. It is not known whether linezolid is excreted in
human milk. Because many drugs are excreted in human milk, caution should be exercised
when linezolid tablets are administered to a nursing woman.
8.4 Pediatric Use
The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in
adults, pharmacokinetic data in pediatric patients, and additional data from a comparatorcontrolled study of Gram-positive infections in pediatric patients ranging in age from birth
through 11 years [see Indications and Usage (1), Clinical Pharmacology (12.3) and Clinical
Studies (14)]:
•
nosocomial pneumonia
•
complicated skin and skin structure infections
•
community-acquired pneumonia (also supported by evidence from an uncontrolled
study in patients ranging in age from 8 months through 12 years)
•
vancomycin-resistant Enterococcus faecium infections
The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients
ranging in age from 5 through 17 years [see Clinical Studies (14)]:
•
uncomplicated skin and skin structure infections caused by Staphylococcus aureus
(methicillin-susceptible strains only) or Streptococcus pyogenes
Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts
showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients
with central nervous system infections is not recommended.
The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years
of age. In general, weight-based clearance of linezolid gradually decreases with increasing age
of pediatric patients. However, in preterm (gestational age < 34 weeks) neonates < 7 days of age,
linezolid clearance is often lower than in full-term neonates < 7 days of age. Consequently,
preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg
every 12 hours [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Grampositive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with
linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid
clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a
sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower
systemic exposure, site and severity of infection, and the underlying medical condition should
be considered when assessing clinical response [see Clinical Pharmacology (12.3) and
Dosage and Administration (2)].
8.5 Geriatric Use
Of the 2,046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials,
589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences
in safety or effectiveness were observed between these patients and younger patients, and
Page 4 of 9
other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
10 OVERDOSAGE
In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial,
approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session
beginning 3 hours after the dose of linezolid was administered. Data are not available for
removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity
in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively.
11 DESCRIPTION
Linezolid tablets contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is N-[[(5S )-3-[3-Fluoro-4-(4-morpholinyl)phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide.
The molecular formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:
O
N
F
O
N
O
H
H
N
CH3
O
Linezolid tablets for oral administration contains 600 mg linezolid as a film-coated compressed tablet. Inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, D&C
Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum
Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin. The sodium (Na+) content is
6.4 mg per 600 mg tablet (0.3 mEq per tablet).
Linezolid is an antibacterial drug [see Microbiology (12.4)].
In a randomized, positive-and placebo-controlled crossover thorough QT study, 40 healthy
subjects were administered a single linezolid 600 mg dose via a one hour IV infusion, a single linezolid 1200 mg dose via a one hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg linezolid doses, no significant effect on QTc
interval was detected at peak plasma concentration or at any other time.
The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and
intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steadystate after oral doses of 600 mg given every 12 hours are shown in Figure 1.
Table 8. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults
Dose of Linezolid
Cmax mcg/mL Cmin mcg/mL Tmax hrs AUC* mcg•h/mL t1/2 hrs CL mL/min
400 mg tablet
single dose†
8.10
—
1.52
55.10
5.20
146
(1.83)
(1.01)
(25)
(1.50)
(67)
every 12 hours
11
3.08
1.12
73.40
4.69
110
(4.37)
(2.25)
(0.47)
(33.50)
(1.70)
(49)
600 mg tablet
single dose
12.70
—
1.28
91.40
4.26
127
(3.96)
(0.66)
(39.30)
(1.65)
(48)
every 12 hours
21.20
6.15
1.03
138
5.40
80
(5.78)
(2.94)
(0.62)
(42.10)
(2.06)
(29)
600 mg IV injection‡
single dose
12.90
—
0.50
80.20
4.40
138
(1.60)
(0.10)
(33.30)
(2.40)
(39)
every 12 hours
15.10
3.68
0.51
89.70
4.80
123
(2.52)
(2.36)
(0.03)
(31)
(1.70)
(40)
600 mg oral suspension
single dose
11
—
0.97
80.80
4.60
141
(2.76)
(0.88)
(35.10)
(1.71)
(45)
* AUC for single dose = AUC0-∞; for multiple dose = AUC0-τ
† Data dose-normalized from 375 mg
‡ Data dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion. Cmax = Maximum
plasma concentration; Cmin = Minimum plasma concentration; Tmax = Time to Cmax; AUC = Area under
concentration-time curve; t1/2 = Elimination half-life; CL = Systemic clearance
Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral
Dosing Every 12 Hours (Mean ± Standard Deviation, n = 16)
Absorption: Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously
without dose adjustment.
Linezolid may be administered without regard to the timing of meals. The time to reach the
maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by
about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-∞ is similar under both conditions.
Distribution: Animal and human pharmacokinetic studies have demonstrated that linezolid
readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at
steady-state averaged 40 to 50 liters in healthy adult volunteers.
Linezolid concentrations have been determined in various fluids from a limited number of
subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of
linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of linezolid in sweat relative to plasma was 0.55 to 1.
Metabolism: Linezolid is primarily metabolized by oxidation of the morpholine ring, which
results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic
acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite
A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated
by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome
P450. However, the metabolic pathway of linezolid is not fully understood.
Excretion: Nonrenal clearance accounts for approximately 65% of the total clearance of
linezolid. Under steady-state conditions, approximately 30% of the dose appears in the
urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min which suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as
metabolite B, and 3% as metabolite A.
A small degree of nonlinearity in clearance was observed with increasing doses of linezolid,
which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the
apparent elimination half-life.
Specific Populations: Geriatric Patients: The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.
Pediatric Patients: The pharmacokinetics of linezolid following a single intravenous dose
were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from
12 through 17 years, and in pediatric patients ranging in age from one week through 12
years. The pharmacokinetic parameters of linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses.
The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in
pediatric patients. However, plasma clearance of linezolid varies as a function of age.
With the exclusion of pre-term neonates less than one week of age, weight-based clearance is most rapid in the youngest age groups ranging from < one week old to 11 years,
resulting in lower single-dose systemic exposure (AUC) and a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance
of linezolid gradually decreases, and by adolescence mean clearance values approach
those observed for the adult population. There is increased inter-subject variability in
linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as
compared with adults.
Similar mean daily AUC values were observed in pediatric patients from birth to 11 years
of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every
8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours [see
Dosage and Administration (2)].
Page 5 of 9
Table 9. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV); [Min, Max Values])
Age Group
Cmax mcg/mL Vss L/kg AUC* mcg•h/mL t1/2 hrs CL mL/min/kg
Neonatal Patients
12.7 (30%) 0.81 (24%)
108 (47%) 5.6 (46%) 2 (52%)
Pre-term**
< one week (N = 9)†
[9.6, 22.2] [0.43, 1.05]
[41, 191]
[2.4, 9.8]
[0.9, 4]
Full-term***
11.5 (24%) 0.78 (20%)
55 (47%)
3 (55%) 3.8 (55%)
< one week (N = 10)†
[8, 18.3]
[0.45, 0.96]
[19, 103]
[1.3, 6.1] [1.5, 8.8]
Full-term***
12.9 (28%) 0.66 (29%)
34 (21%)
1.5 (17%) 5.1 (22%)
≥ one week to ≤ 28 days (N = 10)† [7.7, 21.6] [0.35, 1.06]
[23, 50]
[1.2, 1.9] [3.3, 7.2]
Infant Patients
> 28 days to < 3
11 (27%) 0.79 (26%)
33 (26%)
1.8 (28%) 5.4 (32%)
Months (N = 12)†
[7.2, 18]
[0.42, 1.08]
[17, 48]
[1.2, 2.8] [3.5, 9.9]
Pediatric Patients
3 months through
15.1 (30%) 0.69 (28%)
58 (54%)
2.9 (53%) 3.8 (53%)
11 years† (N = 59)
[6.8, 36.7] [0.31, 1.50]
[19, 153]
[0.9, 8]
[1, 8.5]
Adolescent Subjects and Patients
12 through 17 years‡
16.7 (24%) 0.61 (15%)
95 (44%)
4.1 (46%) 2.1 (53%)
(N = 36)
[9.9, 28.9] [0.44, 0.79]
[32, 178]
[1.3, 8.1] [0.9, 5.2]
Adult Subjects§
12.5 (21%) 0.65 (16%)
91 (33%)
4.9 (35%) 1.7 (34%)
(N = 29)
[8.2, 19.3] [0.45, 0.84]
[53, 155]
[1.8, 8.3] [0.9, 3.3]
*
**
***
†
‡
§
AUC = Single dose AUC0-∞
In this data set, “pre-term” is defined as < 34 weeks gestational age (Note: Only one patient enrolled was
pre-term with a postnatal age between one week and 28 days)
In this data set, “full-term” is defined as ≥ 34 weeks gestational age
Dose of 10 mg/kg
Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg
Dose normalized to 600 mg Cmax = Maximum plasma concentration; Vss = Volume of distribution; AUC = Area
under concentration-time curve; t1/2 = Apparent elimination half-life; CL = Systemic clearance normalized
for body weight
Gender: Females have a slightly lower volume of distribution of linezolid than males. Plasma
concentrations are higher in females than in males, which is partly due to body weight differences. After a 600 mg dose, mean oral clearance is approximately 38% lower in females
than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender
does not appear to be necessary.
Renal Impairment: The pharmacokinetics of the parent drug, linezolid, are not altered in
patients with any degree of renal impairment; however, the two primary metabolites of linezolid accumulate in patients with renal impairment, with the amount of accumulation
increasing with the severity of renal dysfunction (see Table 10). The pharmacokinetics of
linezolid and its two metabolites have also been studied in patients with end-stage renal
disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with linezolid 600 mg every 12 hours for 14.5 days (see Table 11). Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information
on the clinical significance of accumulation of the primary metabolites, use of linezolid in
patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by
hemodialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour
hemodialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.
Table 10. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and
Metabolites A and B in Patients with Varying Degrees of Renal Impairment After a Single
600 mg Oral Dose of Linezolid
Parameter
Healthy Subjects
Moderate Renal
Severe Renal
CLCR > 80 mL/min
Impairment 30
Impairment 10
< CLCR < 80 mL/min < CLCR < 30 mL/min
LINEZOLID
AUC 0-∞ , mcg h/mL
t1/2 , hours
110 (22)
6.4 (2.2)
AUC 0-48 , mcg h/mL
t1/2 , hours
7.6 (1.9)
6.3 (2.1)
128 (53)
6.1 (1.7)
127 (66)
7.1 (3.7)
11.7 (4.3)
6.6 (2.3)
56.5 (30.6)
9 (4.6)
51.1 (38.5)
9.9 (7.4)
203 (92)
11 (3.9)
METABOLITE A
METABOLITE B 1
AUC 0-48 , mcg h/mL
t1/2 , hours
1
30.5 (6.2)
6.6 (2.7)
Metabolite B is the major metabolite of linezolid.
Table 11. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and
Metabolites A and B in Subjects with End-Stage Renal Disease (ESRD) After the Administration of 600 mg Linezolid Every 12 Hours for 14.5 Days
Parameter
ESRD Subjects 1
LINEZOLID
AUC 0-12 , mcg h/mL (after last dose)
t 1/2 , hours (after last dose)
181 (52.3)
8.3 (2.4)
METABOLITE A
t1/2 , hours (after last dose)
153 (40.6)
15.9 (8.5)
METABOLITE B 2
t 1/2 , hours (after last dose)
1
2
356 (99.7)
34.8 (23.1)
between hemodialysis sessions
Metabolite B is the major metabolite of linezolid.
Hepatic Impairment: The pharmacokinetics of linezolid are not altered in patients (n = 7) with
mild-to-moderate hepatic impairment (Child-Pugh class A or B). On the basis of the available
information, no dose adjustment is recommended for patients with mild-to-moderate hepatic
impairment. The pharmacokinetics of linezolid in patients with severe hepatic impairment
have not been evaluated.
Drug Interactions: Drugs Metabolized by Cytochrome P450: Linezolid is not an inducer of
cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major
enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such
as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without
changes in dosage regimen.
Antibiotics: Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when
administered together.
Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together.
Antioxidants: The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg
oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2 to 9,
subjects were given either Vitamin C (1000 mg/day) or Vitamin E (800 IU/ day). The AUC0-∞ of
linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co-administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration
with Vitamin C or Vitamin E.
Strong CYP 3A4 Inducers: Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral
linezolid 600 mg twice daily for five doses with and without rifampin 600 mg once daily for
8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid
Cmax [90% CI, 15% to 27%] and a 32% decrease in linezolid AUC0-12 [90% CI, 27% to 37%].
The clinical significance of this interaction is unknown. The mechanism of this interaction is
not fully understood and may be related to the induction of hepatic enzymes. Other strong
inducers of hepatic enzymes (e.g., carbamazepine, phenytoin, phenobarbital) could cause a
similar or smaller decrease in linezolid exposure.
Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine
oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic
agents.
Adrenergic Agents: Some individuals receiving linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or
dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as
dopamine or epinephrine, should be reduced and titrated to achieve the desired response.
Tyramine: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid
need to avoid consuming large amounts of foods or beverages with high tyramine content [see
Patient Counseling Information (17)].
Pseudoephedrine Hydrochloride or Phenylpropanolamine Hydrochloride: A reversible
enhancement of the pressor response of either pseudoephedrine hydrochloride (PSE) or
phenylpropanolamine hydrochloride (PPA) is observed when linezolid is administered to
healthy normotensive subjects [see Warnings and Precautions (5.6) and Drug Interactions
(7)]. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects
of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid
(600 mg every 12 hours for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4
hours apart. Heart rate was not affected by any of the treatments. Blood pressure was
increased with both combination treatments. Maximum blood pressure levels were seen 2 to
3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after
peak. The results of the PPA study follow, showing the mean (and range) maximum systolic
blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135);
PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the
PSE study were similar to those in the PPA study. The mean maximum increase in systolic
Page 6 of 9
blood pressure over baseline was 32 mm Hg (range: 20 to 52 mm Hg) and 38 mm Hg (range:
18 to 79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.
Serotonergic Agents: Dextromethorphan: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome
effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have
been observed in normal subjects receiving linezolid and dextromethorphan.
12.4 Microbiology
Mechanism of Action: Linezolid is a synthetic antibacterial agent of the oxazolidinone class,
which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the
50S subunit and prevents the formation of a functional 70S initiation complex, which is
essential for bacterial reproduction. The results of time-kill studies have shown linezolid to be
bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to
be bactericidal for the majority of isolates.
Mechanisms of Resistance: In vitro studies have shown that point mutations in the 23S rRNA
are associated with linezolid resistance. Reports of vancomycin-resistant Enterococcus faecium becoming resistant to linezolid during its clinical use have been published. There are
reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid
during clinical use. The linezolid resistance in these organisms is associated with a point
mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding
23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to linezolid. Also linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a
plasmid which is transferable between staphylococci.
Interaction with Other Antimicrobials: In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.
Linezolid has been shown to be active against most isolates of the following microorganisms,
both in vitro and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria
Enterococcus faecium (vancomycin-resistant isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Greater than 90% of the following bacteria exhibit an in vitro MIC less than or equal to the
linezolid-susceptible breakpoint for organisms of similar genus shown in Table 12. The safety and effectiveness of linezolid in treating clinical infections due to these bacteria have not
been established in adequate and well-controlled clinical trials.
Enterococcus faecalis (including vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
Viridans group streptococci
Gram-negative bacteria
Pasteurella multocida
Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in
local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid
the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized
method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 12.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters can
also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial
compounds. The zone size should be determined using a standardized test method2,3. This
procedure uses paper disks impregnated with 30 mcg linezolid to test the susceptibility of
bacteria to linezolid. The disk diffusion interpretive criteria are provided in Table 12.
Table 12. Susceptibility Test Interpretive Criteria for Linezolid
Pathogen
Susceptibility Interpretive Criteria
Minimal Inhibitory Concentrations
Disk Diffusion
(MIC in mcg/mL)
(Zone Diameters in mm)
S
I
R
S
I
R
Enterococcus spp
≤2
4
≥8
≥ 23
21 to 22
≤ 20
Staphylococcus sppa
≤4
—
—
≥ 21
—
—
Streptococcus pneumoniae b
≤2
—
—
≥ 21
—
—
Streptococcus spp other
≤2
—
—
≥ 21
—
—
than S pneumoniae b
S = susceptible, I = intermediate, R = resistant
a
b
For disk diffusion testing of staphylococcal species, petri plates should be held up to the light
source and read with transmitted light. The zone margin should be considered the area showing no
obvious, visible growth that can be detected with the unaided eye. Ignore faint growth of tiny
colonies that can be detected only with a magnifying lens at the edge of the zone of inhibited growth.
Any discernible growth within the zone of inhibition is indicative of resistance. Resistant results
obtained by the disk diffusion method should be confirmed using an MIC method.
The current absence of data on resistant isolates precludes defining any categories other than “Susceptible”. Isolates yielding test results suggestive of a “nonsusceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.
A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the
pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of
infection. A report of “Intermediate” indicates that the result should be considered equivocal,
and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test
should be repeated. This category implies possible clinical applicability in body sites where
the drug product is physiologically concentrated or in situations where a high dosage of the
drug product can be used. This category also provides a buffer zone that prevents small
uncontrolled technical factors from causing major discrepancies in interpretation. A report of
“Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if
the antimicrobial drug reaches the concentration usually achievable at the site of infection;
other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the
assay, and the techniques of the individuals performing the test1,2,3. Standard linezolid powder should provide the following range of MIC values noted in Table 13. For the diffusion technique using the 30 mcg linezolid disk, the criteria in Table 13 should be achieved.
Table 13. Acceptable Quality Control Ranges for Linezolid
Minimum Inhibitory Ranges Disk Diffusion Ranges Zone
(MIC in mcg/mL)
Diameters (mm)
Enterococcus faecalis ATCC 29212
Staphylococcus aureus ATCC 29213
Staphylococcus aureus ATCC 25923
Streptococcus pneumoniae ATCC 49619 a
a
1 to 4
1 to 4
Not applicable
0.25 to 2
Not applicable
Not applicable
25 to 32
25 to 34
This organism may be used for validation of susceptibility test results when testing Streptococcus spp.
other than S. pneumoniae.
Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential
of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests
including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an
in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in
human lymphocytes, and an in vivo mouse micronucleus assay.
Linezolid did not affect the fertility or reproductive performance of adult female rats. It
reversibly decreased fertility and reproductive performance in adult male rats when given at
doses ≥ 50 mg/kg/day, with exposures approximately equal to or greater than the expected
human exposure level (exposure comparisons are based on AUCs). The reversible fertility
effects were mediated through altered spermatogenesis. Affected spermatids contained
abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy
and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.
In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was
observed following treatment with linezolid through most of their period of sexual development
(50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with
exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged 3 months
to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding
to exposure in utero through the early neonatal period (gestation day 6 through postnatal day
5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to
35). Reversible reductions in sperm motility and altered sperm morphology were observed in
rats treated from postnatal day 22 to 35.
Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose-and
time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased
hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased
levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies.
Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid
findings were associated with anorexia, weight loss, and suppression of body weight gain,
which may have contributed to the observed effects.
In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal
degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the
sciatic nerve was also observed in one male at this dose level at a 3-month interim necropsy.
Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident
in two male rats after 6 months of dosing, but the direct relationship to drug was equivocal
because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve
degeneration reported in aging rats and may be an exacerbation of common background
change.
Page 7 of 9
These effects were observed at exposure levels that are comparable to those observed in some
human subjects. The hematopoietic and lymphoid effects were reversible, although in some
studies, reversal was incomplete within the duration of the recovery period.
14 CLINICAL STUDIES
14.1 Adults
Nosocomial Pneumonia: Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients
were treated for 7 to 21 days. One group received linezolid I.V. injection 600 mg every 12 hours,
and the other group received vancomycin 1 g every 12 hours intravenously. Both groups
received concomitant aztreonam (1 g to 2 g every 8 hours intravenously), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated
patients enrolled in the study. One hundred twenty-two (60%) linezolid-treated patients and
103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically
evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated
patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia
were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified
intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated
patients included subjects who had a pathogen isolated before treatment. The cure rates in
the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated
patients. The cure rates by pathogen for microbiologically evaluable patients are presented in
Table 14.
Table 14. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult
Patients with Nosocomial Pneumonia
Pathogen
Cured
Staphylococcus aureus
Methicillin-resistant S. aureus
Linezolid
n/N (%)
23/38 (61)
13/22 (59)
9/9 (100)
Vancomycin
n/N (%)
14/23 (61)
7/10 (70)
9/10 (90)
Complicated Skin and Skin Structure Infections: Adult patients with clinically documented
complicated skin and skin structure infections were enrolled in a randomized, multi-center,
double-blind, double-dummy trial comparing study medications administered intravenously
followed by medications given orally for a total of 10 to 21 days of treatment. One group of
patients received linezolid I.V. injection 600 mg every 12 hours followed by linezolid tablets
600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated
patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242
(58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A
modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillintreated patients included subjects who met all criteria for study entry. The cure rates in the
MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients.
The cure rates by pathogen for microbiologically evaluable patients are presented in Table 15.
Patients with Complicated Skin and Skin Structure Infections
Pathogen
Cured
Linezolid
n/N (%)
73/83 (88)
2/3 (67)
6/6 (100)
18/26 (69)
Oxacillin/Dicloxacillin
n/N (%)
72/84 (86)
0/0 (-)
3/6 (50)
21/28 (75)
A separate study provided additional experience with the use of linezolid in the treatment of
methicillin-resistant Staphylococcus aureus (MRSA) infections. This was a randomized, openlabel trial in hospitalized adult patients with documented or suspected MRSA infection.
One group of patients received linezolid I.V. injection 600 mg every 12 hours followed by linezolid
tablets 600 mg every 12 hours. The other group of patients received vancomycin 1 g every 12
hours intravenously. Both groups were treated for 7 to 28 days, and could receive concomitant
aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable
patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated
patients and 24/33 (73%) for vancomycin-treated patients.
Diabetic Foot Infections: Adult diabetic patients with clinically documented complicated
skin and skin structure infections (“diabetic foot infections”) were enrolled in a randomized
(2:1 ratio), multi-center, open-label trial comparing study medications administered intravenously or orally for a total of 14 to 28 days of treatment. One group of patients received
linezolid 600 mg every 12 hours intravenously or orally; the other group received ampicillin/sulbactam 1.5 g to 3 g intravenously or amoxicillin/clavulanate 500 to 875 mg every
8 to 12 hours orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours was used for the intravenous regimen. Patients
in the comparator group could also be treated with vancomycin 1 g every 12 hours intravenously if MRSA was isolated from the foot infection. Patients in either treatment group who
had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 g
to 2 g every 8 to 12 hours intravenously. All patients were eligible to receive appropriate
adjunctive treatment methods, such as debridement and off-loading, as typically required in
the treatment of diabetic foot infections, and most patients received these treatments. There
were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT)
study population. Two hundred twelve (86%) linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were
68.5% (165/241) in linezolid-treated patients and 64% (77/120) in comparator-treated
patients, where those with indeterminate and missing outcomes were considered failures.
The cure rates in the clinically evaluable patients (excluding those with indeterminate and
missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid-and comparatortreated patients, respectively. A critical post-hoc analysis focused on 121 linezolid-treated
and 60 comparator-treated patients who had a Gram-positive pathogen isolated from the
site of infection or from blood, who had less evidence of underlying osteomyelitis than the
overall study population, and who did not receive prohibited antimicrobials. Based upon that
analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63%
(38/60) in the comparator-treated patients. None of the above analyses were adjusted for the
use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable
patients are presented in Table 16.
Patients with Diabetic Foot Infections
Pathogen
Cured
Linezolid
Comparator
n/N (%)
n/N (%)
49/63 (78)
20/29 (69)
12/17 (71)
2/3 (67)
25/29 (86)
9/16 (56)
Vancomycin-Resistant Enterococcal Infections: Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center,
double-blind trial comparing a high dose of linezolid (600 mg) with a low dose of linezolid
(200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could
receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to
high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in
the high-dose arm and 52 in the low-dose arm.
The cure rates for the ITT population with documented vancomycin-resistant enterococcal
infection at baseline are presented in Table 17 by source of infection. These cure rates do not
include patients with missing or indeterminate outcomes. The cure rate was higher in the
high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level.
Table 17. Cure Rates at the Test-of-Cure Visit for ITT Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at Baseline
Source of Infection
Cured
Linezolid
Linezolid
600 mg every 12 hours
200 mg every 12 hours
n/N (%)
n/N (%)
Any site
39/58 (67)
24/46 (52)
Any site with associated bacteremia
10/17 (59)
4/14 (29)
Bacteremia of unknown origin
5/10 (50)
2/7 (29)
Skin and skin structure
9/13 (69)
5/5 (100)
Urinary tract
12/19 (63)
12/20 (60)
Pneumonia
2/3 (67)
0/1 (0)
Other *
11/13 (85)
5/13 (39)
*
Includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic
abscess, pancreatitis, and catheter-related infection.
Infections due to Gram-positive Bacteria: A safety and efficacy study provided experience
on the use of linezolid in pediatric patients for the treatment of nosocomial pneumonia,
complicated skin and skin structure infections, and other infections due to Gram-positive
bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus
aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age
from birth through 11 years with infections caused by the documented or suspected Grampositive bacteria were enrolled in a randomized, open-label, comparator-controlled trial.
One group of patients received linezolid I.V. injection 10 mg/kg every 8 hours followed by
linezolid for oral suspension 10 mg/kg every 8 hours. A second group received vancomycin
10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance.
Patients who had confirmed VRE infections were placed in a third arm of the study and
received linezolid 10 mg/kg every 8 hours intravenously and/or orally. All patients were
treated for a total of 10 to 28 days and could receive concomitant Gram-negative antibiotics if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients
randomized to linezolid and 102 patients randomized to vancomycin. The cure rates for ITT,
MITT, and clinically evaluable patients are presented in Table 18. After the study was completed, 13 additional patients ranging from 4 days through 16 years of age were enrolled
in an open-label extension of the VRE arm of the study. Table 19 provides clinical cure
rates by pathogen for microbiologically evaluable patients including microbiologically
evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of
this study.
Page 8 of 9
Table 18. Cure Rates at the Test-of-Cure Visit for Intent-to-Treat, Modified Intent-to-Treat,
and Clinically Evaluable Pediatric Patients for the Overall Population and by Select Baseline Diagnosis
ITT
MITT*
Clinically Evaluable
Population
Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin
n/N (%)
n/N (%)
n/N (%)
n/N (%)
n/N (%)
n/N (%)
Any diagnosis
150/186 (81) 69/83 (83) 86/108 (80) 44/49 (90) 106/117 (91) 49/54 (91)
Complicated skin and skin
61/72 (85) 31/34 (91) 37/43 (86) 22/23 (96) 46/49 (94) 26/27 (96)
13/18 (72) 11/12 (92) 5/6 (83) 4/4 (100) 7/7 (100) 5/5 (100)
•
•
•
•
They should inform their physician if they experience changes in vision.
They should inform their physician if they have a history of seizures.
Diarrhea is a common problem caused by antibiotics, which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics,
patients can develop watery and bloody stools (with or without stomach cramps and
fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Inform patient, particularly those with diabetes mellitus that hypoglycemic reactions,
such as diaphoresis and tremulousness, along with low blood glucose measurements
may occur when treated with linezolid. If such reactions occur, patients should contact
a physician or other health professional for proper treatment.
* MITT = ITT patients with an isolated Gram-positive pathogen at baseline
Table 19. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Pediatric
Patients with Infections due to Gram-positive Pathogens
Microbiologically Evaluable
Pathogen
Linezolid
Vancomycin
n/N (%)
n/N (%)
Vancomycin-resistant Enterococcus faecium
6/8 (75)*
0/0 (-)
36/38 (95)
23/24 (96)
16/17 (94)
9/9 (100)
2/2 (100)
1/2 (50)
*
3.
JUNE 2015
LINZ:R1
Includes data from seven patients enrolled in the open-label extension of this study.
15
1.
2.
REFERENCES
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition.
CLSI document M07-A10, Clinical and Laboratory Standards Institiute, 950 West Valley
Road, Suite 2500, Wayne, Pennyslvania 19087, USA, 2015
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document
M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite
2500, Wayne, Pennsylvania 19087, USA, 2015
Clinical and Laboratory Standards, Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI
document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road,
Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
16.2 Tablets
Linezolid Tablets are available containing 600 mg of linezolid.
The 600 mg tablets are yellow, film-coated, oval, unscored tablets debossed with MYLAN on
one side of the tablet and L77 on the other side. They are available as follows:
NDC 0378-7077-94
NDC 0378-7077-01
NDC 0378-7077-05
16.4 Storage
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from
light.
Patients should be counseled that antibacterial drugs including linezolid tablets should only
be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
When linezolid tablets are prescribed to treat a bacterial infection, patients should be told that
although it is common to feel better early in the course of therapy, the medication should be
taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that
bacteria will develop resistance and will not be treatable by linezolid tablets or other antibacterial drugs in the future.
Patients should be advised that:
•
Linezolid tablets may be taken with or without food.
•
They should inform their physician if they have a history of hypertension.
•
Large quantities of foods or beverages with high tyramine content should be avoided
while taking linezolid tablets. Foods high in tyramine content include those that may
have undergone protein changes by aging, fermentation, pickling, or smoking to
improve flavor, such as aged cheeses, fermented or air-dried meats, sauerkraut, soy
sauce, tap beers, and red wines. The tyramine content of any protein-rich food may be
increased if stored for long periods or improperly refrigerated.
•
They should inform their physician if taking medications containing pseudoephedrine
hydrochloride or phenylpropanolamine hydrochloride, such as cold remedies and decongestants.
•
They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.
Page 9 of 9
These highlights do not include all the information needed to use MOXIFLOXACIN HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for MOXIFLOXACIN
HYDROCHLORIDE TABLETS.
MOXIFLOXACIN HYDROCHLORIDE tablets, film-coated, for oral use
WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS
See full prescribing information for complete boxed warning
• Fluoroquinolones, including moxifloxacin hydrochloride tablets, are associated with
an increased risk of tendinitis and tendon rupture in all ages. This risk is further
increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (5.1).
• Fluoroquinolones, including moxifloxacin hydrochloride tablets, may exacerbate
muscle weakness in persons with myasthenia gravis. Avoid moxifloxacin hydrochloride tablets in patients with known history of myasthenia gravis (5.2).
----------------------------------- RECENT MAJOR CHANGES ---------------------------------Indications and Usage (1.7)
5/15
Dosage and Administration (2.1)
5/15
Warnings and Precautions (5.10)
11/14
----------------------------------- INDICATIONS AND USAGE ----------------------------------Moxifloxacin hydrochloride tablets are a fluoroquinolone antibacterial indicated for treating
infections in adults 18 years of age and older caused by designated susceptible bacteria, in
the conditions listed below:
• Acute Bacterial Sinusitis (1.1)
• Acute Bacterial Exacerbation of Chronic Bronchitis (1.2)
• Community Acquired Pneumonia (1.3)
• Skin and Skin Structure Infections: Uncomplicated (1.4) and Complicated (1.5)
• Complicated Intra-Abdominal Infections (1.6)
• Plague (1.7)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of moxifloxacin hydrochloride tablets and other antibacterial drugs. Moxifloxacin hydrochloride
tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.8)
-------------------------------- DOSAGE AND ADMINISTRATION -------------------------------Type of Infection
Acute Bacterial Sinusitis (1.1)
Acute Bacterial Exacerbation of Chronic Bronchitis (1.2)
Community Acquired Pneumonia (1.3)
Uncomplicated Skin and Skin Structure Infections (SSSI) (1.4)
Complicated SSSI (1.5)
Complicated Intra-Abdominal Infections (1.6)
Plague (1.7)
Dose Every
24 hours
400 mg
400 mg
400 mg
400 mg
400 mg
400 mg
400 mg
Duration
(days)
10
5
7 to 14
7
7 to 21
5 to 14
10 to 14
------------------------------- DOSAGE FORMS AND STRENGTHS -----------------------------• Tablets: Moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin) (3.1)
------------------------------------- CONTRAINDICATIONS ------------------------------------Known hypersensitivity to moxifloxacin hydrochloride tablets or other quinolones (4, 5.4)
-------------------------------- WARNINGS AND PRECAUTIONS -------------------------------• Prolongation of the QT interval and isolated cases of torsade de pointes has been reported.
Avoid use in patients with known prolongation, proarrhythmic conditions such as clinically
significant bradycardia or acute myocardial ischemia, hypokalemia, hypomagnesemia, and
with drugs that prolong the QT interval. (5.3, 7.5, 8.5)
• Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions,
including anaphylactic reactions, may occur after first or subsequent doses. Discontinue
drug use at first sign of skin rash, jaundice or any other sign of hypersensitivity. (5.4, 5.5)
• Central nervous system (CNS) events including dizziness, confusion, hallucination, depression, and suicidal thoughts or acts may occur after first dose. Use caution in patients with
known or suspected CNS disorders that may predispose to seizures or lower the seizure
threshold. (5.6)
• Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs. (5.7)
• Peripheral neuropathy: Discontinue if symptoms occur in order to prevent irreversibility.
(5.8)
------------------------------------- ADVERSE REACTIONS ------------------------------------Most common reactions (3% or greater) were nausea, diarrhea, headache, and dizziness. (6)
------------------------------------- DRUG INTERACTIONS ------------------------------------Interacting Drug
Multivalent cationcontaining products
including: antacids,
sucralfate, multivitamins
Warfarin
Class IA and Class III
antiarrhythmics:
Antidiabetic agents
Interaction
Decreased moxifloxacin hydrochloride absorption. Take
moxifloxacin hydrochloride tablet at least 4 hours before
or 8 hours after these products. (2.2, 7.1, 12.3)
Anticoagulant effect enhanced. Monitor prothrombin time/INR,
and bleeding. (6, 7.2, 12.3)
Proarrhythmic effect may be enhanced. Avoid concomitant
use. (5.3, 7.4)
Carefully monitor blood glucose. (5.10, 7.3)
------------------------------- USE IN SPECIFIC POPULATIONS ------------------------------• Pregnancy: Based on animal data may cause fetal harm. (8.1)
• Geriatrics: Increased risk for severe tendon disorders further increased by concomitant
corticosteroid therapy and increased risk of prolongation of the QT interval. (5.1, 5.3, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
REVISED AUGUST 2015
MX:MOXI:R3mh/MX:MG:MOXI:R3mh
• No dosage adjustment in patients with renal or hepatic impairment. (8.6, 8.7)
WARNING: TENDON EFFECTS AND MYASTHENIA GRAVIS
1
1.1 Acute Bacterial Sinusitis
1.2 Acute Bacterial Exacerbation of Chronic Bronchitis
1.3 Community Acquired Pneumonia
1.4 Uncomplicated Skin and Skin Structure Infections
1.5 Complicated Skin and Skin Structure Infections
1.6 Complicated Intra-Abdominal Infections
1.7 Plague
1.8 Usage
2
2.1 Dosage in Adult Patients
3
3.1 Moxifloxacin Hydrochloride Tablets
4
CONTRAINDICATIONS
5
5.1 Tendinopathy and Tendon Rupture
5.2 Exacerbation of Myasthenia Gravis
5.3 QT Prolongation
5.4 Hypersensitivity Reactions
5.5 Other Serious and Sometimes Fatal Reactions
5.6 Central Nervous System Effects
5.7
5.8
5.9
5.10
5.11
5.12
Clostridium Difficile-Associated Diarrhea
Peripheral Neuropathy
Arthropathic Effects in Animals
Blood Glucose Disturbances
Photosensitivity/Phototoxicity
Development of Drug Resistant Bacteria
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1 Antacids, Sucralfate, Multivitamins and Other
Products Containing Multivalent Cations
7.2 Warfarin
7.3 Antidiabetic Agents
7.4 Nonsteroidal Anti-Inflammatory Drugs
7.5 Drugs that Prolong QT
8
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
12.4 Microbiology
13
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
14.2 Acute Bacterial Exacerbation of Chronic
Bronchitis
14.4 Uncomplicated Skin and Skin Structure
Infections
14.7 Plague
15
REFERENCES
16
17
*Sections or subsections omitted from the Full Prescribing Information are not listed
Page 1 of 13
WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS
• Fluoroquinolones, including moxifloxacin hydrochloride tablets, are associated with
an increased risk of tendinitis and tendon rupture in all ages. This risk is further
increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants [see Warnings
• Fluoroquinolones, including moxifloxacin hydrochloride tablets, may exacerbate
muscle weakness in persons with myasthenia gravis. Avoid moxifloxacin hydrochloride tablets in patients with known history of myasthenia gravis [see Warnings and
Precautions (5.2)].
1
Moxifloxacin hydrochloride tablets are indicated in adult patients (18 years of age and older)
for the treatment of Acute Bacterial Sinusitis caused by susceptible isolates of Streptococcus
pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.1)].
Moxifloxacin hydrochloride tablets are indicated in adult patients for the treatment of Acute Bacterial Exacerbation of Chronic Bronchitis caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus, or Moraxella catarrhalis [see Clinical Studies (14.2)].
Moxifloxacin hydrochloride tablets are indicated in adult patients for the treatment of Community Acquired Pneumonia caused by susceptible isolates of Streptococcus pneumoniae (including multi-drug resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae,
Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus, Klebsiella pneumoniae,
Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Clinical Studies (14.3)].
MDRSP isolates are isolates resistant to two or more of the following antibacterial drugs: penicillin (minimum inhibitory concentrations [MIC] ≥ 2 mcg/mL), 2nd generation cephalosporins
(for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
Moxifloxacin hydrochloride tablets are indicated in adult patients for the treatment of Uncomplicated Skin and Skin Structure Infections caused by susceptible isolates of methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes [see Clinical Studies (14.4)].
Moxifloxacin hydrochloride tablets are indicated in adult patients for the treatment of Complicated Skin and Skin Structure Infections caused by susceptible isolates of methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter
cloacae [see Clinical Studies (14.5)].
Moxifloxacin hydrochloride tablets are indicated in adult patients for the treatment of Complicated Intra-Abdominal Infections including polymicrobial infections such as abscess caused by
susceptible isolates of Escherichia coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, or Peptostreptococcus species [see Clinical Studies (14.6)].
1.7 Plague
Moxifloxacin hydrochloride tablets are indicated in adult patients for the treatment of plague,
including pneumonic and septicemic plague, due to susceptible isolates of Yersinia pestis
and prophylaxis of plague in adult patients. Efficacy studies of moxifloxacin could not be conducted in humans with plague for feasibility reasons. Therefore this indication is based on an
efficacy study conducted in animals only [see Clinical Studies (14.7)].
1.8 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of moxifloxacin hydrochloride tablets and other antibacterial drugs, moxifloxacin hydrochloride
tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are
available, they should be considered in selecting or modifying antibacterial therapy. In the
absence of such data, local epidemiology and susceptibility patterns may contribute to the
empiric selection of therapy.
2
2.1 Dosage in Adult Patients
The dose of moxifloxacin hydrochloride tablets is 400 mg (orally) once every 24 hours. The
duration of therapy depends on the type of infection as described in Table 1.
Table 1. Dosage and Duration of Therapy in Adult Patients
Type of Infectiona
Acute Bacterial Sinusitis (1.1)
Acute Bacterial Exacerbation of Chronic Bronchitis (1.2)
Community Acquired Pneumonia (1.3)
Uncomplicated Skin and Skin Structure Infections (SSSI) (1.4)
Complicated SSSI (1.5)
Complicated Intra-Abdominal Infections (1.6)
Plague (1.7)c
a)
Due to the designated pathogens [see Indications and Usage (1)].
b)
c)
Dose
Every 24 hours
400 mg
400 mg
400 mg
400 mg
400 mg
400 mg
400 mg
b
Duration
(days)
10
5
7 to 14
7
7 to 21
5 to 14
10 to 14
Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician
Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia
pestis.
Conversion of Intravenous to Oral Dosing in Adults: Intravenous formulation is indicated when
it offers a route of administration advantageous to the patient (for example, patient cannot tolerate an oral dosage form). When switching from intravenous to oral formulation, no dosage
adjustment is necessary. Patients whose therapy is started with moxifloxacin hydrochloride
injection may be switched to moxifloxacin hydrochloride tablets when clinically indicated at the
discretion of the physician.
Moxifloxacin Hydrochloride Tablets: With Multivalent Cations: Administer moxifloxacin
hydrochloride tablets at least 4 hours before or 8 hours after products containing magnesium,
aluminum, iron or zinc, including antacids, sucralfate, multivitamins and didanosine buffered
tablets for oral suspension or the pediatric powder for oral solution [see Drug Interactions
With Food: Moxifloxacin hydrochloride tablets can be taken with or without food, drink fluids
liberally.
3
Pink, film-coated, capsule shaped tablets debossed with M on one side of the tablet and MO1 on
the other side containing moxifloxacin hydrochloride, USP (equivalent to 400 mg moxifloxacin).
4
CONTRAINDICATIONS
Moxifloxacin hydrochloride tablets are contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antibacterials [see Warnings
5
5.1 Tendinopathy and Tendon Rupture
Fluoroquinolones, including moxifloxacin, are associated with an increased risk of tendinitis
and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles
tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon
rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis
and tendon rupture is further increased in older patients usually over 60 years of age, in
patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
Factors, in addition to age and corticosteroid use, that may independently increase the risk of
tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in
patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can
occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Moxifloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest
at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider
regarding changing to a non-quinolone antimicrobial drug.
5.2 Exacerbation of Myasthenia Gravis
Fluoroquinolones, including moxifloxacin, have neuromuscular blocking activity and may
exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious
adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid moxifloxacin in
patients with known history of myasthenia gravis.
5.3 QT Prolongation
Moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some
patients. Following oral dosing with 400 mg of moxifloxacin the mean (± SD) change in QTc from
the pre-dose value at the time of maximum drug concentration was 6 msec (± 26) (n = 787).
Following a course of daily intravenous dosing (400 mg; 1 hour infusion each day) the mean
change in QTc from the Day 1 pre-dose value was 10 msec (± 22) on Day 1 (n = 667) and 7 msec
(± 24) on Day 3 (n = 667).
Avoid moxifloxacin in patients with the following risk factors due to the lack of clinical experience with the drug in these patient populations:
• Known prolongation of the QT interval
• Ventricular arrhythmias including torsade de pointes because QT prolongation may lead to
an increased risk for these conditions
• Ongoing proarrhythmic conditions, such as clinically significant bradycardia and acute
myocardial ischemia,
• Uncorrected hypokalemia or hypomagnesemia
• Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone,
sotalol) antiarrhythmic agents
• Other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics,
and tricyclic antidepressants
In patients with mild, moderate, or severe liver cirrhosis, metabolic disturbances associated
with hepatic insufficiency may lead to QT prolongation. Monitor ECG in patients with liver cirrhosis treated with moxifloxacin. [See Clinical Pharmacology (12.3).]
The magnitude of QT prolongation may increase with increasing concentrations of the drug or
increasing rates of infusion of the intravenous formulation. Therefore the recommended dose
or infusion rate should not be exceeded.
In premarketing clinical trials, the rate of cardiovascular adverse reactions was similar in 798
moxifloxacin and 702 comparator treated patients who received concomitant therapy with
drugs known to prolong the QTc interval. No excess in cardiovascular morbidity or mortality
attributable to QTc prolongation occurred with moxifloxacin treatment in over 15,500 patients
in controlled clinical studies, including 759 patients who were hypokalemic at the start of
treatment, and there was no increase in mortality in over 18,000 moxifloxacin tablet treated
patients in a postmarketing observational study in which ECGs were not performed.
Page 2 of 13
5.4 Hypersensitivity Reactions
Serious anaphylactic reactions, some following the first dose, have been reported in patients
receiving quinolone therapy, including moxifloxacin. Some reactions were accompanied by
cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Discontinue moxifloxacin at the first appearance of a skin rash or
any other sign of hypersensitivity. [See Warnings and Precautions (5.5).]
5.5 Other Serious and Sometimes Fatal Reactions
Other serious and sometimes fatal reactions, some due to hypersensitivity, and some due to
uncertain etiology, have been reported in patients receiving therapy with fluoroquinolones,
including moxifloxacin. These reactions may be severe and generally occur following the
administration of multiple doses. Clinical manifestations may include one or more of the following:
•
Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis,
Stevens-Johnson syndrome)
•
Vasculitis; arthralgia; myalgia; serum sickness
•
Allergic pneumonitis
•
Interstitial nephritis; acute renal insufficiency or failure
•
Hepatitis; jaundice; acute hepatic necrosis or failure
•
Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other
hematologic abnormalities
Discontinue moxifloxacin immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and institute supportive measures.
5.6 Central Nervous System Effects
Fluoroquinolones, including moxifloxacin, may cause central nervous system (CNS) reactions,
including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
Convulsions and increased intracranial pressure (including pseudotumor cerebri) have been
reported in patients receiving fluoroquinolones, including moxifloxacin. Moxifloxacin may
also cause central nervous system (CNS) reactions including: dizziness, confusion, tremors,
hallucinations, depression, and, suicidal thoughts or acts. These adverse reactions may
occur following the first dose. If these reactions occur in patients receiving moxifloxacin, the
drug should be discontinued and appropriate measures instituted. As with all fluoroquinolones, use moxifloxacin when the benefits of treatment exceed the risks in patients with
known or suspected CNS disorders (for example, severe cerebral arteriosclerosis, epilepsy) or
in the presence of other risk factors that may predispose to seizures or lower the seizure
threshold. [See Drug Interactions (7.4).]
5.7 Clostridium Difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including moxifloxacin, and may range in severity from mild diarrhea to fatal
colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections
can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical
history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may
need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
5.8 Peripheral Neuropathy
Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons
resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in
patients receiving fluoroquinolones including moxifloxacin. Symptoms may occur soon after
initiation of moxifloxacin and may be irreversible. Moxifloxacin should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning,
tingling, numbness, and/or weakness or other alterations of sensation including light touch,
pain, temperature, position sense, and vibratory sensation.
5.9 Arthropathic Effects in Animals
In immature dogs, oral administration of moxifloxacin caused lameness. Histopathological
examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing
joints and other signs of arthropathy in immature animals of various species. [See Nonclinical Toxicology (13.2).]
5.10 Blood Glucose Disturbances
As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and
hyperglycemia have been reported with moxifloxacin. In moxifloxacin-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment
with an oral hypoglycemic agent (for example, sulfonylurea) or with insulin. In diabetic
patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction
occurs, moxifloxacin should be discontinued and appropriate therapy should be initiated
immediately. [See Drug Interactions (7.3).]
5.11 Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest
as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoro-
quinolones, including moxifloxacin, after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Moxifloxacin should be discontinued if phototoxicity occurs. [See Clinical Pharmacology (12.2).]
5.12 Development of Drug Resistant Bacteria
Prescribing moxifloxacin in the absence of a proven or strongly suspected bacterial infection
or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk
of the development of drug-resistant bacteria.
6
ADVERSE REACTIONS
The following serious and otherwise important adverse reactions are discussed in greater
detail in the warnings and precautions section of the label:
•
Tendinopathy and Tendon Rupture [see Warnings and Precautions (5.1)]
•
Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]
•
QT Prolongation [see Warnings and Precautions (5.3)]
•
Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
•
Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.5)]
•
Central Nervous System Effects [see Warnings and Precautions (5.6)]
•
Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]
•
Peripheral Neuropathy that may be irreversible [see Warnings and Precautions (5.8)]
•
Blood Glucose Disturbances [see Warnings and Precautions (5.10)]
•
Photosensitivity/Phototoxicity [see Warnings and Precautions (5.11)]
•
Development of Drug Resistant Bacteria [see Warnings and Precautions (5.12)]
The data described below reflect exposure to moxifloxacin in 14,981 patients in 71 active controlled Phase II to IV clinical trials in different indications [see Indications and Usage (1)]. The
population studied had a mean age of 50 years (approximately 73% of the population was
less than 65 years of age), 50% were male, 63% were Caucasian, 12% were Asian and 9%
were Black. Patients received moxifloxacin 400 mg once daily oral, intravenous, or sequentially (intravenous followed by oral). Treatment duration was usually 6 to 10 days, and the
mean number of days on therapy was 9 days.
Discontinuation of moxifloxacin due to adverse reactions occurred in 5% of patients overall,
4% of patients treated with 400 mg PO, 4% with 400 mg intravenous and 8% with sequential therapy 400 mg oral/intravenous. The most common adverse reactions (> 0.3%) leading
to discontinuation with the 400 mg oral doses were nausea, diarrhea, dizziness, and vomiting. The most common adverse reaction leading to discontinuation with the 400 mg intravenous dose was rash. The most common adverse reactions leading to discontinuation with
the 400 mg intravenous/oral sequential dose were diarrhea, pyrexia.
Adverse reactions occurring in 1% of moxifloxacin-treated patients and less common adverse
reactions, occurring in 0.1 to 1% of moxifloxacin-treated patients, are shown in Table 2 and
Table 3, respectively. The most common adverse drug reactions (3%) are nausea, diarrhea,
headache, and dizziness.
Table 2. Common (1% or more) Adverse Reactions Reported in Active-Controlled Clinical
Trials with Moxifloxacin
System Organ Class
Adverse Reactions
Blood and Lymphatic System Disorders
Anemia
Nausea
Diarrhea
Vomiting
Constipation
Abdominal pain
Dyspepsia
Pyrexia
General Disorders and Administration Site
Conditions
Investigations
Metabolism and Nutritional Disorder
Alanine aminotransferase
increased
Hypokalemia
Headache
Dizziness
Insomnia
%
(N = 14,981)
1
7
6
2
2
2
1
1
1
1
4
3
2
Table 3. Less Common (0.1 to less than 1%) Adverse Reactions Reported in ActiveControlled Clinical Trials with Moxifloxacin (N = 14,981)
System Organ Class
Cardiac Disorders
Adverse Reactions
Thrombocythemia
Eosinophilia
Neutropenia
Thrombocytopenia
Leukopenia
Leukocytosis
Atrial fibrillation
Palpitations
Tachycardia
Continued
Page 3 of 13
System Organ Class
Cardiac Disorders
System Organ Class
Skin and Subcutaneous Tissue Disorders
Ear and Labyrinth Disorders
Eye Disorders
General Disorders and Administration Site
Conditions
Hepatobiliary disorders
Infections and Infestations
Investigations
Metabolism and Nutrition Disorders
Musculoskeletal and Connective Tissue
Disorders
Renal and Urinary Disorders
Reproductive System and Breast Disorders
Respiratory, Thoracic, and Mediastinal
Disorders
Adverse Reactions
Angina pectoris
Cardiac failure
Cardiac arrest
Bradycardia
Vertigo
Tinnitus
Vision blurred
Dry mouth
Abdominal discomfort
Flatulence
Abdominal distention
Gastritis
Gastroesophageal reflux disease
Fatigue
Chest pain
Asthenia
Pain
Malaise
Infusion site extravasation
Edema
Chills
Chest discomfort
Facial pain
Hepatic function abnormal
Candidiasis
Vaginal infection
Fungal infection
Gastroenteritis
Aspartate aminotransferase increased
Gamma-glutamyltransferase increased
Blood alkaline phosphatase increased
Electrocardiogram QT prolonged
Blood lactate dehydrogenase increased
Blood amylase increased
Lipase increased
Blood creatinine increased
Blood urea increased
Hematocrit decreased
Prothrombin time prolonged
Eosinophil count increased
Activated partial thromboplastin time
prolonged
Blood triglycerides increased
Blood uric acid increased
Hyperglycemia
Anorexia
Hyperlipidemia
Decreased appetite
Dehydration
Back pain
Pain in extremity
Arthralgia
Muscle spasms
Musculoskeletal pain
Dysgeusia
Somnolence
Tremor
Lethargy
Paresthesia
Hypoesthesia
Syncope
Anxiety
Confusional state
Agitation
Depression
Nervousness
Restlessness
Hallucination
Disorientation
Renal failure
Dysuria
Vulvovaginal pruritus
Dyspnea
Asthma
Wheezing
Bronchospasm
Continued
Vascular Disorders
Adverse Reactions
Rash
Pruritus
Hyperhidrosis
Erythema
Urticaria
Dermatitis allergic
Night sweats
Hypertension
Hypotension
Phlebitis
Laboratory Changes: Changes in laboratory parameters, which are not listed above and
which occurred in 2% or more of patients and at an incidence greater than in controls included: increases in mean corpuscular hemoglobin (MCH), neutrophils, white blood cells (WBCs),
prothrombin time (PT) ratio, ionized calcium, chloride, albumin, globulin, bilirubin; decreases
in hemoglobin, red blood cells (RBCs), neutrophils, eosinophils, basophils, glucose, oxygen
partial pressure (pO2), bilirubin, and amylase. It cannot be determined if any of the above laboratory abnormalities were caused by the drug or the underlying condition being treated.
Table 4 below lists adverse reactions that have been identified during post-approval use of
moxifloxacin. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Table 4. Postmarketing Reports of Adverse Drug Reactions
System Organ Class
Adverse Reaction
Agranulocytosis
Pancytopenia
Cardiac Disorders
Ventricular tachyarrhythmias (including
in very rare cases cardiac arrest and
torsade de pointes, and usually in patients
with concurrent severe underlying
proarrhythmic conditions)
Ear and Labyrinth Disorders
Hearing impairment, including deafness
(reversible in majority of cases)
Eye Disorders
Vision loss (especially in the course of
CNS reactions, transient in majority
of cases)
Hepatobiliary Disorders
Hepatitis (predominantly cholestatic)
Hepatic failure (including fatal cases)
Jaundice
Acute hepatic necrosis
Immune System Disorders
Anaphylactic reaction
Anaphylactic shock
Angioedema (including laryngeal edema)
[see Warnings and Precautions (5.4, 5.5)]
Musculoskeletal and Connective Tissue
Disorders
Tendon rupture
Altered coordination
Abnormal gait
Myasthenia gravis (exacerbation of)
Muscle weakness
Peripheral neuropathy (that may be
irreversible), polyneuropathy
Psychotic reaction (very rarely culminating
in self-injurious behavior, such as suicidal
ideation/thoughts or suicide attempts)
Interstitial nephritis
Renal and Urinary Disorders
Respiratory, Thoracic and Mediastinal
Disorders
Allergic pneumonitis
Skin and Subcutaneous Tissue Disorders
Photosensitivity/phototoxicity reaction
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Page 4 of 13
7
7.1
DRUG INTERACTIONS
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent
Cations
Fluoroquinolones, including moxifloxacin, form chelates with alkaline earth and transition metal
cations. Oral administration of moxifloxacin with antacids containing aluminum or magnesium,
with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc,
or with formulations containing divalent and trivalent cations such as didanosine buffered
tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere
with the absorption of moxifloxacin, resulting in systemic concentrations considerably lower than
desired. Therefore, moxifloxacin should be taken at least 4 hours before or 8 hours after these
agents. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3).]
7.2 Warfarin
Fluoroquinolones, including moxifloxacin, have been reported to enhance the anticoagulant
effects of warfarin or its derivatives in the patient population. In addition, infectious disease
and its accompanying inflammatory process, age, and general status of the patient are risk
factors for increased anticoagulant activity. Therefore the prothrombin time, International
Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if
moxifloxacin is administered concomitantly with warfarin or its derivatives. [See Adverse
Reactions (6.2) and Clinical Pharmacology (12.3).]
7.3 Antidiabetic Agents
Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported
in patients treated concomitantly with fluoroquinolones, including moxifloxacin, and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these
agents are coadministered. If a hypoglycemic reaction occurs, moxifloxacin should be discontinued and appropriate therapy should be initiated immediately. [See Warnings and Precautions (5.10) and Adverse Reactions (6.1).]
7.4 Nonsteroidal Anti-Inflammatory Drugs
The concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) with a fluoroquinolone, including moxifloxacin, may increase the risks of CNS stimulation and convulsions [see Warnings and Precautions (5.6)].
7.5 Drugs that Prolong QT
There is limited information available on the potential for a pharmacodynamic interaction in
humans between moxifloxacin and other drugs that prolong the QTc interval of the electrocardiogram. Sotalol, a Class III antiarrhythmic, has been shown to further increase the QTc interval when
combined with high doses of intravenous moxifloxacin in dogs. Therefore, moxifloxacin should be
avoided with Class IA and Class III antiarrhythmics. [See Warnings and Precautions (5.3) and
Nonclinical Toxicology (13.2).]
8
8.1 Pregnancy
Teratogenic Effects: Pregnancy Category C: Because no adequate or well-controlled studies
have been conducted in pregnant women, moxifloxacin should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis at
oral doses as high as 500 mg/kg/day or 0.24 times the maximum recommended human dose
based on systemic exposure (AUC), but decreased fetal body weights and slightly delayed fetal
skeletal development (indicative of fetotoxicity) were observed. Intravenous administration of
80 mg/kg/day (approximately two times the maximum recommended human dose based on
body surface area) to pregnant rats resulted in maternal toxicity and a marginal effect on fetal
and placental weights and the appearance of the placenta. There was no evidence of teratogenicity at intravenous doses as high as 80 mg/kg/day. Intravenous administration of
20 mg/kg/day (approximately equal to the maximum recommended human oral dose based
upon systemic exposure) to pregnant rabbits during organogenesis resulted in decreased fetal
body weights and delayed fetal skeletal ossification. When rib and vertebral malformations
were combined, there was an increased fetal and litter incidence of these effects. Signs of
maternal toxicity in rabbits at this dose included mortality, abortions, marked reduction of
food consumption, decreased water intake, body weight loss and hypoactivity. There was no
evidence of teratogenicity when pregnant cynomolgus monkeys were given oral doses as high
as 100 mg/kg/day (2.5 times the maximum recommended human dose based upon systemic
exposure). An increased incidence of smaller fetuses was observed at 100 mg/kg/day. In an
oral pre- and postnatal development study conducted in rats, effects observed at
500 mg/kg/day included slight increases in duration of pregnancy and prenatal loss, reduced
pup birth weight and decreased neonatal survival. Treatment-related maternal mortality
occurred during gestation at 500 mg/kg/day in this study.
8.3 Nursing Mothers
Moxifloxacin is excreted in the breast milk of rats. Moxifloxacin may also be excreted in human
milk. Because of the potential for serious adverse reactions in infants who are nursing from
mothers taking moxifloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients and adolescents less than 18 years of age have
not been established. Moxifloxacin causes arthropathy in juvenile animals [see Boxed Warning,
Warnings and Precautions (5.9), and Clinical Pharmacology (12.3)].
8.5 Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as moxifloxacin. This risk is
further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur
during or after completion of therapy; cases occurring up to several months after fluoro-
quinolone treatment have been reported. Caution should be used when prescribing moxifloxacin to elderly patients especially those on corticosteroids. Patients should be informed
of this potential side effect and advised to discontinue moxifloxacin and contact their
healthcare provider if any symptoms of tendinitis or tendon rupture occur. [See Boxed Warning, and Warnings and Precautions (5.1).]
In controlled multiple-dose clinical trials, 23% of patients receiving oral moxifloxacin were
greater than or equal to 65 years of age and 9% were greater than or equal to 75 years of age.
The clinical trial data demonstrate that there is no difference in the safety and efficacy of oral
moxifloxacin in patients aged 65 or older compared to younger adults.
In trials of intravenous use, 42% of moxifloxacin patients were greater than or equal to 65
years of age, and 23% were greater than or equal to 75 years of age. The clinical trial data
demonstrate that the safety of intravenous moxifloxacin in patients aged 65 or older was similar to that of comparator-treated patients. In general, elderly patients may be more susceptible to drug-associated effects of the QT interval. Therefore, moxifloxacin should be avoided
in patients taking drugs that can result in prolongation of the QT interval (for example, class
IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). [See Warnings and Precautions (5.3),
Drug Interactions (7.4), and Clinical Pharmacology (12.3).]
The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate,
severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal
impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory
peritoneal dialysis (CAPD) [see Dosage and Administration (2) and Clinical Pharmacology
(12.3)].
No dosage adjustment is recommended for mild, moderate, or severe hepatic insufficiency
(Child-Pugh Classes A, B, or C). However, due to metabolic disturbances associated with
hepatic insufficiency, which may lead to QT prolongation, moxifloxacin should be used with
caution in these patients [see Warnings and Precaution (5.3) and Clinical Pharmacology
(12.3)].
10 OVERDOSAGE
Single oral overdoses up to 2.8 g were not associated with any serious adverse events. In the
event of acute overdose, empty the stomach and maintain adequate hydration. Monitor ECG
due to the possibility of QT interval prolongation. Carefully observe the patient and give supportive treatment. The administration of activated charcoal as soon as possible after oral
overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and
9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite
are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively.
11 DESCRIPTION
Moxifloxacin hydrochloride, USP is a synthetic antibacterial agent for oral administration.
Moxifloxacin, a fluoroquinolone, is available as the monohydrochloride salt of 1-Cyclopropyl6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4oxo-3-quinolinecarboxylic acid, monohydrochloride. It is a slightly yellow to yellow powder or
crystals with a molecular weight of 437.93. Its molecular formula is C21H24FN3O4 • HCl and its
chemical structure is as follows:
•
Moxifloxacin Hydrochloride Tablets are available as pink, film-coated, capsule shaped
tablets containing 436.331 mg of moxifloxacin hydrochloride, USP (equivalent to 400 mg
moxifloxacin).
•
The inactive ingredients are copovidone, croscarmellose sodium, lecithin, magnesium
stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, talc, titanium dioxide
and xanthan gum.
Moxifloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)].
Photosensitivity Potential: A study of the skin response to ultraviolet (UVA and UVB) and visible radiation conducted in 32 healthy volunteers (8 per group) demonstrated that moxifloxacin
does not show phototoxicity in comparison to placebo. The minimum erythematous dose (MED)
was measured before and after treatment with moxifloxacin (200 mg or 400 mg once daily),
lomefloxacin (400 mg once daily), or placebo. In this study, the MED measured for both doses of
moxifloxacin were not significantly different from placebo, while lomefloxacin significantly lowered the MED. [See Warnings and Precautions (5.11).]
Absorption: Moxifloxacin, given as an oral tablet, is well absorbed from the gastrointestinal tract.
The absolute bioavailability of moxifloxacin is approximately 90 percent. Coadministration with a
high fat meal (that is, 500 calories from fat) does not affect the absorption of moxifloxacin.
Page 5 of 13
Consumption of one cup of yogurt with moxifloxacin does not affect the rate or extent of systemic absorption (that is, area under the plasma concentration time curve AUC).
Table 5. Mean (± SD) Cmax and AUC Values Following Single and Multiple Doses of 400 mg
Moxifloxacin Given Orally
Cmax
AUC
Half-life
(mg/L)
(mg • h/L)
(hour)
Single Dose Oral
3.1 ± 1
36.1 ± 9.1
11.5 to 15.6a
Healthy (n = 372)
Multiple Dose Oral
Healthy young male/female (n = 15)
4.5 ± 0.5
48 ± 2.7
12.7 ± 1.9
Healthy elderly male (n = 8)
3.8 ± 0.3
51.8 ± 6.7
Healthy elderly female (n = 8)
4.6 ± 0.6
54.6 ± 6.7
Healthy young male (n = 8)
3.6 ± 0.5
48.2 ± 9
Healthy young female (n = 9)
4.2 ± 0.5
49.3 ± 9.5
a)
Range of means from different studies
Table 6. Mean (± SD) Cmax and AUC Values Following Single and Multiple Doses of 400 mg
Moxifloxacin Given by 1 hour Intravenous Infusion
Cmax
AUC
Half-life
(mg/L)
(mg • h/L)
(hour)
Single Dose Intravenous
Healthy young male/female (n = 56)
3.9 ± 0.9
39.3 ± 8.6
8.2 to 15.4a
Patients (n = 118)
Male (n = 64)
4.4 ± 3.7
Female (n = 54)
4.5 ± 2
< 65 years (n = 58)
4.6 ± 4.2
≥ 65 years (n = 60)
4.3 ± 1.3
Multiple Dose Intravenous
Healthy young male (n = 8)
4.2 ± 0.8
38 ± 4.7
14.8 ± 2.2
Healthy elderly (n =12; 8 male, 4 female)
6.1 ± 1.3
48.2 ± 0.9
10.1 ± 1.6
Patientsb (n = 107)
Male (n = 58)
4.2 ± 2.6
Female (n = 49)
4.6 ± 1.5
< 65 years (n = 52)
4.1 ± 1.4
≥ 65 years (n = 55)
4.7 ± 2.7
a)
Range of means from different studies
Expected Cmax (concentration obtained around the time of the end of the infusion)
Plasma concentrations increase proportionately with dose up to the highest dose tested
(1200 mg single oral dose). The mean (± SD) elimination half-life from plasma is 12 ± 1.3
hours; steady-state is achieved after at least three days with a 400 mg once daily regimen.
Mean Steady-state Plasma Concentrations of Moxifloxacin Obtained with Once Daily
Dosing of 400 mg Either Orally (n = 10) or by Intravenous Infusion (n = 12)
b)
Distribution: Moxifloxacin is approximately 30% to 50% bound to serum proteins, independent
of drug concentration. The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg.
Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations. Moxifloxacin has been detected in the saliva, nasal and bronchial
secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle, and
abdominal tissues and fluids following oral or intravenous administration of 400 mg. Moxifloxacin concentrations measured post-dose in various tissues and fluids following a 400 mg oral
or intravenous dose are summarized in Table 7. The rates of elimination of moxifloxacin from
tissues generally parallel the elimination from plasma.
Table 7. Moxifloxacin Concentrations (mean ± SD) in Tissues and the Corresponding Plasa
ma Concentrations After a Single 400 mg Oral or Intravenous Dose
Tissue or Fluid
Respiratory
Alveolar Macrophages
Bronchial Mucosa
Epithelial Lining Fluid
Sinus
Maxillary Sinus Mucosa
Anterior Ethmoid Mucosa
Nasal Polyps
Skin, Musculoskeletal
Blister Fluid
Subcutaneous Tissue
Skeletal Muscle
Intra-Abdominal
Abdominal tissue
Abdominal exudate
Abscess fluid
N
Plasma
Concentration
(mcg/mL)
Tissue or Fluid
Concentration
(mcg/mL or mcg/g)
Tissue
Plasma
Ratio
5
8
5
3.3 ± 0.7
3.3 ± 0.7
3.3 ± 0.7
61.8 ± 27.3
5.5 ± 1.3
24.4 ± 14.7
21.2 ± 10
1.7 ± 0.3
8.7 ± 6.1
4
3
4
3.7 ± 1.1b
3.7 ± 1.1b
3.7 ± 1.1b
7.6 ± 1.7
8.8 ± 4.3
9.8 ± 4.5
2 ± 0.3
2.2 ± 0.6
2.6 ± 0.6
5
6
6
3 ± 0.5c
2.3 ± 0.4d
2.3 ± 0.4d
2.6 ± 0.9
0.9 ± 0.3e
0.9 ± 0.2e
0.9 ± 0.2
0.4 ± 0.6
0.4 ± 0.1
8
10
6
2.9 ± 0.5
2.3 ± 0.5
2.7 ± 0.7
7.6 ± 2
3.5 ± 1.2
2.3 ± 1.5
2.7 ± 0.8
1.6 ± 0.7
0.8 ± 0.4
a)
All moxifloxacin concentrations were measured 3 hours after a single 400 mg dose, except
the abdominal tissue and exudate concentrations which were measured at 2 hours postdose and the sinus concentrations which were measured 3 hours post-dose after 5 days of
dosing.
b)
N=5
c)
N=7
d)
N = 12
e)
Reflects only non-protein bound concentrations of drug.
Metabolism: Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized
via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1)
accounts for approximately 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2),
which is excreted exclusively in the urine. Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less
than 10% those of moxifloxacin.
In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not
inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2.
Excretion: Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as
unchanged drug (~20% in urine and ~25% in feces). A total of 96% ± 4% of an oral dose is
excreted as either unchanged drug or known metabolites. The mean (± SD) apparent total
body clearance and renal clearance are 12 ± 2 L/hr and 2.6 ± 0.5 L/hr, respectively.
Pharmacokinetics in Specific Populations: Geriatric: Following oral administration of 400 mg
moxifloxacin for 10 days in 16 elderly (8 male; 8 female) and 17 young (8 male; 9 female)
healthy volunteers, there were no age-related changes in moxifloxacin pharmacokinetics. In 16
healthy male volunteers (8 young; 8 elderly) given a single 200 mg dose of oral moxifloxacin,
the extent of systemic exposure (AUC and Cmax) was not statistically different between young
and elderly males and elimination half-life was unchanged. No dosage adjustment is necessary based on age. In large phase III studies, the concentrations around the time of the end of
the infusion in elderly patients following intravenous infusion of 400 mg were similar to those
observed in young patients. [See Use In Specific Populations (8.5).]
Pediatric: The pharmacokinetics of moxifloxacin in pediatric subjects has not been studied
[see Use In Specific Populations (8.4)].
Gender: Following oral administration of 400 mg moxifloxacin daily for 10 days to 23 healthy
males (19 to 75 years) and 24 healthy females (19 to 70 years), the mean AUC and Cmax were
8% and 16% higher, respectively, in females compared to males. There are no significant differences in moxifloxacin pharmacokinetics between male and female subjects when differences in body weight are taken into consideration.
A 400 mg single dose study was conducted in 18 young males and females. The comparison
of moxifloxacin pharmacokinetics in this study (nine young females and nine young males)
showed no differences in AUC or Cmax due to gender. Dosage adjustments based on gender are
not necessary.
Race: Steady-state moxifloxacin pharmacokinetics in male Japanese subjects were similar to
those determined in Caucasians, with a mean Cmax of 4.1 mcg/mL, an AUC24 of 47 mcg • h/mL
and an elimination half-life of 14 hours, following 400 mg p.o. daily.
Renal Insufficiency: The pharmacokinetic parameters of moxifloxacin are not significantly
altered in mild, moderate, severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis
(HD) or continuous ambulatory peritoneal dialysis (CAPD).
In a single oral dose study of 24 patients with varying degrees of renal function from normal to
severely impaired, the mean peak concentrations (Cmax) of moxifloxacin were reduced by 21% and
28% in the patients with moderate (CLCR ≥ 30 and ≤ 60 mL/min) and severe (CLCR < 30 mL/min)
renal impairment, respectively. The mean systemic exposure (AUC) in these patients was
increased by 13%. In the moderate and severe renally impaired patients, the mean AUC for the
sulfate conjugate (M1) increased by 1.7-fold (ranging up to 2.8-fold) and mean AUC and Cmax for
the glucuronide conjugate (M2) increased by 2.8-fold (ranging up to 4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively. [See Use in Specific Populations (8.6).]
Page 6 of 13
The pharmacokinetics of single dose and multiple dose moxifloxacin were studied in patients
with CLCR < 20 mL/min on either hemodialysis or continuous ambulatory peritoneal dialysis
(8 HD, 8 CAPD). Following a single 400 mg oral dose, the AUC of moxifloxacin in these HD and
CAPD patients did not vary significantly from the AUC generally found in healthy volunteers.
Cmax values of moxifloxacin were reduced by about 45% and 33% in HD and CAPD patients,
respectively, compared to healthy, historical controls. The exposure (AUC) to the sulfate conjugate (M1) increased by 1.4- to 1.5-fold in these patients. The mean AUC of the glucuronide
conjugate (M2) increased by a factor of 7.5, whereas the mean Cmax values of the glucuronide
conjugate (M2) increased by a factor of 2.5 to 3, compared to healthy subjects. The sulfate
and the glucuronide conjugates of moxifloxacin are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal disease
including those undergoing HD and CAPD has not been studied.
Oral administration of 400 mg once a day moxifloxacin for 7 days to patients on HD or CAPD
produced mean systemic exposure (AUCss) to moxifloxacin similar to that generally seen in
healthy volunteers. Steady-state Cmax values were about 22% lower in HD patients but were
comparable between CAPD patients and healthy volunteers. Both HD and CAPD removed only
small amounts of moxifloxacin from the body (approximately 9% by HD, and 3% by CAPD). HD
and CAPD also removed about 4% and 2% of the glucuronide metabolite (M2), respectively.
Hepatic Insufficiency: No dosage adjustment is recommended for mild, moderate, or severe
hepatic insufficiency (Child-Pugh Classes A, B, or C). However, due to metabolic disturbances
associated with hepatic insufficiency, which may lead to QT prolongation, moxifloxacin should
be used with caution in these patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].
In 400 mg single oral dose studies in six patients with mild (Child-Pugh Class A) and ten
patients with moderate (Child-Pugh Class B) hepatic insufficiency, moxifloxacin mean systemic exposure (AUC) was 78% and 102%, respectively, of 18 healthy controls and mean peak
concentration (Cmax) was 79% and 84% of controls.
The mean AUC of the sulfate conjugate of moxifloxacin (M1) increased by 3.9-fold (ranging up
to 5.9-fold) and 5.7-fold (ranging up to 8-fold) in the mild and moderate groups, respectively.
The mean Cmax of M1 increased by approximately 3-fold in both groups (ranging up to 4.7- and
3.9-fold). The mean AUC of the glucuronide conjugate of moxifloxacin (M2) increased by 1.5-fold
(ranging up to 2.5-fold) in both groups. The mean Cmax of M2 increased by 1.6- and 1.3-fold
(ranging up to 2.7- and 2.1-fold), respectively. The clinical significance of increased exposure to
the sulfate and glucuronide conjugates has not been studied. In a subset of patients participating in a clinical trial, the plasma concentrations of moxifloxacin and metabolites determined
approximately at the moxifloxacin Tmax following the first intravenous or oral moxifloxacin dose in
the Child-Pugh Class C patients (n = 10) were similar to those in the Child-Pugh Class A/B
patients (n = 5), and also similar to those observed in healthy volunteer studies.
Drug-Drug Interactions: The following drug interactions were studied in healthy volunteers or
patients.
Antacids and iron significantly reduced bioavailability of moxifloxacin, as observed with other
fluoroquinolones [see Drug Interactions (7.1)].
Calcium, digoxin, itraconazole, morphine, probenecid, ranitidine, theophylline, cyclosporine,
and warfarin did not significantly affect the pharmacokinetics of moxifloxacin. These results
and the data from in vitro studies suggest that moxifloxacin is unlikely to significantly alter
the metabolic clearance of drugs metabolized by CYP3A4, CYP2D6, CYP2C9, CYP2C19, or
CYP1A2 enzymes.
Moxifloxacin had no clinically significant effect on the pharmacokinetics of atenolol, digoxin, glyburide, itraconazole, oral contraceptives, theophylline, cyclosporine and warfarin.
However, fluoroquinolones, including moxifloxacin, have been reported to enhance the anticoagulant effects of warfarin or its derivatives in the patient population [see Drug Interactions (7.2)].
Antacids: When moxifloxacin (single 400 mg tablet dose) was administered 2 hours before, concomitantly, or 4 hours after an aluminum/magnesium-containing antacid (900 mg aluminum
hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 12 healthy volunteers there
was a 26%, 60% and 23% reduction in the mean AUC of moxifloxacin, respectively. Moxifloxacin should be taken at least 4 hours before or 8 hours after antacids containing magnesium or
aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with
zinc, or didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.
[See Dosage and Administration (2.2) and Drug Interactions (7.1).]
Atenolol: In a crossover study involving 24 healthy volunteers (12 male; 12 female), the mean
atenolol AUC following a single oral dose of 50 mg atenolol with placebo was similar to that
observed when atenolol was given concomitantly with a single 400 mg oral dose of moxifloxacin. The mean Cmax of single dose atenolol decreased by about 10% following coadministration with a single dose of moxifloxacin.
Calcium: Twelve healthy volunteers were administered concomitant moxifloxacin (single
400 mg dose) and calcium (single dose of 500 mg Ca++ dietary supplement) followed by an
additional two doses of calcium 12 and 24 hours after moxifloxacin administration. Calcium
had no significant effect on the mean AUC of moxifloxacin. The mean Cmax was slightly reduced
and the time to maximum plasma concentration was prolonged when moxifloxacin was given
with calcium compared to when moxifloxacin was given alone (2.5 hours versus 0.9 hours).
These differences are not considered to be clinically significant.
Digoxin: No significant effect of moxifloxacin (400 mg once daily for two days) on digoxin
(0.6 mg as a single dose) AUC was detected in a study involving 12 healthy volunteers. The
mean digoxin Cmax increased by about 50% during the distribution phase of digoxin. This transient increase in digoxin Cmax is not viewed to be clinically significant. Moxifloxacin pharmacokinetics were similar in the presence or absence of digoxin. No dosage adjustment for moxifloxacin or digoxin is required when these drugs are administered concomitantly.
Glyburide: In diabetics, glyburide (2.5 mg once daily for two weeks pretreatment and for five
days concurrently) mean AUC and Cmax were 12% and 21% lower, respectively, when taken
with moxifloxacin (400 mg once daily for five days) in comparison to placebo. Nonetheless,
blood glucose levels were decreased slightly in patients taking glyburide and moxifloxacin in
comparison to those taking glyburide alone, suggesting no interference by moxifloxacin on the
activity of glyburide. These interaction results are not viewed as clinically significant.
Iron: When moxifloxacin tablets were administered concomitantly with iron (ferrous sulfate
100 mg once daily for two days), the mean AUC and Cmax of moxifloxacin was reduced by 39%
and 59%, respectively. Moxifloxacin should only be taken more than 4 hours before or 8 hours
after iron products [see Dosage and Administration (2.2) and Drug Interactions (7.1)].
Itraconazole: In a study involving 11 healthy volunteers, there was no significant effect of
itraconazole (200 mg once daily for 9 days), a potent inhibitor of cytochrome P4503A4, on
the pharmacokinetics of moxifloxacin (a single 400 mg dose given on the 7th day of itraconazole dosing). In addition, moxifloxacin was shown not to affect the pharmacokinetics of
itraconazole.
Morphine: No significant effect of morphine sulfate (a single 10 mg intramuscular dose) on
the mean AUC and Cmax of moxifloxacin (400 mg single dose) was observed in a study of 20
healthy male and female volunteers.
Oral Contraceptives: A placebo-controlled study in 29 healthy female subjects showed that
moxifloxacin 400 mg daily for 7 days did not interfere with the hormonal suppression of oral
contraception with 0.15 mg levonorgestrel/0.03 mg ethinylestradiol (as measured by serum
progesterone, FSH, estradiol, and LH), or with the pharmacokinetics of the administered contraceptive agents.
Probenecid: Probenecid (500 mg twice daily for two days) did not alter the renal clearance and
total amount of moxifloxacin (400 mg single dose) excreted renally in a study of 12 healthy
volunteers.
Ranitidine: No significant effect of ranitidine (150 mg twice daily for three days as pretreatment) on the pharmacokinetics of moxifloxacin (400 mg single dose) was detected in a study
involving ten healthy volunteers.
Theophylline: No significant effect of moxifloxacin (200 mg every 12 hours for 3 days) on the
pharmacokinetics of theophylline (400 mg every 12 hours for 3 days) was detected in a study
involving 12 healthy volunteers. In addition, theophylline was not shown to affect the pharmacokinetics of moxifloxacin. The effect of coadministration of 400 mg once daily of moxifloxacin with theophylline has not been studied.
Warfarin: No significant effect of moxifloxacin (400 mg once daily for 8 days) on the pharmacokinetics of R- and S-warfarin (25 mg single dose of warfarin sodium on the fifth day) was
detected in a study involving 24 healthy volunteers. No significant change in prothrombin time
was observed. However, fluoroquinolones, including moxifloxacin, have been reported to
enhance the anticoagulant effects of warfarin or its derivatives in the patient population [see
Adverse Reactions (6.2) and Drug Interactions (7.2)].
12.4 Microbiology
Mechanism of Action: The bactericidal action of moxifloxacin results from inhibition of the
topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication,
transcription, repair, and recombination.
Mechanism of Resistance: The mechanism of action for fluoroquinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines;
therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. Resistance to fluoroquinolones occurs primarily by a mutation in topoisomerase II
(DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or drug efflux.
In vitro resistance to moxifloxacin develops slowly via multiple-step mutations. Resistance
to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10-9 to < 1 x 10-11 for
Gram-positive bacteria.
Cross Resistance: Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria. Gram-positive bacteria resistant to other
fluoroquinolones may, however, still be susceptible to moxifloxacin. There is no known crossresistance between moxifloxacin and other classes of antimicrobials.
Moxifloxacin has been shown to be active against most isolates of the following bacteria, both
in vitro and in clinical infections [see Indications and Usage (1)].
Enterococcus faecalis
Streptococcus anginosus
Streptococcus constellatus
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]**)
**
MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known
as PRSP (Penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the
following antibiotics: penicillin (MIC) ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Yersinia pestis
Page 7 of 13
Anaerobic bacteria
Bacteroides fragilis
Bacteroides thetaiotaomicron
Clostridium perfringens
Peptostreptococcus species
Other microorganisms
Chlamydophila pneumoniae
Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance is unknown. At least
90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC)
less than or equal to the susceptible breakpoint for moxifloxacin. However, the efficacy of moxifloxacin in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.
Staphylococcus epidermidis
Streptococcus viridans group
Citrobacter freundii
Klebsiella oxytoca
Legionella pneumophila
Anaerobic bacteria
Fusobacterium species
Prevotella species
Susceptibility Tests Methods: When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in
resident hospitals to the physician as periodic reports that describe the susceptibility profile
of nosocomial and community acquired pathogens. These reports should aid the physician in
selecting an antibacterial drug product for treatment.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth and/or agar).1,2,4
The MIC values should be interpreted according to the criteria in Table 8.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters can
also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial
compounds. The zone size prove should be determined using a standardized test method.2,3 This
procedure uses paper disks impregnated with 5 mcg moxifloxacin to test the susceptibility of
bacteria to moxifloxacin. The disc diffusion interpretive criteria are provided in Table 8.
Anaerobic Techniques: For anaerobic bacteria, the susceptibility to moxifloxacin can be determined by a standardized test method.2,5 The MIC values obtained should be interpreted
according to the criteria provided in Table 8.
Table 8. Susceptibility Test Interpretive Criteria for Moxifloxacin
Species
Enterobacteriaceae
Streptococcus species
Anaerobic bacteria
Yersinia pestis
S
≤2
≤1
≤2
≤1
≤1
≤1
≤1
≤2
≤ 0.25
MIC (mcg/mL)
I
R
4
≥8
2
≥4
4
≥8
a
a
a
a
2
2
4
≥4
≥4
≥8
a
a
Zone Diameter (mm)
S
I
R
≥ 19
16 to 18
≤ 15
≥ 18
15 to 17
≤ 14
≥ 19
16 to 18
≤ 15
a
a
≥ 18
a
a
≥ 18
≥ 18
15 to 17
≤ 14
≥ 18
15 to 17
≤ 14
-
S = susceptible, I = Intermediate and R = resistant.
a)
The current absence of data on moxifloxacin-resistant isolates precludes defining any
results other than “Susceptible”. Isolates yielding test results (MIC or zone diameter) other
than susceptible, should be submitted to a reference laboratory for additional testing.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the
pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result
should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations
where a high dosage of the drug product can be used. This category also provides a buffer
zone that prevents small uncontrolled technical factors from causing major discrepancies in
interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit
growth of the pathogen if the antimicrobial compound reaches the concentrations usually
achievable at the infection site; other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the
1,2,3,4,5
assay and the techniques of the individuals performing the test.
Standard moxifloxacin
powder should provide the following range of MIC values noted in Table 9. For the diffusion
technique using the 5 mcg moxifloxacin disk, the criteria in Table 9 should be achieved.
Table 9. Acceptable Quality Control Ranges for Moxifloxacin
Strains
ATCC 29212
Escherichia coli
ATCC 25922
ATCC 49247
ATCC29213
ATCC25923
ATCC 49619
Bacteroides fragilis
ATCC 25285
Bacteroides thetaiotaomicron
ATCC 29741
Eubacterium lentum
ATCC 43055
MIC range (mcg/mL)
Zone Diameter (mm)
0.06 to 0.5
-
0.008 to 0.06
28 to 35
0.008 to 0.03
31 to 39
0.015 to 0.06
-
-
28 to 35
0.06 to 0.25
25 to 31
0.125 to 0.5
-
1 to 4
-
0.125 to 0.5
-
Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not
been performed.
Moxifloxacin was not mutagenic in four bacterial strains (TA 98, TA 100, TA 1535, TA 1537)
used in the Ames Salmonella reversion assay. As with other fluoroquinolones, the positive
response observed with moxifloxacin in strain TA 102 using the same assay may be due to the
inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell
gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were
used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not
induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of
genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.
Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as
500 mg/kg/day, approximately 12 times the maximum recommended human dose based on
body surface area, or at intravenous doses as high as 45 mg/kg/day, approximately equal to
the maximum recommended human dose based on body surface area. At 500 mg/kg orally
there were slight effects on sperm morphology (head-tail separation) in male rats and on the
estrous cycle in female rats.
Fluoroquinolones have been shown to cause arthropathy in immature animals. In studies in
juvenile dogs oral doses of moxifloxacin 30 mg/kg/day or more (approximately 1.5 times the
maximum recommended human dose based upon systemic exposure) for 28 days resulted in
arthropathy. There was no evidence of arthropathy in mature monkeys and rats at oral doses
up to 135 and 500 mg/kg/day, respectively.
Moxifloxacin at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential for CNS toxicity (for example, seizures) in mice when used in combination with NSAIDs
such as diclofenac, ibuprofen, or fenbufen. Some fluoroquinolones have been reported to have
proconvulsant activity that is exacerbated with concomitant use of NSAIDs.
A QT-prolonging effect of moxifloxacin was found in dog studies, at plasma concentrations
about five times the human therapeutic level. The combined infusion of sotalol, a Class III
antiarrhythmic agent, with moxifloxacin induced a higher degree of QTc prolongation in dogs
than that induced by the same dose (30 mg/kg) of moxifloxacin alone. Electrophysiological
in vitro studies suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr ) as an underlying mechanism.
No signs of local intolerability were observed in dogs when moxifloxacin was administered
intravenously. After intra-arterial injection, inflammatory changes involving the peri-arterial
soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should
be avoided.
14 CLINICAL STUDIES
In a controlled double-blind study conducted in the U.S., moxifloxacin tablets (400 mg once
daily for ten days) were compared with cefuroxime axetil (250 mg twice daily for ten days) for
the treatment of acute bacterial sinusitis. The trial included 457 patients valid for the efficacy analysis. Clinical success (cure plus improvement) at the 7 to 21 day post-therapy test of
cure visit was 90% for moxifloxacin and 89% for cefuroxime.
An additional non-comparative study was conducted to gather bacteriological data and to
evaluate microbiological eradication in adult patients treated with moxifloxacin 400 mg once
daily for seven days. All patients (n = 336) underwent antral puncture in this study. Clinical
success rates and eradication/presumed eradication rates at the 21 to 37 day follow-up visit
were 97% (29 out of 30) for Streptococcus pneumoniae, 83% (15 out of 18) for Moraxella
catarrhalis, and 80% (24 out of 30) for Haemophilus influenzae.
Moxifloxacin hydrochloride tablets (400 mg once daily for five days) were evaluated for the
treatment of acute bacterial exacerbation of chronic bronchitis in a randomized, double-blind,
controlled clinical trial conducted in the US. This study compared moxifloxacin with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients. Clinical success was
Page 8 of 13
assessed at 7 to 17 days post-therapy. The clinical success for moxifloxacin was 89% (222/250)
compared to 89% (224/251) for clarithromycin.
Table 10. Clinical Success Rates at Follow-Up Visit for Clinically Evaluable Patients by
Pathogen (Acute Bacterial Exacerbation of Chronic Bronchitis)
PATHOGEN
Moxifloxacin
Clarithromycin
16/16 (100%)
20/23 (87%)
33/37 (89%)
36/41 (88%)
16/16 (100%)
14/14 (100%)
29/34 (85%)
24/24 (100%)
15/16 (94%)
6/8 (75%)
18/20 (90%)
10/11 (91%)
The microbiological eradication rates (eradication plus presumed eradication) in moxifloxacin
treated patients were Streptococcus pneumoniae 100%, Haemophilus influenzae 89%,
Haemophilus parainfluenzae 100%, Moraxella catarrhalis 85%, Staphylococcus aureus 94%,
and Klebsiella pneumoniae 85%.
A randomized, double-blind, controlled clinical trial was conducted in the U.S. to compare the
efficacy of moxifloxacin hydrochloride tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically
documented community acquired pneumonia. This study enrolled 474 patients (382 of whom
were valid for the efficacy analysis conducted at the 14 to 35 day follow-up visit). Clinical success for clinically evaluable patients was 95% (184/194) for moxifloxacin and 95% (178/188)
for high dose clarithromycin.
A randomized, double-blind, controlled trial was conducted in the U.S. and Canada to compare
the efficacy of sequential intravenous/oral moxifloxacin 400 mg once a day for 7 to 14 days to
an intravenous/oral fluoroquinolone control (trovafloxacin or levofloxacin) in the treatment of
patients with clinically and radiologically documented community acquired pneumonia. This
study enrolled 516 patients, 362 of whom were valid for the efficacy analysis conducted at the
7 to 30 day post-therapy visit. The clinical success rate was 86% (157/182) for moxifloxacin
therapy and 89% (161/180) for the fluoroquinolone comparators.
An open-label ex-U.S. study that enrolled 628 patients compared moxifloxacin to sequential
intravenous/oral amoxicillin/clavulanate (1.2 gram intravenously every 8 hours/625 mg orally
every 8 hours) with or without high-dose intravenous/oral clarithromycin (500 mg twice a day).
The intravenous formulations of the comparators are not FDA approved. The clinical success
rate at Day 5 to 7 for moxifloxacin therapy was 93% (241/258) and demonstrated superiority
to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I. of difference in success
rates between moxifloxacin and comparator (2.9%, 13.2%)]. The clinical success rate at the
21 to 28 days post-therapy visit for moxifloxacin was 84% (216/258), which also demonstrated superiority to the comparators (74%, 208/280) [95% C.I. of difference in success
rates between moxifloxacin and comparator (2.6%, 16.3%)].
The clinical success rates by pathogen across four CAP studies are presented in Table 11.
Table 11. Clinical Success Rates By Pathogen (Pooled CAP Studies)
PATHOGEN
Chlamydophila pneumoniae
Mycoplasma pneumoniae
MOXIFLOXACIN
80/85
17/20
11/12
56/61
119/128
73/76
11/12
(94%)
(85%)
(92%)
(92%)
(93%)
(96%)
(92%)
Community Acquired Pneumonia Caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)*: Moxifloxacin was effective in the treatment of community acquired pneumonia (CAP) caused by multi-drug resistant Streptococcus pneumoniae MDRSP* isolates. Of 37
microbiologically evaluable patients with MDRSP isolates, 35 patients (95%) achieved clinical and bacteriological success post-therapy. The clinical and bacteriological success rates
based on the number of patients treated are shown in Table 12.
*
MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as
PRSP (Penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC ≥ 2 mcg/mL), 2nd generation cephalosporins (for example,
cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
Table 12. Clinical and Bacteriological Success Rates for Moxifloxacin-Treated MDRSP CAP
Patients (Population: Valid for Efficacy)
Screening Susceptibility
Penicillin-resistant
2nd generation cephalosporin-resistant
Macrolide-resistantd
Trimethoprim/sulfamethoxazole-resistant
Tetracycline-resistant
a)
b)
c)
Clinical Success
a
n/N
%
21/21
100%c
25/26
96%c
22/23
96%
28/30
93%
17/18
94%
Bacteriological Success
b
n/N
%
21/21
100%c
25/26
96%c
22/23
96%
28/30
93%
17/18
94%
n = number of patients successfully treated; N = number of patients with MDRSP (from a
total of 37 patients)
n = number of patients successfully treated (presumed eradication or eradication);
N = number of patients with MDRSP (from a total of 37 patients)
One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a
blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in
the database based on the respiratory isolate.
d)
Azithromycin, clarithromycin, and erythromycin were the macrolide antimicrobials tested.
Not all isolates were resistant to all antimicrobial classes tested. Success and eradication
rates are summarized in Table 13.
Table 13. Clinical Success Rates and Microbiological Eradication Rates for Resistant
Streptococcus pneumoniae (Community Acquired Pneumonia)
S. pneumoniae with MDRSP
Clinical Success
Resistant to two antimicrobials
Resistant to three antimicrobials
Resistant to four antimicrobials
Resistant to five antimicrobials
Bacteremia with MDRSP
12/13 (92.3%)
10/11 (90.9%)a
6/6 (100%)
7/7 (100%)a
9/9 (100%)
Bacteriological
Eradication Rate
12/13 (92.3%)
10/11 (90.9%)a
6/6 (100%)
7/7 (100%)a
9/9 (100%)
a)
One patient had a respiratory isolate resistant to five antimicrobials and a blood isolate
resistant to three antimicrobials. The patient was included in the category resistant to five
antimicrobials.
A randomized, double-blind, controlled clinical trial conducted in the U.S. compared the efficacy of moxifloxacin 400 mg once daily for 7 days with cephalexin HCl 500 mg three times
daily for 7 days. The percentage of patients treated for uncomplicated abscesses was 30%,
furuncles 8%, cellulitis 16%, impetigo 20%, and other skin infections 26%. Adjunctive procedures (incision and drainage or debridement) were performed on 17% of the moxifloxacin
treated patients and 14% of the comparator treated patients. Clinical success rates in evaluable patients were 89% (108/122) for moxifloxacin and 91% (110/121) for cephalexin HCl.
Two randomized, active controlled trials of cSSSI were performed. A double-blind trial was
conducted primarily in North America to compare the efficacy of sequential intravenous/oral
moxifloxacin 400 mg once a day for 7 to 14 days to an intravenous/oral beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 617
patients, 335 of which were valid for the efficacy analysis. A second open-label International
study compared moxifloxacin 400 mg once a day for 7 to 21 days to sequential intravenous/oral beta-lactam/beta-lactamase inhibitor control in the treatment of patients with
cSSSI. This study enrolled 804 patients, 632 of which were valid for the efficacy analysis. Surgical incision and drainage or debridement was performed on 55% of the moxifloxacin treated and 53% of the comparator treated patients in these studies and formed an integral part
of therapy for this indication. Success rates varied with the type of diagnosis ranging from
61% in patients with infected ulcers to 90% in patients with complicated erysipelas. These
rates were similar to those seen with comparator drugs. The overall success rates in the
evaluable patients and the clinical success by pathogen are shown in Tables 14 and 15.
Table 14. Overall Clinical Success Rates in Patients with Complicated Skin and Skin Structure Infections
Moxifloxacin
Comparator
95% Confidence
Study
n/N (%)
n/N (%)
Intervala
North America
125/162 (77.2%)
141/173 (81.5%)
(-14.4%, 2%)
International
254/315 (80.6%)
268/317 (84.5%)
(-9.4%, 2.2%)
a
of difference in success rates between moxifloxacin and comparator (moxifloxacin - comparator)
Table 15. Clinical Success Rates by Pathogen in Patients with Complicated Skin and Skin
Structure Infections
Moxifloxacin
Comparator
Pathogen
n/N (%)
n/N (%)
(methicillin-susceptible isolates)a
106/129 (82.2%)
120/137 (87.6%)
Escherichia coli
31/38 (81.6%)
28/33 (84.8%)
11/12 (91.7%)
7/10 (70%)
Enterobacter cloacae
9/11 (81.8%)
4/7 (57.1%)
a)
methicillin susceptibility was only determined in the North American Study
Two randomized, active controlled trials of cIAI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential intravenous/oral moxifloxacin 400 mg once a day for 5 to 14 days to intravenous/piperacillin/tazobactam followed
by oral amoxicillin/clavulanic acid in the treatment of patients with cIAI, including peritonitis,
abscesses, appendicitis with perforation, and bowel perforation. This study enrolled 681
patients, 379 of which were considered clinically evaluable. A second open-label international
study compared moxifloxacin 400 mg once a day for 5 to 14 days to intravenous ceftriaxone
plus intravenous metronidazole followed by oral amoxicillin/clavulanic acid in the treatment of
patients with cIAI. This study enrolled 595 patients, 511 of which were considered clinically
evaluable. The clinically evaluable population consisted of subjects with a surgically confirmed
complicated infection, at least 5 days of treatment and a 25 to 50 day follow-up assessment
for patients at the Test of Cure visit. The overall clinical success rates in the clinically evaluable patients are shown in Table 16.
Page 9 of 13
Table 16. Clinical Success Rates in Patients with Complicated Intra-Abdominal Infections
Study
North America (overall)
Abscess
Non-abscess
International (overall)
Abscess
Non-abscess
Moxifloxacin
n/N (%)
146/183 (79.8%)
40/57 (70.2%)
106/126 (84.1%)
199/246 (80.9%)
73/93 (78.5%)
126/153 (82.4%)
Comparator
n/N (%)
153/196 (78.1%)
49/63 (77.8%)b
104/133 (78.2%)
218/265 (82.3%)
86/99 (86.9%)
132/166 (79.5%)
95% Confidence
Intervala
(-7.4%, 9.3%)
NAc
NA
(-8.9%, 4.2%)
NA
NA
a)
of difference in success rates between moxifloxacin and comparator (moxifloxacin - comparator)
Excludes two patients who required additional surgery within the first 48 hours.
c)
NA - not applicable
14.7 Plague
Efficacy studies of moxifloxacin could not be conducted in humans with pneumonic plague for
ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals and supportive pharmacokinetic data in adult humans and
animals.
A randomized, blinded, placebo-controlled study was conducted in an African Green Monkey
(AGM) animal model of pneumonic plague. Twenty AGM (10 males and 10 females) were
exposed to an inhaled mean (± SD) dose of 100 ± 50 LD50 (range 92 to 127 LD50) of Yersinia
pestis (CO92 strain) aerosol. The minimal inhibitory concentration (MIC) of moxifloxacin for
the Y. pestis strain used in this study was 0.06 mcg/mL. Development of sustained fever for
at least 4 hours duration was used as the trigger for the initiation of 10 days of treatment with
either a humanized regimen of moxifloxacin or placebo. All study animals were febrile and
bacteremic with Y. pestis prior to the initiation of study treatment. Ten of 10 (100%) of the
animals receiving the placebo succumbed to disease between 83 to 139 h (mean 115 ±19
hours) post treatment. Ten of 10 (100%) moxifloxacin-treated animals survived for the 30-day
period after completion of the study treatment. Compared to the placebo group, mortality in
the moxifloxacin group was significantly lower (difference in survival: 100% with a two-sided
95% exact confidence interval [66.3%, 100%], p-value < 0.0001).
The mean plasma concentrations of moxifloxacin associated with a statistically significant
improvement in survival over placebo in an AGM model of pneumonic plague are reached or
exceeded in human adults receiving the recommended oral and intravenous dosage regimens.
The mean (± SD) peak plasma concentration (Cmax) and total plasma exposure defined as the
area under the plasma concentration-time curve (AUC) in human adults receiving 400 mg
intravenously were 3.9 ± 0.9 mcg/mL and 39.3 ± 8.6 mcg•h/mL, respectively [see Clinical
Pharmacology (12.3)]. The mean (± SD) peak plasma concentration and AUC0-24 in AGM following one-day administration of a humanized dosing regimen simulating the human AUC0-24
at a 400 mg dose were 4.4 ± 1.5 mcg/mL and 22 ± 8.0 mcg•h/mL, respectively.
b)
15 REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI), Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard – Tenth Edition. CLSI
Document M7-A10 [2015], CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, USA.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25
[2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500,
Wayne, Pennsylvania 19087, USA.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document
M02-A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite
2500, Wayne, Pennsylvania 19087, USA.
4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and
Disk Susceptibility Testing for Infrequently Isolated or Fastidious Bacteria: Approved Guidelines—Second Edition CLSI document M45-A2 [2010], Clinical and Laboratory Standards
Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility
Testing of Anaerobic Bacteria; Approved Standard -Eighth Edition. CLSI document M11-A8
[2012]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500,
Wayne, Pennsylvania 19087, USA.
Moxifloxacin Hydrochloride Tablets are available containing 436.331 mg of moxifloxacin hydrochloride, USP (equivalent to 400 mg of moxifloxacin).
The 400 mg tablets are pink, film-coated, capsule shaped, unscored tablets debossed with M
on one side of the tablet and MO1 on the other side. They are available as follows:
NDC 0378-2080-93
NDC 0378-2080-89
NDC 0378-2080-01
NDC 0378-2080-05
Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.]
Avoid high humidity.
closure.
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Antibacterial Resistance
Inform patients that antibacterial drugs including moxifloxacin hydrochloride tablets should
only be used to treat bacterial infections. They do not treat viral infections (for example, the
common cold). When moxifloxacin hydrochloride tablets are prescribed to treat a bacterial
infection, patients should be told that although it is common to feel better early in the course
of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be
treatable by moxifloxacin hydrochloride tablets or other antibacterial drugs in the future.
Administration with Food, Fluids, and Drug Products Containing Multivalent Cations
Inform patients that moxifloxacin hydrochloride tablets may be taken with or without food.
Advise patients to drink fluids liberally.
Inform patients that moxifloxacin hydrochloride tablets should be taken at least 4 hours before
or 8 hours after multivitamins (containing iron or zinc), antacids (containing magnesium or
aluminum), sucralfate, or didanosine buffered tablets for oral suspension or the pediatric
powder for oral solution.
Serious and Potentially Serious Adverse Reactions
Inform patients about the following serious adverse reactions associated with moxifloxacin
hydrochloride tablets or other fluoroquinolones:
•
Tendon Disorders: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of
their joints; rest and refrain from exercise; and discontinue moxifloxacin hydrochloride
tablet treatment. The risk of severe tendon disorder with fluoroquinolones is higher in
older patients usually over 60 years of age, in patients taking corticosteroid drugs, and
in patients with kidney, heart or lung transplants.
•
Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any
history of myasthenia gravis, as fluoroquinolones like moxifloxacin hydrochloride
tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Advise patients to seek medical care right away if they
have any worsening muscle weakness or breathing problems.
•
Prolongation of the QT interval: Moxifloxacin hydrochloride tablets may produce
changes in the electrocardiogram (QTc interval prolongation). Moxifloxacin hydrochloride tablets should be avoided in patients receiving Class IA (for example quinidine,
procainamide) or Class III (for example amiodarone, sotalol) antiarrhythmic agents.
Moxifloxacin hydrochloride tablets may add to the QTc prolonging effects of other drugs
such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. Instruct
patients to inform their physician of any personal or family history of QTc prolongation
or proarrhythmic conditions such as recent hypokalemia, significant bradycardia, and
acute myocardial ischemia. Advise patients to contact their physician if they experience
palpitations or fainting spells while taking moxifloxacin hydrochloride tablets.
•
Hypersensitivity Reactions: Advise patients that moxifloxacin hydrochloride tablets
may be associated with hypersensitivity reactions, including anaphylactic reactions,
even following a single dose and to discontinue moxifloxacin hydrochloride tablets at
the first sign of a skin rash or other signs of an allergic reaction.
•
Convulsions: Inform the patients that convulsions have been reported in patients
receiving fluoroquinolones, including moxifloxacin hydrochloride tablets. Patients
should notify their physician before taking moxifloxacin hydrochloride tablets if they
have a history of this condition and if they are taking NSAIDs.
•
Neurologic Adverse Effects (for example, dizziness, lightheadedness): Inform patients
that moxifloxacin hydrochloride tablets may cause dizziness, lightheadedness, and vision
disorders; therefore, they should know how they react to this drug before they operate an
automobile or machinery or engage in activities requiring mental alertness or coordination.
•
Psychotic Reaction: Psychotic reactions sometimes resulting in self-injurious behavior have been reported in patients receiving fluoroquinolones. Patients should notify
their physician if they have a history of psychiatric illness before taking moxifloxacin
hydrochloride tablets.
•
Peripheral Neuropathies: Inform patients that peripheral neuropathy has been associated with moxifloxacin hydrochloride tablet use. Symptoms may occur soon after initiation of therapy and may be irreversible. Advise patients to discontinue moxifloxacin
hydrochloride tablets if symptoms of peripheral neuropathy including pain, burning,
tingling, numbness, and/or weakness develop.
•
Blood Glucose Disturbances: Inform the patients that if they are diabetic and are being
treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs,
they should discontinue moxifloxacin hydrochloride tablets and consult a physician.
•
Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has
been reported in patients receiving fluoroquinolones, including moxifloxacin hydrochloride tablets. Patients should minimize or avoid exposure to natural or artificial sunlight
(tanning beds or UVA/B treatment) while taking moxifloxacin hydrochloride tablets. If
patients need to be outdoors while using moxifloxacin hydrochloride tablets, they should
wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption
occurs, patients should contact their physician.
Page 10 of 13
•
Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends
when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps
and fever) even as late as two or more months after having taken the last dose of the
antibiotic. If this occurs, patients should contact their physician as soon as possible.
Plague Studies
Inform patients given moxifloxacin hydrochloride tablets for plague that efficacy studies could
not be conducted in humans for feasibility reasons. Therefore, approval for plague was based
on efficacy studies conducted in animals.
FDA-Approved Medication Guide
MEDICATION GUIDE
MOXIFLOXACIN HYDROCHLORIDE TABLETS
(mox'' i flox' a sin hye'' droe klor' ide)
400 mg
Read the Medication Guide that comes with moxifloxacin hydrochloride
tablets before you start taking it and each time you get a refill. There may
be new information. This Medication Guide does not take the place of
talking to your healthcare provider about your medical condition or your
treatment.
What is the most important information I should know about moxifloxacin
Moxifloxacin hydrochloride tablets belong to a class of antibiotics called
fluoroquinolones. Moxifloxacin hydrochloride tablets can cause side effects
that may be serious or even cause death. If you get any of the following
serious side effects, get medical help right away. Talk with your healthcare
provider about whether you should continue to take moxifloxacin hydrochloride tablets.
1. Tendon rupture or swelling of the tendon (tendinitis).
• Tendon problems can happen in people of all ages who take
moxifloxacin hydrochloride tablets. Tendons are tough cords of
tissue that connect muscles to bones. Symptoms of tendon problems may include:
• Pain, swelling, tears and inflammation of tendons including the
back of the ankle (Achilles), shoulder, hand, or other tendon
sites.
• The risk of getting tendon problems while you take moxifloxacin
hydrochloride tablets is higher if you:
• Are over 60 years of age
• Are taking steroids (corticosteroids)
• Have had a kidney, heart or lung transplant
Tendon problems can happen in people who do not have the above risk
factors when they take moxifloxacin hydrochloride tablets.
• Other reasons that can increase your risk of tendon problems
can include:
• Physical activity or exercise
• Kidney failure
• Tendon problems in the past, such as in people with rheumatoid
arthritis (RA).
• Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation.
Stop taking moxifloxacin hydrochloride tablets until tendinitis or
tendon rupture has been ruled out by your healthcare provider.
Avoid exercise and using the affected area. The most common area
of pain and swelling is in the Achilles tendon at the back of your
ankle. This can also happen with other tendons.
• Talk to your healthcare provider about the risk of tendon rupture
with continued use of moxifloxacin hydrochloride tablets.
You may need a different antibiotic that is not a fluoroquinolone to
treat your infection.
• Tendon rupture can happen while you are taking or after you
have finished taking moxifloxacin hydrochloride tablets.
Tendon ruptures have happened up to several months after
patients have finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs
or symptoms of a tendon rupture:
• Hear or feel a snap or pop in a tendon area
• Bruising right after an injury in a tendon area
• Unable to move the affected area or bear weight.
2. Worsening of myasthenia gravis (a disease which causes muscle
weakness).
Fluoroquinolones like moxifloxacin hydrochloride tablets may cause
worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away
if you have any worsening muscle weakness or breathing problems.
See the section “What are the possible side effects of moxifloxacin hydrochloride tablets?” for more information about side effects.
What are moxifloxacin hydrochloride tablets?
Moxifloxacin hydrochloride tablets are a fluoroquinolone antibiotic medicine used to treat certain types of infections caused by certain germs called
bacteria in adults 18 years or older. These bacterial infections include:
• Acute Bacterial Sinusitis
• Acute Bacterial Exacerbation of Chronic Bronchitis
• Community Acquired Pneumonia
• Uncomplicated Skin and Skin Structure Infections
• Complicated Skin and Skin Structure Infections
• Complicated Intra-Abdominal Infections
• Plague
Studies of moxifloxacin hydrochloride tablets for use in the treatment of
plague were done in animals only, because plague could not be studied in
people.
It is not known if moxifloxacin hydrochloride tablets are safe and work in
people under 18 years of age. Children have a higher chance of getting
bone, joint, and tendon (musculoskeletal) problems while taking fluoroquinolone antibiotic medicines.
Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common
cold or flu. Antibiotics, including moxifloxacin hydrochloride tablets, do not
kill viruses. Call your healthcare provider if you think your condition is not
getting better while you are taking moxifloxacin hydrochloride tablets.
Who should not take moxifloxacin hydrochloride tablets?
Do not take moxifloxacin hydrochloride tablets if you have ever had a severe
allergic reaction to an antibiotic known as a fluoroquinolone, or if you are
allergic to any of the ingredients in moxifloxacin hydrochloride tablets. Ask
your healthcare provider if you are not sure. See the list of ingredients in
moxifloxacin hydrochloride tablets at the end of this Medication Guide.
What should I tell my healthcare provider before taking moxifloxacin
See “What is the most important information I should know about moxifloxacin hydrochloride tablets?”
Tell your healthcare provider about all your medical conditions, including if you:
• Have tendon problems
• Have a disease that causes muscle weakness (myasthenia gravis)
• Have central nervous system problems (such as epilepsy)
• Have nerve problems
• Have or anyone in your family has an irregular heartbeat, especially a
condition called “QT prolongation”
• Have low blood potassium (hypokalemia)
• Have a slow heartbeat (bradycardia)
• Have a history of seizures
• Have kidney problems
• Have rheumatoid arthritis (RA) or other history of joint problems
• Are pregnant or planning to become pregnant. It is not known if moxifloxacin hydrochloride tablets will harm your unborn child
• Are breast-feeding or planning to breast-feed. It is not known if
Page 11 of 13
moxifloxacin hydrochloride passes into breast milk. You and your
healthcare provider should decide whether you will take moxifloxacin
hydrochloride tablets or breast-feed.
• Have diabetes or problems with low blood sugar (hypoglycemia).
Tell your healthcare provider about all the medicines you take, including
prescription and non-prescription medicines, vitamins and herbal and
dietary supplements. Moxifloxacin hydrochloride tablets and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:
• An NSAID (Nonsteroidal Anti-Inflammatory Drug). Many common
medicines for pain relief are NSAIDs. Taking an NSAID while you take
moxifloxacin hydrochloride tablets or other fluoroquinolones may
increase your risk of central nervous system effects and seizures. See
“What are the possible side effects of moxifloxacin hydrochloride
tablets?”
• A blood thinner (warfarin, Coumadin, Jantoven).
• A medicine to control your heart rate or rhythm (antiarrhythmic) See
“What are the possible side effects of moxifloxacin hydrochloride
tablets?”
• An anti-psychotic medicine.
• A tricyclic antidepressant.
• An oral anti-diabetes medicine or insulin.
• Erythromycin.
• A water pill (diuretic).
• A steroid medicine. Corticosteroids taken by mouth or by injection may
increase the chance of tendon injury. See “What is the most important information I should know about moxifloxacin hydrochloride
tablets?”
• Certain medicines may keep moxifloxacin hydrochloride tablets from
working correctly. Take moxifloxacin hydrochloride tablets either
4 hours before or 8 hours after taking these products:
• An antacid, multivitamin, or other product that has magnesium,
aluminum, iron, or zinc
• Sucralfate (Carafate®)
• Didanosine oral suspension or solution
Ask your healthcare provider if you are not sure if any of your medicines
are listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get
a new medicine.
How should I take moxifloxacin hydrochloride tablets?
• Take moxifloxacin hydrochloride tablets once a day exactly as prescribed by your healthcare provider.
• Take moxifloxacin hydrochloride tablets at about the same time each
day.
• Moxifloxacin hydrochloride tablets should be swallowed.
• Moxifloxacin hydrochloride tablets can be taken with or without food.
• Drink plenty of fluids while taking moxifloxacin hydrochloride tablets.
• Do not skip any doses, or stop taking moxifloxacin hydrochloride
tablets even if you begin to feel better, until you finish your prescribed
treatment, unless:
• You have tendon effects (see “What is the most important information I should know about moxifloxacin hydrochloride
tablets?”).
• You have a serious allergic reaction (see “What are the possible
side effects of moxifloxacin hydrochloride tablets?”), or your
healthcare provider tells you to stop.
• This will help make sure that all of the bacteria are killed and lower
the chance that the bacteria will become resistant to moxifloxacin
hydrochloride tablets. If this happens, moxifloxacin hydrochloride
tablets and other antibiotic medicines may not work in the future.
• If you miss a dose of moxifloxacin hydrochloride tablets, take it as
soon as you remember. Do not take more than one dose of moxifloxacin hydrochloride tablets in one day.
•
If you take too much, call your healthcare provider or get medical help
immediately.
What should I avoid while taking moxifloxacin hydrochloride tablets?
• Moxifloxacin hydrochloride tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that
require mental alertness or coordination until you know how moxifloxacin hydrochloride tablets affect you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun.
Moxifloxacin hydrochloride tablets can make your skin sensitive to the
sun (photosensitivity) and the light from sunlamps and tanning beds.
You could get severe sunburn, blisters or swelling of your skin. If you
get any of these symptoms while taking moxifloxacin hydrochloride
tablets, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have
to be in sunlight.
What are the possible side effects of moxifloxacin hydrochloride tablets?
Moxifloxacin hydrochloride tablets can cause side effects that may be serious or even cause death. See “What is the most important information I
should know about moxifloxacin hydrochloride tablets?”
Other serious side effects of moxifloxacin hydrochloride tablets include:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone
antibiotics including moxifloxacin hydrochloride tablets. Tell your
healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking moxifloxacin hydrochloride tablets will
change your risk of having a seizure.
Central Nervous System (CNS) side effects may happen as soon as
after taking the first dose of moxifloxacin hydrochloride tablets. Talk
to your healthcare provider right away if you have any of these side
effects, or other changes in mood or behavior:
• Feeling dizzy
• Seizures
• Hear voices, see things, or sense things that are not there (hallucinations)
• Feel restless
• Tremors
• Feel anxious or nervous
• Confusion
• Depression
• Trouble sleeping
• Feel more suspicious (paranoia)
• Suicidal thoughts or acts
• Nightmares
• Vision loss
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones,
including moxifloxacin hydrochloride tablets, even after only one dose.
Stop taking moxifloxacin hydrochloride tablets and get emergency
medical help right away if you get any of the following symptoms of a
severe allergic reaction:
• Hives
• Trouble breathing or swallowing
• Swelling of the lips, tongue, face
• Throat tightness, hoarseness
• Rapid heartbeat
• Faint
• Yellowing of the skin or eyes. Stop taking moxifloxacin hydrochloride
tablets and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark
urine. These can be signs of a serious reaction to moxifloxacin
hydrochloride tablets (a liver problem).
Page 12 of 13
•
Skin rash
Skin rash may happen in people taking moxifloxacin hydrochloride
tablets even after only one dose. Stop taking moxifloxacin hydrochloride tablets at the first sign of a skin rash and call your healthcare
provider. Skin rash may be a sign of a more serious reaction to moxifloxacin hydrochloride tablets.
• Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your
heart beat (a fast or irregular heartbeat), or if you faint. Moxifloxacin
hydrochloride tablets may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal
heartbeat and can be very dangerous. The chances of this event are
higher in people:
• Who are elderly
• With a family history of prolonged QT interval
• With low blood potassium (hypokalemia)
• Who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including moxifloxacin hydrochloride tablets. Call your healthcare provider
right away if you get watery diarrhea, diarrhea that does not go away,
or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.
• Changes in sensation and nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including moxifloxacin hydrochloride
tablets. Stop moxifloxacin hydrochloride tablets and talk with your
healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
• Pain
• Burning
• Tingling
• Numbness
• Weakness
The nerve damage may be permanent.
• Changes in blood sugar
People who take moxifloxacin hydrochloride tablets and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin
can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how often
to check your blood sugar. If you have diabetes and you get low blood
sugar while taking moxifloxacin hydrochloride tablets, stop taking
moxifloxacin hydrochloride tablets and call your healthcare provider
right away. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking moxifloxacin hydrochloride
tablets?”. The most common side effects of moxifloxacin hydrochloride tablets include nausea and diarrhea.
These are not all the possible side effects of moxifloxacin hydrochloride
tablets. Tell your healthcare provider about any side effect that bothers you
or that does not go away.
a Medication Guide. Do not use moxifloxacin hydrochloride tablets for a
condition for which it is not prescribed. Do not give moxifloxacin hydrochloride tablets to other people, even if they have the same symptoms that
you have. It may harm them.
This Medication Guide summarizes the most important information about
moxifloxacin hydrochloride tablets. If you would like more information about
moxifloxacin hydrochloride tablets, talk with your healthcare provider. You
can ask your healthcare provider or pharmacist for information about moxifloxacin hydrochloride tablets that is written for healthcare professionals.
(1-877-4-INFO-RX).
What are the ingredients in moxifloxacin hydrochloride tablets?
• Moxifloxacin Hydrochloride Tablets:
• Active ingredient: moxifloxacin hydrochloride, USP
• Inactive ingredients: copovidone, croscarmellose sodium, lecithin,
magnesium stearate, microcrystalline cellulose, polyvinyl alcohol,
red iron oxide, talc, titanium dioxide and xanthan gum.
The brands mentioned are trademarks of their respective owners.
Administration.
Manufactured for:
75057236
REVISED AUGUST 2015
MX:MOXI:R3mh
How should I store moxifloxacin hydrochloride tablets?
• Store moxifloxacin hydrochloride tablets at 20° to 25°C (68° to 77°F).
• Keep moxifloxacin hydrochloride tablets away from moisture (humidity).
Keep moxifloxacin hydrochloride tablets and all medicines out of the
reach of children.
General Information about moxifloxacin hydrochloride tablets
Page 13 of 13
These highlights do not include all the information needed to use nevirapine extendedrelease tablets safely and effectively. See full prescribing information for nevirapine
NEVIRAPINE extended-release tablets, for oral use
•
WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY
and SKIN REACTIONS
• Fatal and non-fatal hepatotoxicity (5.1)
• Fatal and non-fatal skin reactions (5.2)
Discontinue immediately if experiencing:
• Signs or symptoms of hepatitis (5.1)
• Increased transaminases combined with rash or other systemic symptoms (5.1)
• Severe skin or hypersensitivity reactions (5.2)
• Any rash with systemic symptoms (5.2)
Monitoring during the first 18 weeks of therapy is essential. Extra vigilance is
warranted during the first 6 weeks of therapy, which is the period of greatest risk of
these events. (5)
•
----------------------------- DOSAGE FORMS AND STRENGTHS ---------------------------• 100 mg tablets (3)
----------------------------------- CONTRAINDICATIONS ----------------------------------• Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. (4.1, 5.1, 8.7)
• Use as part of occupational and non-occupational post-exposure prophylaxis (PEP)
regimens, an unapproved use. (4.2, 5.1)
------------------------------- WARNINGS AND PRECAUTIONS ----------------------------• Hepatotoxicity: Fatal and non-fatal hepatotoxicity has been reported. Monitor liver function
tests before and during therapy. Permanently discontinue nevirapine if clinical hepatitis or
transaminase elevations combined with rash or other systemic symptoms occur. Do not
restart nevirapine after recovery. (5.1)
• Rash: Fatal and non-fatal skin reactions, including Stevens-Johnson syndrome, toxic
epidermal necrolysis, and hypersensitivity reactions, have been reported. Permanently
discontinue nevirapine if severe skin reactions or hypersensitivity reactions occur. Check
transaminase levels immediately for all patients who develop a rash in the first 18 weeks
of treatment. (5.2)
• Monitor patients for immune reconstitution syndrome and fat redistribution. (5.5, 5.6)
----------------------------------- ADVERSE REACTIONS ---------------------------------• Adult patients: The most common adverse reaction is rash. During the lead-in period with
immediate-release nevirapine, the incidence of Grade 2 or higher drug-related rash in
adults is 3%. After the lead-in period the incidence of Grade 2 or higher drug-related rash
in subjects taking nevirapine extended-release tablets is 3%. The incidence of Grade 2 or
higher drug-related clinical hepatitis after the lead-in phase was 2%. (6.1)
• Pediatric patients: The incidence of Grade 2 or higher drug-related rash was 1%. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals
Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or
--------------------------------- INDICATIONS AND USAGE --------------------------------• Nevirapine extended-release tablets are an NNRTI indicated for combination antiretroviral
treatment of HIV-1 infection in adults and in children 6 to less than 18 years of age. (1)
Important Considerations:
• Initiation of treatment is not recommended in the following populations unless the benefits
outweigh the risks. (1, 5.1)
o adult females with CD4+ cell counts greater than 250 cells/mm3
o adult males with CD4+ cell counts greater than 400 cells/mm3
• The 14-day lead-in period with immediate-release nevirapine (200 mg once daily) must
be strictly followed; it has been demonstrated to reduce the frequency of rash. (2.5, 5.2)
------------------------------ DOSAGE AND ADMINISTRATION ----------------------------• The nevirapine extended-release tablets must be swallowed whole and must not be
chewed, crushed, or divided. (2.1)
• Adult patients must initiate therapy with one 200 mg tablet of immediate-release nevirapine once daily for the first 14 days, followed by one 400 mg tablet of nevirapine
extended-release once daily. (2.2)
• Adult patients already on a regimen of immediate-release nevirapine twice daily can be
switched to nevirapine extended-release tablets 400 mg once daily without the 14-day
lead-in period of immediate-release nevirapine. (2.2)
• Pediatric patients (ages 6 to less than 18 years) must initiate therapy with immediaterelease nevirapine (as 150 mg/m2 of nevirapine oral suspension or as nevirapine tablet) at
a dose not to exceed 200 mg per day administered once daily for the first 14 days, followed
by nevirapine extended-release tablets once daily as shown in the following table. (2.3)
Recommended Dosing for Pediatric Patients 6 to less than 18 years of age by
BSA after the Lead-in Period
BSA range (m2)
Nevirapine Extended-release Tablets Dose (mg)
0.58 to 0.83
200 mg once daily (2 x 100 mg)
0.84 to 1.16
Greater than or equal to 1.17
•
immediate-release nevirapine tablets can be switched to nevirapine extended-release
tablets once daily without the 14-day lead-in period of nevirapine oral suspension or
immediate-release nevirapine tablets. (2.3)
If any patient experiences rash during the 14-day lead-in period with immediate-release
nevirapine do not initiate nevirapine extended-release tablets until the rash has resolved.
Do not continue the immediate-release nevirapine lead-in dosing regimen beyond 28 days.
(2.5)
If dosing is interrupted for greater than 7 days, restart 14-day lead-in dosing. (2.5)
----------------------------------- DRUG INTERACTIONS ----------------------------------Co-administration of nevirapine extended-release tablets can alter the concentrations of other
drugs, and other drugs may alter the concentration of nevirapine. The potential for drug interactions must be considered prior to and during therapy. (5.4, 7, 12.3)
------------------------------ USE IN SPECIFIC POPULATIONS -----------------------------• No dose adjustment is required for patients with renal impairment with a creatinine clearance greater than or equal to 20 mL per min. Patients on dialysis receive an additional dose
of immediate-release nevirapine (200 mg) following each dialysis treatment. (2.5, 8.6)
• Monitor patients with hepatic fibrosis or cirrhosis carefully for evidence of drug-induced
toxicity. Do not administer nevirapine extended-release tablets to patients with Child-Pugh
B or C. (5.1, 8.7)
MAY 2015
MXA:NEV1:R1mmh/MXA:MG:NEV1:R1m/MXA:MG:NEV1:R1mh
Pediatric patients already on a regimen of twice-daily nevirapine oral suspension or
WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN
REACTIONS
1
2
2.1
General Dosing Considerations
2.2
Adult Patients
2.3
Pediatric Patients
2.4
Monitoring of Patients
2.5
Dosage Adjustment
3
4CONTRAINDICATIONS
4.1
Hepatic Impairment
4.2
Post-Exposure Prophylaxis
5
5.1
Hepatotoxicity and Hepatic Impairment
5.2
Skin Reactions
5.3Resistance
5.4
Drug Interactions
5.5
Immune Reconstitution Syndrome
5.6
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience in Adult Patients
6.2
Clinical Trial Experience in Pediatric Patients
6.3
Post-Marketing Experience
DRUG INTERACTIONS
8.1Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10OVERDOSAGE
11DESCRIPTION
12.4Microbiology
14 CLINICAL STUDIES
14.1 Adult Patients
7
8
1
area (BSA) calculated using the Mosteller formula. All pediatric patients must initiate therapy with immediate-release nevirapine (as 150 mg/m2 of nevirapine oral suspension or as
nevirapine tablets), at a dose not to exceed 200 mg per day, administered once daily for
the first 14 days. This lead-in period should be used because it has been demonstrated to
reduce the frequency of rash. This lead-in period is not required if the patient is already
on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents.
The recommended oral doses of nevirapine extended-release tablets for pediatric patients
6 to less than 18 years of age based upon their BSA are described in the table below. The
total daily dose should not exceed 400 mg for any patient.
WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN
REACTIONS
HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity,
particularly in the first 18 weeks, has been reported in patients treated with
nevirapine. In some cases, patients presented with non-specific prodromal signs
or symptoms of hepatitis and progressed to hepatic failure. These events are often
associated with rash. Female gender and higher CD4+ cell counts at initiation of
therapy place patients at increased risk; women with CD4+ cell counts greater than
250 cells/mm3, including pregnant women receiving nevirapine in combination
with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest
risk. However, hepatotoxicity associated with nevirapine use can occur in both
genders, all CD4+ cell counts and at any time during treatment. Hepatic failure has
also been reported in patients without HIV taking nevirapine for post-exposure
prophylaxis (PEP). Use of nevirapine for occupational and non-occupational PEP is
contraindicated [see Contraindications (4.2)]. Patients with signs or symptoms of
hepatitis, or with increased transaminases combined with rash or other systemic
symptoms, must discontinue nevirapine and seek medical evaluation immediately
[see Warnings and Precautions (5.1)].
SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases,
have occurred in patients treated with nevirapine. These have included cases
of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity
reactions characterized by rash, constitutional findings, and organ dysfunction.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity
reactions must discontinue nevirapine and seek medical evaluation immediately.
Transaminase levels should be checked immediately for all patients who develop a
rash in the first 18 weeks of treatment. The 14-day lead-in period with immediaterelease nevirapine 200 mg daily dosing has been observed to decrease the
incidence of rash and must be followed [see Warnings and Precautions (5.2)].
MONITORING: Patients must be monitored intensively during the first 18 weeks of
therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin
reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which
is the period of greatest risk of these events. Do not restart nevirapine following
clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some
cases, hepatic injury has progressed despite discontinuation of treatment.
Table 1: Recommended Nevirapine Extended-release Tablets Dosing for Pediatric
Patients 6 to Less Than 18 Years of Age by BSA After the Lead-in Period
with Immediate-release Nevirapine
Nevirapine Extended-release Tablets Dose (mg)
BSA range (m2)
0.58 to 0.83
0.84 to 1.16
Greater than or equal to 1.17
Mosteller Formula: BSA (m2 ) =
2.4 Monitoring of Patients
Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at
baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency
of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would
include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with
immediate-release nevirapine, prior to initiation of nevirapine extended-release tablets,
and at 2 weeks after initiation of nevirapine extended-release tablets therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine extended-release tablets treatment [see Warnings and Precautions (5)]. In
some cases, hepatic injury has progressed despite discontinuation of treatment.
Patients already on a regimen of immediate-release nevirapine twice daily who switch to
nevirapine extended-release tablets once daily should continue with their ongoing clinical
and laboratory monitoring.
2.5 Dosage Adjustment
Patients with Rash: Discontinue nevirapine if a patient experiences severe rash or
any rash accompanied by constitutional findings [see Boxed Warning and Warnings
and Precautions (5.2)]. Do not initiate therapy with nevirapine extended-release tablets if a patient experiences mild to moderate rash without constitutional symptoms
during the 14-day lead-in period of immediate-release nevirapine until the rash has
resolved [see Warnings and Precautions (5.2)]. The total duration of the once daily
lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.
Patients with Hepatic Events: If a clinical (symptomatic) hepatic event occurs,
permanently discontinue nevirapine. Do not restart nevirapine after recovery [see
Patients with Dose Interruption: For patients who interrupt nevirapine extendedrelease tablets dosing for more than 7 days, restart the recommended lead-in dosing with
immediate-release nevirapine, using one 200 mg tablet daily for the first 14 days.
Patients with Renal Impairment: Patients with CrCL greater than or equal to 20 mL per
min and not requiring dialysis do not require an adjustment in dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCL less than 20 mL per
min. An additional 200 mg dose of immediate-release nevirapine following each dialysis
treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is
not known [see Clinical Pharmacology (12.3)]. Nevirapine extended-release tablets have
not been studied in patients with renal dysfunction.
1
Nevirapine extended-release tablets are indicated for use in combination with other
antiretroviral agents for the treatment of HIV-1 infection in adults and in children 6 to less
than 18 years of age [see Clinical Studies (14.1, 14.2)].
Additional important information regarding the use of nevirapine extended-release tablets for the treatment of HIV-1 infection:
•
Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine should not be initiated in adult females with CD4+ cell
counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater
than 400 cells/mm3 unless the benefit outweighs the risk [see Boxed Warning and
•
The 14-day lead-in period with immediate-release nevirapine dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash [see Dosage
and Administration (2.5) and Warnings and Precautions (5.2)].
•
If rash persists beyond the 14-day lead-in period with immediate-release nevirapine, do not begin dosing with nevirapine extended-release tablets. The lead-in dosing with 200 mg once daily immediate-release nevirapine should not be continued
beyond 28 days, at which point an alternative regimen should be sought.
2
2.1 General Dosing Considerations
•
Nevirapine extended-release tablets must be swallowed whole and must not be
chewed, crushed, or divided.
•
Children should be assessed for their ability to swallow tablets before prescribing
nevirapine extended-release tablets.
•
Nevirapine extended-release tablets can be taken with or without food.
•
No recommendations can be made regarding substitution of four nevirapine extended-release 100 mg tablets for one nevirapine extended-release 400 mg tablet.
2.2 Adult Patients
Patients Not Currently Taking Immediate-release Nevirapine: Patients must initiate
therapy with one 200 mg tablet of immediate-release nevirapine daily for the first 14
days in combination with other antiretroviral agents (this lead-in period should be used
because it has been found to lessen the frequency of rash), followed by one 400 mg tablet
of nevirapine extended-release once daily.
Switching Patients from Immediate-release Nevirapine to Nevirapine Extendedrelease Tablets: Patients already on a regimen of immediate-release nevirapine twice
daily in combination with other antiretroviral agents can be switched to nevirapine
extended-release tablets 400 mg once daily in combination with other antiretroviral
agents without the 14-day lead-in period of immediate-release nevirapine.
Pediatric patients may be dosed using nevirapine extended-release 400 mg or 100 mg
tablets. Nevirapine extended-release tablets are dosed based on a patient’s body surface
3
Nevirapine Extended-release Tablets:
•
The 100 mg tablets are white to off-white, round, unscored tablets debossed with M
on one side of the tablet and N100 on the other side.
4CONTRAINDICATIONS
Nevirapine extended-release tablets are contraindicated in patients with moderate or
severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and
Precautions (5.1) and Use in Specific Populations (8.7)].
4.2 Post-Exposure Prophylaxis
Nevirapine extended-release tablets are contraindicated for use as part of occupational
and non-occupational post-exposure prophylaxis (PEP) regimens [see Warnings and
Precautions (5.1)].
5
The most serious adverse reactions associated with nevirapine are hepatitis/hepatic
failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity
2
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one
instance) has been reported in HIV-1 uninfected individuals receiving multiple doses
of immediate-release nevirapine in the setting of post-exposure prophylaxis (PEP), an
unapproved use. Use of nevirapine extended-release tablets for occupational and nonoccupational PEP is contraindicated [see Contraindications (4.2)].
5.2 Skin Reactions
Severe and life-threatening skin reactions, including fatal cases, have been reported in
patients taking nevirapine. These have occurred most frequently during the first 6 weeks
of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal
necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings,
and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in
some patients experiencing skin and/or liver reactions associated with nevirapine use.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity
reactions (including, but not limited to, severe rash or rash accompanied by fever, general
malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema,
and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction)
must permanently discontinue nevirapine and seek medical evaluation immediately [see
Boxed Warning]. Do not restart nevirapine following severe skin rash, skin rash combined
with increased transaminases or other symptoms, or hypersensitivity reaction.
If patients present with a suspected nevirapine-associated rash, measure transaminases
immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations [see Warnings and Precautions (5.1)].
Patients must initiate therapy with immediate-release nevirapine daily for the first 14
days. This lead-in period has been shown to reduce the frequency of rash. Discontinue
nevirapine if a patient experiences severe rash or any rash accompanied by constitutional
findings. Do not initiate nevirapine extended-release tablets if a patient experiences a mild
to moderate rash without constitutional symptoms during the 14-day immediate-release
nevirapine lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the
rash has resolved. The total duration of the immediate-release nevirapine lead-in dosing
period must not exceed 28 days at which point an alternative regimen should be sought
[see Dosage and Administration (2.5)]. Patients must be monitored closely if isolated rash
of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may
result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with nevirapine.
In a clinical trial of immediate-release nevirapine, concomitant prednisone use (40 mg per
day for the first 14 days of nevirapine administration) was associated with an increase in
incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore,
use of prednisone to prevent nevirapine-associated rash is not recommended.
5.3Resistance
Nevirapine extended-release tablets must not be used as a single agent to treat HIV-1
or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when
nevirapine is administered as monotherapy. The choice of new antiretroviral agents to
be used in combination with nevirapine should take into consideration the potential for
cross-resistance. When discontinuing an antiretroviral regimen containing nevirapine
extended-release tablets, the long half-life of nevirapine should be taken into account; if
antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma
concentrations of nevirapine alone may persist for a week or longer and virus resistance
may subsequently develop [see Microbiology (12.4)].
5.4 Drug Interactions
See Table 4 for listings of established and potential drug interactions [see Drug
Interactions (7)].
Concomitant use of St. John’s wort (Hypericum perforatum) or St. John’s wort-containing
products and nevirapine is not recommended. Co-administration of St. John’s wort with
non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected
to substantially decrease NNRTI concentrations and may result in sub-optimal levels of
nevirapine and lead to loss of virologic response and possible resistance to nevirapine or
to the class of NNRTIs.
Co-administration of nevirapine and efavirenz is not recommended as this combination
has been associated with an increase in adverse reactions and no improvement in efficacy.
5.5 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory
response to indolent or residual opportunistic infections (such as Mycobacterium avium
infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may
necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however,
the time to onset is more variable, and can occur many months after initiation of treatment.
5.6 Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A
causal relationship has not been established.
Increased nevirapine trough concentrations have been observed in some patients with
hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic
fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine
to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic
impairment [see Contraindications (4.1), Use in Specific Populations (8.7), and Clinical
Pharmacology (12.3)]. Nevirapine extended-release tablets have not been evaluated in
subjects with hepatic impairment.
6
ADVERSE REACTIONS
6.1 Clinical Trial Experience in Adult Patients
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most serious adverse reactions associated with nevirapine are hepatitis, hepatic
reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity
which can include severe rash or rash accompanied by fever, general malaise, fatigue,
muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia,
granulocytopenia, lymphadenopathy, or renal dysfunction.
The first 18 weeks of therapy with nevirapine are a critical period during which
intensive clinical and laboratory monitoring of patients is required to detect
potentially life-threatening hepatic events and skin reactions. The optimal frequency
of monitoring during this time period has not been established. Some experts recommend
clinical and laboratory monitoring more often than once per month, and in particular,
include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with
immediate-release nevirapine, prior to initiation of nevirapine extended-release tablets
(during the lead-in period), and at 2 weeks after initiation of nevirapine extended-release
tablets therapy. After the initial 18-week period, frequent clinical and laboratory monitoring
should continue throughout nevirapine extended-release tablets treatment. In addition,
the 14-day lead-in period with immediate-release nevirapine has been demonstrated to
reduce the frequency of rash [see Dosage and Administration (2.2, 2.5)].
Patients already on a regimen of immediate-release nevirapine twice daily who switch to
nevirapine extended-release tablets therapy should continue with their ongoing clinical
and laboratory monitoring.
5.1 Hepatotoxicity and Hepatic Impairment
Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and
cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients
treated with nevirapine.
The risk of symptomatic hepatic events regardless of severity is greatest in the first 6
weeks of therapy. The risk continued to be greater in the nevirapine groups in controlled
clinical trials through 18 weeks of treatment. However, hepatic events may occur at any
time during treatment. In some cases, patients presented with non-specific, prodromal
signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or
hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was
observed in approximately half of the patients with symptomatic hepatic adverse events.
Fever and flu-like symptoms accompanied some of these hepatic events. Some events,
particularly those with rash and other symptoms, have progressed to hepatic failure with
transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy,
prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed
in some patients experiencing skin and/or liver reactions associated with nevirapine use.
Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine
and immediately seek medical evaluation, which should include liver enzyme tests.
Transaminases should be checked immediately if a patient experiences signs or
symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases
should also be checked immediately for all patients who develop a rash in the
first 18 weeks of treatment. Physicians and patients should be vigilant for the
appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia,
nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly.
The diagnosis of hepatotoxicity should be considered in this setting, even if
transaminases are initially normal or alternative diagnoses are possible [see Boxed
Warning and Dosage and Administration (2.4)].
If clinical hepatitis or transaminase elevations combined with rash or other systemic
symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events, including potentially fatal events, are
women with high CD4+ cell counts. In a retrospective analysis of pooled clinical trials
with immediate-release nevirapine, during the first 6 weeks of treatment women had a
3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6%
versus 2%). Patients with higher CD4+ cell counts at initiation of nevirapine therapy are
at higher risk for symptomatic hepatic events. Women with CD4+ cell counts greater than
250 cells/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events
compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%).
An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3
(6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). However, all
patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be
monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported
at all CD4+ cell counts. Co-infection with hepatitis B or C and/or increased transaminase
elevations at the start of therapy with nevirapine are associated with a greater risk of
later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic
increases in AST or ALT.
3
failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity
reactions. Hepatitis/hepatic failure may be isolated or associated with signs of
hypersensitivity which may include severe rash or rash accompanied by fever, general
malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema,
eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed
Warning and Warnings and Precautions (5.1, 5.2)].
The most common clinical toxicity of nevirapine is rash, which can be severe or lifethreatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most
frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate,
maculopapular erythematous cutaneous eruptions, with or without pruritus, located on
the trunk, face and extremities.
The safety database in nevirapine extended-release tablets clinical trials contains data
from 800 subjects treated with nevirapine extended-release tablets and 654 subjects
treated with immediate release nevirapine.
Trial 1100.1486 (VERxVE): In Trial 1100.1486 (VERxVE) treatment-naïve subjects received
a lead-in dose of immediate-release nevirapine 200 mg once daily for 14 days (n = 1,068)
and then were randomized to receive either immediate-release nevirapine 200 mg twice
daily (n = 506) or nevirapine extended-release tablets 400 mg once daily (n = 505). All
subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled
with CD4+ counts less than 250 cells/mm3 for women and less than 400 cells/mm3 for
men [see Indications and Usage (1)]. Data on potential symptoms of hepatic events were
prospectively collected in this trial. The safety data include all subject visits up to the time
of the last subject’s completion of the 96 week endpoint in the trial (mean observation
period 98 weeks).
After the lead-in period, the incidence of any hepatic event was 9% in the immediaterelease nevirapine group and 6% in the nevirapine extended-release tablets group; the
incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and
2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 8% in both the
immediate-release nevirapine group and nevirapine extended-release tablets group.
Overall, there was a comparable incidence of symptomatic hepatic events among men and
women enrolled in VERxVE.
Severe or life-threatening rash considered to be related to nevirapine treatment occurred
in 1% of subjects during the lead-in phase with immediate-release nevirapine, and in
1% of subjects in either treatment group during the randomization phase. In addition, six
cases of Stevens-Johnson syndrome were reported in the trial; all but one occurred within
the first 30 days of nevirapine treatment.
No Grade 2 or above adverse reactions judged to be related to treatment by the investigator
occurred in more than 2% of subjects during the 14-day lead-in with immediate-release
nevirapine (200 mg once daily), with the exception of rash which occurred in 4% of
subjects.
Adverse reactions of at least moderate intensity (Grades 2 or above) 2% or more of treatment-naïve subjects receiving either immediate-release nevirapine or nevirapine extended-release tablets after randomization in Trial 1100.1486 are shown in Table 2.
Table 3: Grade 2 to Grade 4 Laboratory Abnormalities that Represent a Worsening
from Baseline Observed in at least 5% of Subjects in Either Treatment
Group - Trial 1100.1486
Laboratory
Limit
Nevirapine
Nevirapine
Parameter
Immediate-release Extended-release
(unit)
(%)
Tablets
(N = 506)
(%)
(N = 505)
Chemistry
SGPT/ALT (U/L)
Grade 2
2.6 to 5.0 x ULN
13
10
Grade 3
5.1 to 10.0 x ULN
3
4
Grade 4
> 10.0 x ULN
4
2
SGOT/AST (U/L)
Grade 2
2.6 to 5.0 x ULN
9
7
Grade 3
5.1 to 10.0 x ULN
2
3
Grade 4
> 10.0 x ULN
2
2
Amylase (U/L)
Grade 2
1.6 to 2.0 x ULN
4
5
Grade 3
2.1 to 5.0 x ULN
4
2
Grade 4
> 5.0 x ULN
0
<1
Phosphate (mg/dL)
Grade 2
2.0 to 2.4 x ULN
38
33
Grade 3
1.0 to 1.9 x ULN
6
7
Grade 4
< 1.0 x ULN
<1
0
Hematology
Neutrophils
Grade 2
750 to 999/mm3
7
4
2
2
Grade 3
500 to 749/mm3
Grade 4
< 500/mm3
1
1
Lipids
LDL (mg/dL)
Grade 2
160 to 190 mg/dL
15
15
Grade 3
> 190 mg/dL
5
5
Cholesterol (mg/dL)
Grade 2
240 to 300 mg/dL
18
19
Grade 3
> 300 mg/dL
4
3
Table 2: Selected Clinical Adverse Drug Reactions* of At Least Moderate Intensity
(Grade 2 or Above) Occurring in 2% or More of Adult Subjects - Week 96
Analysis of Trial 1100.14861
Adverse Drug
Nevirapine ImmediateNevirapine ExtendedReaction
release
release Tablets
N = 506 (%)
N = 505 (%)
Rash2
Diarrhea
Headache
Clinical Hepatitis3
Abdominal Pain
Arthralgia
Pyrexia
Nausea
Fatigue
4
4
4
4
2
2
2
2
2
5
4
4
2
3
2
1
1
2
* Excludes laboratory abnormalities reported as ADRs
1 Mean observation period 98 weeks.
2 Rash includes terms rash, rash maculopapular, erythema
nodosum, rash erythematous, rash
papular, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic
symptoms (DRESS).
3 Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis
toxic, hepatic failure, jaundice.
Laboratory Abnormalities: Liver enzyme test abnormalities (AST, ALT) were observed in
subjects receiving nevirapine extended-release tablets. Asymptomatic elevations in GGT
occur frequently but are not a contraindication to continue therapy with nevirapine in the
absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred
in trial 1100.1486 are shown in Table 3.
4
Trial 1100.1526 (TRANxITION): In Trial 1100.1526 (TRANxITION) subjects on immediate-release nevirapine 200 mg twice daily for at least 18 weeks were randomized to
either receive nevirapine extended-release tablets 400 mg once daily (n = 295) or remain
on their immediate-release nevirapine treatment (n = 148). Adverse reactions observed
for nevirapine extended-release tablets subjects (48 week analysis) were similar to those
observed in trial 1100.1486, as displayed in Table 2.
6.2 Clinical Trial Experience in Pediatric Patients
Adverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, nonrandomized, crossover trial to evaluate the safety and steady-state pharmacokinetic
parameters of nevirapine extended-release tablets in HIV-1-infected pediatric subjects
3 to less than 18 years of age. Safety was further examined in an optional extension
phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were
treated with nevirapine extended-release tablets once daily in combination with other
antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse
reactions related to nevirapine extended-release tablets in pediatric subjects were similar
to those observed in adults. In pediatric subjects the incidence of Grade 2 or higher drugrelated rash was 1%. There were no adverse reactions of Grade 2 or above which were
considered to be related to treatment by the investigator that occurred in more than 1% of
subjects [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical
Studies (14.2)].
The following adverse reactions have been identified during post-approval use of
immediate-release nevirapine. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Body as a Whole: fever, somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)]
Gastrointestinal: vomiting
Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic
failure
Hematology: anemia, eosinophilia, neutropenia
Investigations: decreased serum phosphorus
Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions
Neurologic: paraesthesia
Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous
eruptions, ulcerative stomatitis and urticaria have all been reported. In addition,
hypersensitivity syndrome and hypersensitivity reactions with rash associated with
constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema,
muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities [see
Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia,
granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.
Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in
Dose or Regimen May Be Needed Due to Drug Interaction Established Drug
Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of
Interaction.
Clinical Comment
Drug Name
Effect on
Concentration
of Nevirapine or
Concomitant Drug
The appropriate doses of the combination
Saquinavir/Ritonavir
The interaction
between nevirapine and of nevirapine and saquinavir/ritonavir
saquinavir/ritonavir has with respect to safety and efficacy have
not been evaluated
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*
↓ Efavirenz
The appropriate doses of these
combinations with respect to safety and
efficacy have not been established.
Plasma concentrations may be altered.
Delavirdine
Nevirapine should not be co-administered
Etravirine
with another NNRTI as this combination
Rilpivirine
has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir
Plasma concentrations Nevirapine and boceprevir should not be
co-administered because decreases in
of boceprevir may
boceprevir plasma concentrations may
be decreased due to
result in a reduction in efficacy.
induction of CYP3A4/5
by nevirapine.
Telaprevir
Plasma concentrations Nevirapine and telaprevir should not be
co-administered because changes in
of telaprevir may be
plasma concentrations of nevirapine,
decreased due to
telaprevir, or both may result in a reduction
induction of CYP3A4
in telaprevir efficacy or an increase in
by nevirapine and
plasma concentrations nevirapine-associated adverse events.
of nevirapine may
be increased due to
inhibition of CYP3A4 by
telaprevir.
Other Agents
Analgesics:
Methadone*
↓ Methadone
Methadone levels were decreased;
increased dosages may be required to
prevent symptoms of opiate withdrawal.
Methadone-maintained
patients
beginning nevirapine therapy should be
monitored for evidence of withdrawal
and methadone dose should be adjusted
accordingly.
7
DRUG INTERACTIONS
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A
and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that
are metabolized by these enzyme systems may have lower than expected plasma levels
when co-administered with nevirapine.
The results of drug interactions studies with immediate-release nevirapine are expected
to also apply to nevirapine extended-release tablets. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical
Pharmacology, Table 5. Clinical comments about possible dosage modifications based on
established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based
on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless
otherwise indicated. In addition to established drug interactions, there may be potential
pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in
Table 4. Although specific drug interaction studies in HIV-1 seropositive subjects have not
been conducted for some classes of drugs listed in Table 4, additional clinical monitoring
may be warranted when co-administering these drugs.
The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may
change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently.
Interaction.
Clinical Comment
Drug Name
Effect on
Concentration
of Nevirapine or
Concomitant Drug
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*
↓ Atazanavir
Do not co-administer nevirapine
↑ Nevirapine
with atazanavir because nevirapine
substantially decreases atazanavir
exposure and there is a potential risk
for nevirapine-associated toxicity due to
increased nevirapine exposures.
Fosamprenavir*
↓ Amprenavir
↑ Nevirapine
Fosamprenavir/
Ritonavir*
↓ Amprenavir
↑ Nevirapine
Co-administration of nevirapine and
fosamprenavir without ritonavir is not
recommended.
No dosing adjustments are required
when nevirapine is co-administered
with 700 mg/100 mg of fosamprenavir/
ritonavir twice daily. The combination
of nevirapine administered with
fosamprenavir/ritonavir once daily has
not been studied.
Indinavir*
↓ Indinavir
The appropriate doses of this
combination of indinavir and nevirapine
with respect to efficacy and safety have
Lopinavir/Ritonavir*
↓ Lopinavir
Dosing in adult patients: A dose
adjustment of lopinavir/ritonavir to
500 mg/125 mg tablets twice daily or
533 mg/133 mg (6.5 mL) oral solution
twice daily is recommended when used
in combination with nevirapine. Neither
lopinavir/ritonavir tablets nor oral solution
should be administered once daily in
combination with nevirapine.
Dosing in pediatric patients: Please refer
to the Kaletra® prescribing information
for dosing recommendations based on
body surface area and body weight.
Neither lopinavir/ritonavir tablets nor oral
solution should be administered once
daily in combination with nevirapine.
Nelfinavir*
↓ Nelfinavir M8
Metabolite
↓ Nelfinavir Cmin
Antiarrhythmics:
Amiodarone,
disopyramide, lidocaine
Plasma
concentrations
may be
decreased.
Appropriate doses for this combination
have not been established.
↓ Clarithromycin
↑ 14-OH clarithromycin
Clarithromycin exposure was significantly
decreased by nevirapine; however,
14-OH metabolite concentrations were
increased. Because clarithromycin active
metabolite has reduced activity against
Mycobacterium
avium-intracellulare
complex, overall activity against this
pathogen may be altered. Alternatives
to clarithromycin, such as azithromycin,
should be considered.
Rifabutin*
↑ Rifabutin
Rifabutin and its metabolite
concentrations were moderately
increased. Due to high intersubject
variability, however, some patients
may experience large increases in
rifabutin exposure and may be at higher
risk for rifabutin toxicity. Therefore,
caution should be used in concomitant
administration.
Rifampin*
↓ Nevirapine
Nevirapine and rifampin should not be
administered concomitantly because
decreases in nevirapine plasma
concentrations may reduce the efficacy
of the drug. Physicians needing to treat
patients co-infected with tuberculosis and
using a nevirapine-containing regimen
may use rifabutin instead.
Antibiotics:
Clarithromycin*
The appropriate doses of the
combination of nevirapine and nelfinavir
with respect to safety and efficacy have
Continued
Continued
5
women exposed to immediate-release nevirapine and nevirapine extended-release tablets,
an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to
register patients by calling (800) 258-4263.
Animal Data: No observable teratogenicity was detected in reproductive studies performed
in pregnant rats and rabbits. The maternal and developmental no-observable-effect level
dosages produced systemic exposures approximately equivalent to or approximately
50% higher in rats and rabbits, respectively, than those seen at the recommended daily
human dose (based on AUC). In rats, decreased fetal body weights were observed due to
administration of a maternally toxic dose (exposures approximately 50% higher than that
seen at the recommended human clinical dose).
8.3 Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1 infected
mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for
HIV-1 transmission and the potential for serious adverse reactions in nursing
infants, mothers should be instructed not to breastfeed if they are receiving
8.4 Pediatric Use
Nevirapine extended-release tablets are indicated for use in combination with other
antiretroviral agents for the treatment of HIV-1 infection in children 6 to less than 18 years
of age [see Indications and Usage (1), Dosage and Administration (2.3)].
The use of nevirapine extended-release tablets for the treatment of HIV-1 infection in
pediatric patients 6 to less than 18 years of age is based on pharmacokinetic, safety, and
antiviral activity data from an open-label trial with nevirapine extended-release tablets. The
results of this trial were supported by previous demonstration of efficacy in adult patients
[see Adverse Reactions (6.2), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
Nevirapine extended-release tablets are not recommended for children less than 6 years
of age. Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to
less than 6 years of age to support the use of nevirapine extended-release tablets in this
age group. Furthermore, nevirapine extended-release tablets are not recommended for
children less than 3 years of age because they are not able to swallow tablets.
8.5 Geriatric Use
Clinical studies of nevirapine extended-release tablets did not include sufficient numbers
of subjects aged 65 and older to determine whether elderly subjects respond differently
from younger subjects. In general, dose selection for an elderly patient should be cautious,
reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of
concomitant disease or other drug therapy.
In subjects with renal impairment (mild, moderate or severe), there were no significant
changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by
the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine
metabolites may accumulate in patients receiving dialysis; however, the clinical significance
of this accumulation is not known. No adjustment in nevirapine dosing is required in patients
with CrCL greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have
not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing
chronic hemodialysis, an additional dose of immediate-release nevirapine (200 mg)
following each dialysis treatment is indicated [see Dosage and Administration (2.5) and
Clinical Pharmacology (12.3)]. Nevirapine extended-release tablets have not been studied
in patients with renal dysfunction.
Because increased nevirapine levels and nevirapine accumulation may be observed in
patients with serious liver disease, do not administer nevirapine to patients with moderate
or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. Nevirapine
extended-release tablets have not been evaluated in subjects with hepatic impairment.
Interaction.
Clinical Comment
Drug Name
Effect on
Concentration
of Nevirapine or
Concomitant Drug
Plasma concentrations Use with caution and monitor virologic
Anticonvulsants:
response and levels of anticonvulsants.
of nevirapine and the
Carbamazepine,
anticonvulsant may be
clonazepam,
decreased.
ethosuximide
Antifungals:
Fluconazole*
↑ Nevirapine
Because of the risk of increased
exposure to nevirapine, caution should be
used in concomitant administration, and
patients should be monitored closely for
nevirapine-associated adverse events.
Ketoconazole*
↓ Ketoconazole
Nevirapine and ketoconazole should not
be administered concomitantly because
decreases in ketoconazole plasma
concentrations may reduce the efficacy
of the drug.
Itraconazole
↓ Itraconazole
Nevirapine and itraconazole should not
be administered concomitantly due
to potential decreases in itraconazole
plasma concentrations that may reduce
efficacy of the drug.
Antithrombotics:
Warfarin
Plasma concentrations Potential effect on anticoagulation.
may be increased.
Monitoring of anticoagulation levels is
recommended.
Calcium channel
Plasma concentrations Appropriate doses for these combinations
blockers:
may be decreased.
Diltiazem, nifedipine,
verapamil
Cancer
chemotherapy:
Plasma concentrations Appropriate doses for this combination
Cyclophosphamide
may be decreased.
Ergot alkaloids:
Ergotamine
may be decreased.
Immunosuppressants:
Cyclosporine,
Plasma concentrations Appropriate doses for these combinations
tacrolimus, sirolimus
may be decreased.
Motility agents:
Cisapride
may be decreased.
Opiate agonists:
Fentanyl
may be decreased.
Oral contraceptives:
Ethinyl estradiol and
↓ Ethinyl estradiol
Oral contraceptives and other hormonal
Norethindrone*
↓ Norethindrone
methods of birth control should not be
used as the sole method of contraception
in women taking nevirapine, since
nevirapine may lower the plasma levels
of these medications. An alternative or
additional method of contraception is
recommended.
*
10OVERDOSAGE
There is no known antidote for nevirapine overdosage. Cases of immediate-release
nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have
been reported. Patients have experienced events including edema, erythema nodosum,
fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting
and weight decrease. All events subsided following discontinuation of immediate-release
nevirapine.
The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study.
The results of drug interaction studies with immediate-release nevirapine are expected to also apply to
8
8.1Pregnancy
Pregnancy Category B: There are no adequate and well-controlled trials of nevirapine
in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying
pregnancy outcomes since January 1989, has not found an increased risk of birth defects
following first trimester exposures to nevirapine. The prevalence of birth defects after any
trimester exposure to nevirapine is comparable to the prevalence observed in the general
population.
Severe hepatic events, including fatalities, have been reported in pregnant women receiving
chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless
of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not
initiate nevirapine unless the benefit outweighs the risk. It is unclear if pregnancy augments
the risk observed in non-pregnant women [see Boxed Warning].
Nevirapine extended-release tablets should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
11DESCRIPTION
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against
Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the
dipyridodiazepinone chemical class of compounds.
The chemical name of nevirapine is 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1, 4]diazepin-6-one. Nevirapine, USP is a white to off-white, odorless to
nearly odorless crystalline powder with the molecular weight of 266.30 and the molecular
formula C15H14N4O. Nevirapine has the following structural formula:
O
CH3
H
N
N
6
C
N
N
Nevirapine extended-release tablets are for oral administration. Each tablet contains
100 mg of nevirapine, USP (anhydrous) and the inactive ingredients hypromellose, lactose
monohydrate and sodium stearyl fumarate.
portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3
to 4), or severe (n = 9; marked bridging with occasional cirrhosis without decompensation
indicating Child-Pugh A; Ishak Score 5 to 6) fibrosis as a measure of hepatic impairment,
the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative
metabolites were not altered. However, approximately 15% of these subjects with hepatic
fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual
mean trough). Therefore, patients with hepatic impairment should be monitored carefully
for evidence of drug-induced toxicity [see Warnings and Precautions (5.1)]. The subjects
studied were receiving antiretroviral therapy containing immediate-release nevirapine
200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median
duration of therapy of 3.4 years.
In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh
A; n = 6) or moderate (Child-Pugh B; n = 4) hepatic impairment received a single 200 mg
dose of immediate-release nevirapine, a significant increase in the AUC of nevirapine
was observed in one subject with Child-Pugh B and ascites suggesting that patients
with worsening hepatic function and ascites may be at risk of accumulating nevirapine
in the systemic circulation. Because nevirapine induces its own metabolism with multiple
dosing, this single-dose trial may not reflect the impact of hepatic impairment on multipledose pharmacokinetics.
Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or
C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions
(5.1), and Use in Specific Populations (8.7)]. Nevirapine extended-release tablets have not
been evaluated in patients with hepatic impairment.
Gender: In the multinational 2NN trial of immediate-release nevirapine, a population
pharmacokinetic substudy of 1,077 subjects was performed that included 391 females.
Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since
neither body weight nor Body Mass Index (BMI) had an influence on the clearance of
nevirapine, the effect of gender cannot solely be explained by body size.
The effects of gender on the pharmacokinetics of nevirapine extended-release tablets
have been investigated in Trial 1100.1486. Female subjects tend to have higher (approximately 20% to 30%) trough concentrations in both nevirapine extended-release tablets
and immediate-release nevirapine treatment groups.
Race: An evaluation of nevirapine plasma concentrations (pooled data from several clinical
trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked
difference in nevirapine steady-state trough concentrations (median Cmin,ss = 4.7 mcg per mL
Black, 3.8 mcg per mL Hispanic, 4.3 mcg per mL Caucasian) with long-term treatment with
immediate-release nevirapine at 400 mg per day. However, the pharmacokinetics of nevirapine
have not been evaluated specifically for the effects of ethnicity.
Black subjects (n = 80/group) in Trial 1100.1486 showed approximately 30% to 35%
higher trough concentrations than Caucasian subjects (250 to 325 subjects/group) in both
immediate-release nevirapine and nevirapine extended-release tablets treatment groups
over 96 weeks of treatment at 400 mg per day.
Geriatric Patients: Nevirapine pharmacokinetics in HIV-1-infected adults do not appear
to change with age (range 18 to 68 years); however, nevirapine has not been extensively
evaluated in patients beyond the age of 65 years [see Use in Specific Populations (8.5)].
Pediatric Patients: The pharmacokinetics of nevirapine extended-release tablets were
assessed in HIV-1 infected children 3 to less than 18 years of age. Children enrolled
received weight or body surface area dose-adjusted immediate-release nevirapine in
combination with other antiretrovirals for a minimum of 18 weeks and then were switched
to nevirapine extended-release tablets in combination with other antiretrovirals for 10 days,
after which steady-state pharmacokinetic parameters were determined.
Overall, the mean systemic nevirapine exposures in children 6 to less than 18 years of age
following administration of nevirapine extended-release tablets and immediate-release
nevirapine were similar. Based on intensive PK data (N = 17), the observed geometric
mean ratios of nevirapine extended-release tablets to immediate-release nevirapine were
approximately 97% for Cmin,ss and 94% for AUCss with 90% confidence intervals within
80% to 125%; the ratio for Cmax,ss was lower and consistent with a once daily extended-release dosage form.
Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than
6 years of age to support the use of nevirapine extended-release tablets in this age group.
Drug Interactions: [See Drug Interactions (7).]
Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Coadministration of nevirapine extended-release tablets and drugs primarily metabolized
by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and
attenuate their therapeutic effects.
While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also
inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in
vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the
inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in
patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may
have minimal inhibitory effect on other substrates of CYP3A.
Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.
Table 5 (see below) contains the results of drug interaction trials performed with
immediate-release nevirapine and other drugs likely to be co-administered. The effects of
nevirapine on the AUC, Cmax, and Cmin of co-administered drugs are summarized. Results
Nevirapine is an antiviral drug [see Microbiology (12.4)].
Adults: Absorption and Bioavailability: The single-dose pharmacokinetics of nevirapine
extended-release tablets was studied in 17 healthy volunteers. Nevirapine was absorbed
with a median tmax of approximately 24 hrs. The mean Cmax and AUC0-∞ of nevirapine
were 2060 ng per mL and 161,000 ng*hr/mL, respectively. The bioavailability of 400 mg of
nevirapine extended-release tablets, relative to 400 mg of immediate-release nevirapine,
was approximately 75%.
The multiple-dose pharmacokinetics of nevirapine extended-release tablets was studied
in 24 HIV-1 infected subjects who switched from chronic immediate-release nevirapine
to nevirapine extended-release tablets. The mean nevirapine AUC0-24,ss and Cmin,ss
after 19 days of nevirapine extended-release tablets dosing under fasted conditions
were 82,000 ng*hr/mL and 2920 ng per mL, respectively. When nevirapine extendedrelease tablets were administered under fed conditions, the mean nevirapine AUC0-24,ss
and Cmin,ss were 96,700 ng*hr/mL and 3150 ng per mL, respectively. The bioavailability
of 400 mg of nevirapine extended-release tablets, relative to 400 mg of immediaterelease nevirapine, under fasted and fed conditions, was 80% and 94%, respectively. The
difference in the bioavailability of nevirapine, when nevirapine extended-release tablets
are dosed under fasted or fed conditions, is not considered clinically relevant. Nevirapine
extended-release tablets can be taken with or without food.
In single-dose, parallel-group bioavailability trial (1100.1517) in adults, the nevirapine
extended-release 100 mg tablet exhibited extended-release characteristics of prolonged
absorption and lower maximal concentration, as compared to the immediate-release
nevirapine 200 mg tablet.
Distribution: Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH.
Following intravenous administration to healthy adults, the apparent volume of distribution
(Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed
in humans. Nevirapine readily crosses the placenta and is also found in breast milk [see
Use In Specific Populations (8.3)]. Nevirapine is about 60% bound to plasma proteins in the
plasma concentration range of 1 to 10 mcg per mL. Nevirapine concentrations in human
cerebrospinal fluid (n = 6) were 45% (± 5%) of the concentrations in plasma; this ratio is
approximately equal to the fraction not bound to plasma protein.
Metabolism/Elimination: In vivo studies in humans and in vitro studies with human liver
microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450
(oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human
liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily
by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other
isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male
volunteers dosed to steady-state with immediate-release nevirapine 200 mg given twice
daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the
radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route
of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine
was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome
P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated
metabolites represent the primary route of nevirapine biotransformation and elimination in
humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less
than 3% of the total dose) was made up of parent compound; therefore, renal excretion
plays a minor role in elimination of the parent compound.
Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and
2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20% to 25%, as indicated
by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and
CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the
apparent oral clearance of nevirapine as treatment continues from a single dose to 2
to 4 weeks of dosing with 200 to 400 mg per day of immediate-release nevirapine.
Autoinduction also results in a corresponding decrease in the terminal phase half-life of
nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25 to
30 hours following multiple dosing with 200 to 400 mg per day.
Specific Populations: Renal Impairment: HIV-1 seronegative adults with mild (CrCL 50 to
79 mL per min; n = 7), moderate (CrCL 30 to 49 mL per min; n = 6), or severe (CrCL less
than 30 mL per min; n = 4) renal impairment received a single 200 mg dose of immediaterelease nevirapine in a pharmacokinetic trial. These subjects did not require dialysis. The
trial included six additional subjects with renal failure requiring dialysis.
In subjects with renal impairment (mild, moderate or severe), there were no significant
changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis
exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was
also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects
requiring dialysis. An additional 200 mg dose of immediate-release nevirapine following
each dialysis treatment is indicated [see Dosage and Administration (2.5) and Use in
Specific Populations (8.6)]. Nevirapine extended-release tablets have not been studied in
patients with renal dysfunction.
Hepatic Impairment: In a steady-state trial comparing 46 subjects with mild (n = 17;
expansion of some portal areas; Ishak Score 1 to 2), moderate (n = 20; expansion of most
7
of drug interaction studies with immediate-release nevirapine are expected to also apply
to nevirapine extended-release tablets.
Table 5: Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the
Presence of Immediate-release Nevirapine (All Interaction Studies Were Conducted in HIV-1
Positive Subjects)
Table 5: Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the
Presence of Immediate-release Nevirapine (All Interaction Studies Were Conducted in HIV-1
Positive Subjects)
Co-administered Drug Dose of Coadministered Drug
Dose Regimen of
n % Change of Co-administered Drug
Immediate-release
Pharmacokinetic Parameters (90% CI)
Nevirapine
Antiretrovirals
Atazanavir/
Ritonavira,d
AUC
200 mg BID day 1 to 23. 23 Atazanavir
300 mg/100 mg
Subjects were treated
with nevirapine prior to
↓42
trial entry.
(↓52 to ↓29)
300 mg/100 mg QD day
4 to 13, then
400 mg/100 mg QD,
day 14 to 23
Cmin
Cmax
Atazanavir
Atazanavir
300 mg/100 mg 300 mg/100 mg
↓28
(↓40 to ↓14)
Co-administered Drug Dose of Coadministered Drug
Dose Regimen of
n % Change of Co-administered Drug
Immediate-release
Pharmacokinetic Parameters (90% CI)
Nevirapine
Ketoconazolea
400 mg QD
200 mg QD x
14 days; 200 mg BID
x 14 days
21 ↓72
(↓80 to ↓60)
Methadonea
Individual Subject
Dosing
200 mg QD x
14 days; 200 mg BID
≥ 7 days
Rifabutina
150 mg or
300 mg QD
200 mg QD x 14 days;
200 mg BID x 14 days
9 In a controlled pharmacokinetic trial with nine
subjects receiving chronic methadone to whom
steady-state nevirapine therapy was added, the
clearance of methadone was increased by 3-fold,
resulting in symptoms of withdrawal, requiring dose
adjustments in 10 mg segments, in seven of the
nine subjects. Methadone did not have any effect on
nevirapine clearance.
↔
19 ↑17
↑28
(↓2 to ↑40)
(↑9 to ↑51)
↓72
(↓80 to ↓60)
Atazanavir
Atazanavir
Atazanavir
400 mg/100 mg 400 mg/100 mg 400 mg/100 mg
Darunavir/
Ritonavire
400 mg/100 mg BID
200 mg BID
Didanosine
100 mg to
150 mg BID
200 mg QD x
14 days; 200 mg BID
x 14 days
Efavirenza
600 mg QD
200 mg QD x
14 days; 400 mg QD
x 14 days
Fosamprenavir
1400 mg BID
Fosamprenavir/Ritonavir 700 mg/100 mg BID
↓19
(↓35 to ↑2)
8 ↑24
(↓3 to ↑57)
18 ↔
↑2
(↓15 to ↑24)
↑40
(↑14 to ↑73)
↔
↓59
(↓73 to ↓40)
↑2
(↓21 to ↑32)
§
Rifampina
17 ↓28
(↓34 to ↓14)
↓12
(↓23 to ↑1)
↓32
(↓35 to ↓19)
200 mg BID.
17 ↓33
Subjects were
(↓45 to ↓20)
treated with nevirapine
prior to trial entry.
↓25
(↓37 to ↓10)
↓35
(↓50 to ↓15)
200 mg BID.
17 ↓11
Subjects were
(↓23 to ↑3)
treated with nevirapine
prior to trial entry
↔
↓19
(↓32 to ↓4)
Indinavira
800 mg q8H
200 mg QD x
14 days; 200 mg BID
x 14 days
19 ↓31
(↓39 to ↓22)
↓15
(↓24 to ↓4)
↓44
(↓53 to ↓33)
Lopinavira, b
300 mg/75 mg/m2
(lopinavir/ritonavir)b
12, ↓22
15c (↓44 to ↑9)
↓14
(↓36 to ↑16)
↓55
(↓75 to ↓19)
Lopinavira
400 mg/100 mg BID
(lopinavir/ritonavir)
7 mg/kg or 4 mg/kg QD
x 2 weeks; BID
x one week
200 mg BID > one year
22, ↓27
19c (↓47 to ↓2)
↓19
(↓38 to ↑5)
Maravirocf
300 mg SD
200 mg BID
Nelfinavira
750 mg TID
200 mg QD x
14 days; 200 mg BID
x 14 days
8 ↑1
(↓35 to ↑55)
23 ↔
↑54
(↓6 to ↑151)
↔
↓51
(↓72 to ↓26)
↔
↓62
(↓70 to ↓53)
18 ↔
↓59
(↓68 to ↓48)
↔
↓66
(↓74 to ↓55)
↔
Nelfinavir-M8 metabolite
600 mg BID
200 mg QD x
14 days; 200 mg BID
x 14 days
Stavudine
30 mg to
40 mg BID
22 ↔
↔
§
Zalcitabine
0.125 mg to
0.25 mg TID
200 mg QD x
14 days; 200 mg BID
x 14 days
200 mg QD x
14 days; 200 mg BID
x 14 days
6 ↔
↔
§
Zidovudine
100 mg to
200 mg TID
200 mg QD x
14 days; 200 mg BID
x 14 days
11 ↓28
(↓40 to ↓4)
↓30
(↓51 to ↑14)
§
500 mg BID
200 mg QD x
14 days; 200 mg BID
x 14 days
AUC
15 ↓31
(↓38 to ↓24)
Cmax
↓23
(↓31 to ↓14)
Cmin
↓56
(↓70 to ↓36)
↑42
(↑16 to ↑73)
↑47
(↑21 to ↑80)
↔
↔
↓19
(↓30 to ↓7)
32 ↔
↓16
(↓27 to ↓3)
↔
§
19 ↔
↔
↔
Metabolite
14-OH-clarithromycin
Ethinyl estradiola
and
0.035 mg (as OrthoNovum® 1/35)
200 mg QD x
14 days; 200 mg BID
x 14 days
Norethindronea
1 mg (as OrthoNovum® 1/35)
Depomedroxyprogesterone
acetate
Fluconazole
150 mg every 3 months 200 mg QD x
14 days; 200 mg BID
x 14 days
200 mg QD
200 mg QD x
14 days; 200 mg BID
x 14 days
10 ↓20
(↓33 to ↓3)
↑24
(↓16 to ↑84)
600 mg QD
200 mg BID x 14 days
14 ↑11
(↓4 to ↑28)
§
↑29
(↓2 to ↑68)
↑22
(↓14 to ↑74)
↔
§
§ = Cmin below detectable level of the assay
↑ = Increase, ↓ = Decrease, ↔ = No Effect
a For information regarding clinical recommendations, see Drug Interactions (7).
b Pediatric subjects ranging in age from 6 months to 12 years
c Parallel group design; n for nevirapine + lopinavir/ritonavir, n for lopinavir/ritonavir alone.
d Parallel group design; n = 23 for atazanavir/ritonavir + nevirapine, n = 22 for atazanavir/ritonavir without nevirapine. Changes in
atazanavir PK are relative to atazanavir/ritonavir 300 mg/100 mg alone.
e Based on between-trial comparison.
f Based on historical controls.
Because of the design of the drug interaction trials (addition of 28 days of nevirapine
therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine
steady-state concentrations was estimated by comparison to historical controls.
Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison
to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table 5 on
nevirapine pharmacokinetics was not significant. No significant interaction was observed
when tipranavir was co-administered with low-dose ritonavir and nevirapine.
12.4Microbiology
Mechanism of Action: Nevirapine is a non-nucleoside reverse transcriptase inhibitor
(NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the
RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of
the enzyme’s catalytic site. The activity of nevirapine does not compete with template or
nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA
polymerases α, ß, γ, or δ) are not inhibited by nevirapine.
Antiviral Activity: The antiviral activity of nevirapine has been measured in a variety of
cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages,
and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the
median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel
of 2,923 wild-type isolates of HIV-1 that were primarily (93%) clade B clinical isolates from
the United States. The 99th percentile EC50 value was 470 nM in this trial. The median
EC50 value was 63 nM (range 14-302 nM, n = 29) against clinical isolates of HIV-1 clades
A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and
CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates
(n = 3) or HIV-2 isolates (n = 3) replicating in cord blood mononuclear cells. Nevirapine in
combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture
and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor
enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination
with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir,
saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine,
stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized
by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.
Resistance: HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine
emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding
Y181C and/or V106A substitutions depending upon the virus strain and cell line employed.
Time to emergence of nevirapine resistance in cell culture was not altered when selection
included nevirapine in combination with several other NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects
receiving either nevirapine (n = 24) or nevirapine and zidovudine (n = 14) were monitored
in Phase 1 and 2 trials ranging from 1 to 12 weeks or longer. After one week of nevirapine
monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell
culture. One or more of the RT mutations resulting in amino acid substitutions K103N,
V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some
subjects as early as 2 weeks after therapy initiation. By week 8 of nevirapine monotherapy,
100% of the subjects tested (n = 24) had HIV-1 isolates with a greater than 100-fold
↓32
(↓50 to ↑5)
Ritonavir
Other Medications
Clarithromycina
Metabolite
25-O-desacetyl-rifabutin
↓44
(↓58 to ↓27)
§
↔
Continued
8
decrease in susceptibility to nevirapine in cell culture compared to baseline, and had
one or more of the nevirapine-associated RT resistance substitutions. Nineteen of these
subjects (80%) had isolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic
failure (n = 71) receiving nevirapine once daily (n = 25) or twice daily (n = 46) in
combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates
from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI
resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I,
Y188C/L, A98G, F227L, and M230L.
For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy
isolates from 23 and 34 subjects who experienced virologic failure in the nevirapine
extended-release tablets and immediate-release nevirapine treatment group, respectively.
Nevirapine resistance-associated substitutions developed in the on-therapy isolates of
78% (18/23) of the subjects who had virologic failures in the nevirapine extended-release
tablets treatment group and 88% (30/34) of the subjects in the immediate-release
nevirapine treatment group, respectively. The Y181C nevirapine resistance-associated
substitution was found alone or in combination with other nevirapine resistanceassociated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A,
P225H, F227L, M230L) in isolates from 14 subjects failing nevirapine extended-release
tablets treatment and 25 subjects failing immediate-release nevirapine treatment. Ontherapy isolates from one subject in nevirapine extended-release tablets treatment group
developed a novel amino acid substitution Y181I and isolates from another subject in the
immediate-release nevirapine treatment group developed a novel amino acid substitution
Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103and 22-fold reductions in susceptibility to nevirapine, respectively.
Cross-resistance: Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs
has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant
to the NNRTIs delavirdine, efavirenz, and etravirine. The Y188N conferred 22- and 7-fold
reductions in susceptibility to delavirdine and efavirenz, respectively, but showed no
decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility
to delavirdine and etravirine 3-and 8-fold, respectively, but did not reduce susceptibility to
efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV.
Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.
of subjects had clade B HIV-1 subtype. Approximately two-thirds of the subjects had a
baseline HIV-RNA level of less than or equal to 100,000 copies per mL.
Table 6 describes week 96 outcomes in the Trial 1100.1486 (VERxVE). These outcomes
include all subjects who were randomized after the 14 day lead-in with immediate-release
nevirapine and received at least one dose of blinded study medication.
Table 6: Outcomes at Week 96 in Trial 1100.1486
Week 96
Nevirapine
Nevirapine
Immediate-release Extended-release
N = 506
Tablets
N = 505
Virologic Success - HIV RNA < 50 copies/mL
67%
69%
Virologic Failure#
18%
17%
No Virologic Data at Week 96 Window
Reasons
10%
8%
Discontinued trial/study drug due to
adverse event or death*
Discontinued trial/study drug for other
5%
5%
reasons**
Missing data during window but on trial
< 1%
1%
#
Includes subjects who changed optimized background therapy (OBT) to new class or changed
OBT not permitted per protocol or due to lack of efficacy prior to Week 96, subjects who
discontinued prior to Week 96 for lack or loss of efficacy and subjects with HIV RNA greater than
or equal to 50 copies/mL in the Week 96 window.
* Includes subjects who discontinued due to adverse events or death at any time point from Day
1 through the Week 96 window if this resulted in no virologic data on treatment during the
specified window.
** Other includes: withdrew consent, lost to follow-up, moved away, etc.
At 96 weeks, mean change from baseline in CD4+ cell count adjusting for baseline HIV-1
viral load stratum was 222 cells/mm3 and 244 cells/mm3 for the groups receiving immediate-release nevirapine and nevirapine extended-release tablets, respectively.
Subjects Switching from Immediate-release Nevirapine to Nevirapine Extendedrelease Tablets: Trial 1100.1526 (TRANxITION) is a Phase 3 trial to evaluate safety and
antiviral activity of switching from immediate-release nevirapine to nevirapine extendedrelease tablets. In this open-label trial, 443 subjects already on an antiviral regimen
containing immediate-release nevirapine 200 mg twice daily with HIV-1 RNA less than
50 copies per mL were randomized in a 2:1 ratio to nevirapine extended-release tablets
400 mg once daily or immediate-release nevirapine 200 mg twice daily. Approximately
half of the subjects had tenofovir + emtricitabine as their background therapy, with the
remaining subjects receiving abacavir sulfate + lamivudine or zidovudine + lamivudine.
Approximately half of the subjects had at least 3 years of exposure to immediate-release
nevirapine prior to entering the trial.
At 48 weeks after randomization in Trial 1100.1526, 91% of subjects receiving immediaterelease nevirapine 200 mg twice daily and 93% of subjects receiving nevirapine extendedrelease tablets 400 mg once daily continued to have HIV-1 RNA less than 50 copies per mL.
Trial 1100.1518 was an open-label, multiple-dose, non-randomized, crossover trial performed in 85 HIV-1 infected pediatric subjects 3 to less than 18 years of age who had
received at least 18 weeks of immediate-release nevirapine and had plasma HIV-1 RNA
less than 50 copies per mL prior to trial enrollment. Subjects were stratified according to
age (3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years). Following
a 10-day period with immediate-release nevirapine, subjects were treated with nevirapine
extended-release tablets once daily in combination with other antiretrovirals for 10 days,
after which steady-state pharmacokinetic parameters were determined. Forty of the 80
subjects who completed the initial part of the study were enrolled in an optional extension
phase of the trial which evaluated the safety and antiviral activity of nevirapine extended-release tablets through a minimum of 24 weeks of treatment. Zidovudine or stavudine
plus lamivudine were the most commonly used background therapies in subjects who
entered the optional extension phase.
Baseline demographics included: 55% of the subjects were female, 93% were black, 7%
were white, and approximately 84% were from Africa. Subjects had a median baseline
CD4+ cell count of 925 cells/mm3 (range 207 to 2057 cells/mm3).
Of the 40 subjects who entered the treatment extension phase, 39 completed at least 24
weeks of treatment and one subject discontinued prematurely due to an adverse reaction.
After 24 weeks or more of treatment with nevirapine extended-release tablets, all 39
subjects continued to have plasma HIV-1 RNA less than 50 copies per mL. Median CD4+
cell counts for the 3 to less than 6 year, 6 to less than 12 year, and 12 to less than 18 year
age groups were 1113 cells/mm3, 853 cells/mm3, and 682 cells/mm3, respectively. These
CD4+ cell counts were similar to those observed at baseline.
Carcinogenesis: Long-term carcinogenicity studies in mice and rats were carried out
with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for 2 years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two
high doses in females. In studies in which rats were administered nevirapine at doses of
0, 3.5, 17.5 or 35 mg/kg/day for 2 years, an increase in hepatocellular adenomas was
seen in males at all doses and in females at the high dose. The systemic exposure (based
on AUCs) at all doses in the two animal studies was lower than that measured in humans
at the 200 mg twice daily dose of immediate-release nevirapine. The mechanism of the
carcinogenic potential is unknown.
Mutagenesis: However, in genetic toxicology assays, nevirapine showed no evidence of
mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included
microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell
gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell
line and a mouse bone marrow micronucleus assay following oral administration. Given
the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular
neoplasms in nevirapine-treated mice and rats is not known.
Impairment of Fertility: In reproductive toxicology studies, evidence of impaired fertility
was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose.
Animal studies have shown that nevirapine is widely distributed to nearly all tissues and
readily crosses the blood-brain barrier.
14 CLINICAL STUDIES
14.1 Adult Patients
The clinical efficacy of nevirapine extended-release tablets is based on 96-week data
from an ongoing, randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486,
VERxVE) in treatment-naïve subjects and on 48-week data in an ongoing, randomized,
open-label trial in subjects who switched from immediate-release nevirapine tablets
administered twice daily to nevirapine extended-release tablets administered once daily
(Trial 1100.1526, TRANxITION).
Treatment-naïve Subjects: Trial 1100.1486 (VERxVE) is a Phase 3 trial in which
treatment-naïve subjects received immediate-release nevirapine 200 mg once daily
for 14 days and then were randomized to receive either immediate-release nevirapine
200 mg twice daily or nevirapine extended-release tablets 400 mg once daily. All subjects
received tenofovir + emtricitabine as background therapy. Randomization was stratified
by screening HIV-1 RNA level (less than or equal to 100,000 copies per mL and greater
than 100,000 copies per mL). Subject demographic and baseline disease characteristics
were balanced between the two treatment groups. With respect to demographics: 85%
of the subjects were male, 75% were white, 20% were black, and approximately 29%
were from North America. With respect to baseline disease characteristics: mean viral
load was 4.7 log10 copies per mL, mean CD4+ cell count was 228 cells/mm3 and 73%
Nevirapine Extended-release Tablets are available containing 100 mg of nevirapine, USP.
The 100 mg tablets are white to off-white, round, unscored tablets debossed with M on
one side of the tablet and N100 on the other side. They are available as follows:
NDC 0378-6950-93
9
NDC 0378-6950-77
NDC 0378-6950-05
Store in a safe place out of the reach of children.
closure.
release tablets in their stool, which sometimes resemble intact tablets. These occurrences
have not been shown to affect drug levels or response.
•
Drug Interactions
Nevirapine extended-release tablets may interact with some drugs; therefore, patients
should be advised to report to their doctor the use of any other prescription, nonprescription medication or herbal products, particularly St. John’s wort [see Warnings and
Precautions (5.4) and Drug Interactions (7)].
•
Contraceptives
Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA),
should not be used as the sole method of contraception in women taking nevirapine
extended-release tablets, since nevirapine extended-release tablets may lower the plasma
levels of these medications. Additionally, when oral contraceptives are used for hormonal
regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the
hormonal therapy should be monitored [see Drug Interactions (7)].
•
Methadone
Nevirapine extended-release tablets may decrease plasma concentrations of methadone
by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported
in patients treated with nevirapine and methadone concomitantly. Monitor methadonemaintained patients beginning nevirapine therapy for evidence of withdrawal and adjust
methadone dose accordingly [see Drug Interactions (7)].
•
Fat Redistribution
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these
conditions are not known at this time [see Warnings and Precautions (5.6)].
17
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
•
Hepatotoxicity and Skin Reactions
Inform patients of the possibility of severe liver disease or skin reactions associated
with nevirapine that may result in death. Instruct patients developing signs or
symptoms of liver disease or severe skin reactions to discontinue nevirapine
and seek medical attention immediately, including performance of laboratory
monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea,
jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe
skin or hypersensitivity reactions include rash accompanied by fever, general
malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial
edema, and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the
first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity
and skin reactions. However, liver disease can occur after this period; therefore, monitoring
should continue at frequent intervals throughout nevirapine treatment. Extra vigilance
is warranted during the first 6 weeks of therapy, which is the period of greatest risk of
hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis
to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is
discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with
increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 cells/mm3
in women and greater than 400 cells/mm3 in men) are at substantially higher risk for
development of symptomatic hepatic events, often associated with rash. Advise patients
that co-infection with hepatitis B or C and/or increased transaminases at the start of
therapy with nevirapine are associated with a greater risk of later symptomatic events (6
weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT [see
Boxed Warning and Warnings and Precautions (5.1)].
The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation
of therapy. Instruct patients that if any rash occurs during the 2-week lead-in period with
immediate-release nevirapine, do not initiate nevirapine extended-release tablets until
the rash resolves. The total duration of the lead-in dosing period with immediate-release
nevirapine should not exceed 28 days, at which point an alternative regimen may need
to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT)
evaluated immediately. Patients with severe rash or hypersensitivity reactions should
discontinue nevirapine immediately and consult a physician. Nevirapine should not be
restarted following severe skin rash or hypersensitivity reaction. Women tend to be at
higher risk for development of nevirapine-associated rash. For patients who interrupt
nevirapine extended-release tablets dosing for more than 7 days and for whom restarting
nevirapine therapy is not contraindicated, restart the recommended lead-in dosing with
immediate-release nevirapine using one 200 mg tablet daily (150 mg/m2/day in pediatric
patients) for the first 14 days [see Boxed Warning, Dosage and Administration (2.5), and
•
Administration
Inform patients to take nevirapine extended-release tablets every day as prescribed.
Patients should not alter the dose without consulting their doctor. If a dose is missed,
patients should take the next dose as soon as possible. However, if a dose is skipped, the
patient should not double the next dose. Advise patients to report to their doctor the use
of any other medications.
Instruct patients to swallow nevirapine extended-release tablets whole. They must not be
chewed, crushed, or divided.
Nevirapine extended-release tablets are not a cure for HIV-1 infection; patients may
continue to experience illnesses associated with advanced HIV-1 infection, including
opportunistic infections. Advise patients to remain under the care of a physician when
using nevirapine extended-release tablets.
Patients should be told that sustained decreases in plasma HIV RNA have been associated
with a reduced risk of progression to AIDS and death.
Advise patients to avoid doing things that can spread HIV-1 infection to others:
•
Do not share needles or other injection equipment.
•
Do not share personal items that can have blood or body fluids on them, like
toothbrushes and razor blades.
•
Do not have any kind of sex without protection. Always practice safe sex by
using a latex or polyurethane condom to lower the chance of sexual contact with
semen, vaginal secretions, or blood.
•
Do not breastfeed. We do not know if nevirapine can be passed to your baby in your
breast milk and whether it could harm your baby. Also, mothers with HIV-1 should
not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Inform patients that they may occasionally see soft remnants of nevirapine extended-
MEDICATION GUIDE
NEVIRAPINE EXTENDED-RELEASE TABLETS
(ne vir′ a peen)
100 mg
Read this Medication Guide before you start taking nevirapine extended-release tablets and each time you get a refill. There may be
new information. This information does not take the place of talking to
your doctor about your medical condition or treatment.
What is the most important information I should know about
nevirapine?
Nevirapine can cause serious side effects. These include severe
liver and skin problems that can cause death. These problems can
happen at any time during treatment, but your risk is higher during
the first 18 weeks of treatment.
1. Severe liver problems: Anyone who takes nevirapine may get
severe liver problems. In some cases these liver problems can lead
to liver failure and the need for a liver transplant, or death.
People who have a higher CD4+ cell count when they begin
nevirapine treatment have a higher risk of liver problems, especially:
• Women with CD4+ counts higher than 250 cells/mm3. This
group has the highest risk.
• Men with CD4+ counts higher than 400 cells/mm3.
If you are a woman with CD4+ counts higher than 250 cells/mm3
or a man with CD4+ counts higher than 400 cells/mm3, you and
your doctor will decide whether starting nevirapine is right for you.
In general, women have a higher risk of liver problems compared
to men.
People who have abnormal liver test results before starting nevirapine
treatment and people with hepatitis B or C also have a greater risk of
getting liver problems.
You may get a rash if you have liver problems.
Stop taking nevirapine and call your doctor right away if you
have any of the following symptoms of liver problems:
• dark (tea colored) urine • nausea (feeling sick to your
stomach)
• yellowing of your skin or • feel unwell or like you have the flu
whites of your eyes
• light-colored bowel
• pain or tenderness on your right
movements (stools)
side below your ribs
• fever
• tiredness
• loss of appetite
10
Your doctor should see you and do blood tests often to check your
liver function during the first 18 weeks of treatment with nevirapine.
You should continue to have your liver checked regularly during
your treatment with nevirapine. It is important for you to keep all of
your doctor appointments.
2. Severe rash and skin reactions: Skin rash is the most common
side effect of nevirapine. Most rashes happen in the first 6 weeks
of taking nevirapine. Rashes and skin reactions may be severe,
life-threatening, and in some people, may lead to death. Stop
using nevirapine and call your doctor right away if you get a
rash with any of the following symptoms:
• blisters
• swelling of your face
• mouth sores
• fever
• red or inflamed eyes, like
• feel unwell or like you
“pink eye” (conjunctivitis)
have the flu
• liver problems (see symptoms • tiredness
of liver problems above)
• muscle or joint aches
If your doctor tells you to stop treatment with nevirapine because
you have had any of the serious liver or skin problems described
above, you should never take nevirapine again.
See the section “What are the possible side effects of nevirapine?”
for more information.
tell you not to take nevirapine if you have certain liver problems.
Nevirapine is only for people diagnosed with HIV. If you have not been
diagnosed as HIV positive, then do not take nevirapine.
What should I tell my doctor before taking nevirapine?
Before you take nevirapine, tell your doctor if you:
• have or have had hepatitis (inflammation of your liver) or problems
with your liver. See “What is the most important information I
should know about nevirapine?” and “Who should not take
nevirapine?”
• receive dialysis
• have skin problems, such as a rash
• or your child has trouble swallowing pills
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if
nevirapine will harm your unborn baby.
Pregnancy Registry: There is a pregnancy registry for women
who take antiviral medicines during pregnancy. The purpose of the
registry is to collect information about the health of you and your
baby. Talk to your doctor about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Nevirapine can pass into
your breast milk and may harm your baby. You should not breastfeed
if you have HIV because of the risk of passing HIV to your baby. Do
not breastfeed during treatment with nevirapine. Talk to your doctor
about the best way to feed your baby.
Tell your doctor and pharmacist about all the medicines you take,
including prescription and over-the-counter medicines, vitamins and
herbal supplements. Nevirapine may affect the way other medicines
work, and other medicines may affect how nevirapine works.
You should not take nevirapine if you also take:
• St. John’s wort. St. John’s wort can lower the amount of nevirapine
in your body.
• efavirenz (Sustiva®, Atripla®) , etravirine (Intelence®), rilpivirine
(Edurant®, Complera®), or delavirdine (Rescriptor®).
• boceprevir (Victrelis®)
• telaprevir (Incivek®)
• atazanavir (Reyataz®)
• lopinavir and ritonavir (Kaletra®) once daily
• fosamprenavir calcium (Lexiva®) without ritonavir (Norvir®)
• itraconazole (Sporanox®)
• ketoconazole (Nizoral®)
• rifampin (Rifadin®, Rifamate®, Rifater®)
• birth control pills. Birth control pills taken by mouth (oral contraceptives) and other hormone types of birth control may not work to
prevent pregnancy. Talk with your doctor about other types of birth
control that you can use to prevent pregnancy during treatment with
nevirapine.
Also tell your doctor if you take:
• clarithromycin (Biaxin®)
• fluconazole (Diflucan®)
• indinavir sulfate (Crixivan®)
• methadone
• nelfinavir mesylate (Viracept®)
• rifabutin (Mycobutin®)
• warfarin (Coumadin®, Jantoven®)
• saquinavir mesylate (Invirase®)
• amiodarone, disopyramide (Norpace®), lidocaine
• carbamazepine, clonazepam (Klonopin®), ethosuximide (Zarontin®)
• diltiazem, nifedipine, verapamil
• cyclophosphamide
• ergotamine
• cyclosporine, tacrolimus, sirolimus (Rapamune®)
• cisapride (Propulsid®)
• fentanyl
If you are not sure if you take a medicine above, ask your doctor
What is nevirapine?
• Nevirapine tablets and nevirapine oral solution are prescription
HIV medicines used with other HIV medicines to treat HIV (Human
Immunodeficiency Virus). HIV is the virus that causes AIDS (Acquired
Immune Deficiency Syndrome).
• Nevirapine extended-release tablets are a prescription medicine
used with other HIV medicines to treat HIV (Human Immunodeficiency Virus) in adults and in children who are 6 years of age to less
than 18 years of age.
• Nevirapine tablets and nevirapine extended-release tablets are a
type of HIV medicine called a non-nucleoside reverse transcriptase
inhibitor (NNRTI).
Nevirapine extended-release tablets are not for use in children less than
6 years of age.
When used with other HIV medicines, nevirapine may:
1. Reduce the amount of HIV in your blood (called “viral load”).
2. Help increase the number of CD4 (T) cells in your blood which help
fight off other infections.
Reducing the amount of HIV and increasing the CD4 (T) cell count may
improve your immune system. This may reduce your risk of death
or infections that can happen when your immune system is weak
(opportunistic infections).
Nevirapine does not cure HIV infection or AIDS.
Nevirapine does not cure HIV or AIDS and you may continue to experience
illnesses associated with HIV-1 infection, including opportunistic
infections. You should remain under the care of a doctor when using
nevirapine.
You must stay on continuous HIV therapy to control HIV infection and
decrease HIV-related illnesses.
Avoid doing things that can spread HIV-1 infection to others:
• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids
on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice
safe sex by using a latex or polyurethane condom to lower the
chance of sexual contact with semen, vaginal secretions, or blood.
Ask your doctor if you have any questions on how to prevent passing
HIV to other people.
Who should not take nevirapine?
Tell your doctor if you have or have had liver problems. Your doctor may
11
or pharmacist.
Know the medicines you take. Keep a list of them to show your doctor or
pharmacist when you get a new medicine.
legs, arms, and face can also happen. The cause and long-term
health effects of these problems are not known at this time.
The most common side effect of nevirapine is rash.
Tell your doctor if you have any side effect that bothers you or that does
not go away.
These are not all the possible side effects of nevirapine. For more
information, ask your doctor or pharmacist.
How should I take nevirapine?
• Nevirapine is always taken in combination with other anti-HIV
medications.
• Nevirapine comes in three different forms. Your doctor will prescribe
the form of nevirapine that is right for you.
o Nevirapine tablets
o Nevirapine oral suspension
o Nevirapine extended-release tablets
• Take nevirapine exactly as your doctor tells you to take it. Do not
change your dose unless your doctor tells you to.
• You should never take more than one form of nevirapine at the
same time. Talk to your doctor if you have any questions.
• If your child is prescribed nevirapine, your child’s doctor will tell you
exactly how nevirapine should be taken.
• Swallow nevirapine extended-release tablets whole. Do not chew,
crush, or divide nevirapine extended-release tablets.
• You may take nevirapine with or without food.
• Do not miss a dose of nevirapine. If you miss a dose of nevirapine,
take the missed dose as soon as you remember. If it is almost time
for your next dose, do not take the missed dose, just take the next
dose at your regular time. Do not take two doses at the same time.
• If you stop taking nevirapine for more than 7 days, ask your doctor
how much to take before you start taking it again. You may need to
begin taking the nevirapine starting dose again, which is taken one
time each day for 14 days.
Starting nevirapine extended-release tablets when this is the first
time you are taking any form of nevirapine:
1. Your doctor should start you with one dose of nevirapine tablets
or oral suspension each day to lower your risk of getting a serious
rash. It is important that you only take one dose of nevirapine
each day for the first 14 days.
• Call your doctor right away if you get a skin rash during
the first 14 days of nevirapine treatment.
• You should never take your starting dose for longer than 28
days. If after 28 days you are still receiving this starting dose
because you have a rash, you and your doctor should talk about
prescribing another HIV medicine for you instead of nevirapine.
• Do not start nevirapine extended-release tablets if you
have a rash.
2. Day 15, take nevirapine extended-release tablets one time a day as
prescribed by your doctor.
Switching from nevirapine tablets or oral suspension to nevirapine
extended-release tablets:
Take nevirapine extended-release tablets one time a day as prescribed
by your doctor.
You may sometimes pass a soft mass in your stools (bowel movement)
that looks like your nevirapine extended-release tablets. This will not
affect the way your medicine works.
What are the possible side effects of nevirapine?
Nevirapine may cause serious side effects, including:
• See “What is the most important information I should know
about nevirapine?”
• Changes in your immune system (Immune Reconstitution
Syndrome) can happen when you start taking HIV medicines. Your
immune system may get stronger and begin to fight infections that
have been hidden in your body for a long time. Tell your doctor if you
start having new symptoms after starting your HIV medicine.
• Changes in body fat can happen in some people who take
antiretroviral therapy. These changes may include increased
amount of fat in the upper back and neck (“buffalo hump”), breast,
and around the middle of your body (trunk). Loss of fat from your
How should I store nevirapine extended-release tablets?
• Store nevirapine extended-release tablets at room temperature
between 20° to 25°C (68° to 77°F).
• Throw away nevirapine extended-release tablets that are no longer
needed or out-of-date.
Keep nevirapine extended-release tablets and all medicines out of
the reach of children.
General information about nevirapine extended-release tablets.
Medicines are sometimes prescribed for purposes other than those
listed in a Medication Guide. Do not take nevirapine for a condition for
which it was not prescribed. Do not give nevirapine extended-release
tablets to other people, even if they have the same condition you have.
They may harm them.
This Medication Guide summarizes the most important information
about nevirapine extended-release tablets. If you would like more
information, talk with your doctor. You can ask your pharmacist or doctor
for information about nevirapine extended-release tablets that is written
for health professionals.
(1-877-4-INFO-RX).
What are the ingredients in nevirapine extended-release tablets?
Active ingredient: nevirapine, USP
Inactive ingredients: hypromellose, lactose monohydrate and sodium
stearyl fumarate
This Medication Guide has been approved by the U.S. Food and
Drug Administration
The brands listed are trademarks of their respective owners.
Manufactured for:
Code No.: MH/DRUGS/AD/089
MAY 2015
75056349MXA:NEV1:R1mmh
12
•
Pregnancy (4)
These highlights do not include all the information needed to use
NORGESTIMATE and ETHINYL ESTRADIOL tablets safely and effectively.
See full prescribing information for NORGESTIMATE and ETHINYL
ESTRADIOL tablets.
•
Breast cancer or other estrogen- or progestin-sensitive cancer (4)
------------------------ WARNINGS AND PRECAUTIONS ------------------------------•
Thromboembolic Disorders and Other Vascular Problems: Stop
norgestimate and ethinyl estradiol tablets if a thrombotic event occurs.
Stop at least 4 weeks before and through 2 weeks after major surgery.
Start no earlier than 4 weeks after delivery, in women who are not
breastfeeding. (5.1)
•
Liver disease: Discontinue norgestimate and ethinyl estradiol tablets if
jaundice occurs. (5.2)
•
High blood pressure: If used in women with well-controlled hypertension,
monitor blood pressure and stop norgestimate and ethinyl estradiol
tablets if blood pressure rises significantly. (5.3)
•
Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic
women taking norgestimate and ethinyl estradiol tablets. Consider an
alternate contraceptive method for women with uncontrolled dyslipidemia.
(5.5)
•
Headache: Evaluate significant change in headaches and discontinue
norgestimate and ethinyl estradiol tablets if indicated. (5.6)
•
Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or
amenorrhea. (5.7)
NORGESTIMATE and ETHINYL ESTRADIOL tablets, USP for oral use
WARNING: CIGARETTE SMOKING AND SERIOUS
CARDIOVASCULAR EVENTS
• Norgestimate and ethinyl estradiol tablets are contraindicated in
women over 35 years old who smoke. (4)
• Cigarette smoking increases the risk of serious cardiovascular
events from combination oral contraceptives (COC) use. (4)
------------------------------- INDICATIONS AND USAGE ------------------------------Norgestimate and ethinyl estradiol tablets, USP are estrogen/progestin COC,
indicated for use by women to prevent pregnancy. (1.1)
--------------------------- DOSAGE AND ADMINISTRATION --------------------------•
Take one tablet daily by mouth at the same time every day. (2.2)
•
Take tablets in the order directed on the blister pack. (2.2)
•
Do not skip or delay tablet intake. (2.2)
------------------------- DOSAGE FORMS AND STRENGTHS ------------------------Norgestimate and ethinyl estradiol tablets consist of 28 round, flat-faced,
beveled edge tablets in the following order (3):
•
7 white tablets each containing 0.18 mg norgestimate and 0.025 mg
ethinyl estradiol
•
7 light yellow tablets each containing 0.215 mg norgestimate and 0.025
mg ethinyl estradiol
•
7 yellow tablets each containing 0.25 mg norgestimate and 0.025 mg
ethinyl estradiol
•
7 green tablets (inert)
---------------------------------- ADVERSE REACTIONS ---------------------------------The most common adverse reactions reported during clinical trials (greater
than or equal to 2%) were: headache/migraine, nausea/vomiting, breast issues,
abdominal pain, menstrual disorders, mood disorders, acne, vulvovaginal
infection, abdominal distension, weight increased, fatigue. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan
Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------------- DRUG INTERACTIONS ---------------------------------Drugs or herbal products that induce certain enzymes including CYP3A4,
may decrease the effectiveness of COCs or increase breakthrough bleeding.
Counsel patients to use a back-up or alternative method of contraception when
enzyme inducers are used with COCs. (7.1)
---------------------------------- CONTRAINDICATIONS ----------------------------------
--------------------------- USE IN SPECIFIC POPULATIONS ---------------------------
•
A high risk of arterial or venous thrombotic diseases (4)
Nursing mothers: Not recommended; can decrease milk production. (8.3)
•
Liver tumors or liver disease (4)
•
Undiagnosed abnormal uterine bleeding (4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
patient labeling.
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR
EVENTS
1
2
3
4
5
Oral Contraception
1.1
2.1
How to Start Norgestimate and Ethinyl Estradiol Tablets
2.2
How to Take Norgestimate and Ethinyl Estradiol Tablets
Missed Tablets
2.3
2.4
Advice in Case of Gastrointestinal Disturbances
CONTRAINDICATIONS
Thromboembolic Disorders and Other Vascular Problems
5.1
5.2
Liver Disease
5.3
High Blood Pressure
5.4
Gallbladder Disease
5.5
Carbohydrate and Lipid Metabolic Effects
5.6Headache
5.7
Bleeding Irregularities and Amenorrhea
5.8
COC Use Before or During Early Pregnancy
5.9Depression
5.10
Carcinoma of Breast and Cervix
5.11
Effect on Binding Globulins
5.12Monitoring
5.13
Hereditary Angioedema
5.14Chloasma
Revised: 09/2015
ADVERSE REACTIONS
Clinical Trial Experience
6.1
Postmarketing Experience
6.2
7
DRUG INTERACTIONS
Effects of Other Drugs on Combined Oral Contraceptives
7.1
7.2
Effects of Combined Oral Contraceptives on Other Drugs
7.3
Interference with Laboratory Tests
8
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10
OVERDOSAGE
DESCRIPTION
11
12
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
Carcinogenesis, Mutagenesis, and Impairment of Fertility
13.1
CLINICAL STUDIES
14
16
How Supplied
16.1
16.2
Storage Conditions
17
*Sections or subsections omitted from the full prescribing information are not
listed.
Page 1 of 10
6
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR
EVENTS
Cigarette smoking increases the risk of serious cardiovascular
events from combination oral contraceptive (COC) use. This risk
increases with age, particularly in women over 35 years of age, and
with the number of cigarettes smoked. For this reason, COCs are
contraindicated in women who are over 35 years of age and smoke
[see Contraindications (4)].
1
Switching from another
contraceptive method to
norgestimate and ethinyl
estradiol tablets
Transdermal patch
•
2
•
On the day when next application
would have been scheduled
•
Vaginal ring
•
On the day when next insertion
•
Injection
•
On the day when next injection
•
On the day of removal
1.1 Oral Contraception
Norgestimate and ethinyl estradiol tablets, USP are indicated for use by females
of reproductive potential to prevent pregnancy [see Clinical Studies (14)].
Start norgestimate and ethinyl
estradiol tablets:
•
Intrauterine contraceptive
•
If the IUD is not removed on first
day of the patient’s menstrual
cycle, additional non-hormonal
contraceptive (such as condoms
and spermicide) is needed for
the first seven days of the first
cycle pack.
•
Implant
•
On the day of removal
2.1 How to Start Norgestimate and Ethinyl Estradiol Tablets
Norgestimate and ethinyl estradiol tablets are dispensed in a carton of 3
pouches; each pouch contains a blister pack of 28 tablets [see How
Supplied/Storage and Handling (16)]. Norgestimate and ethinyl estradiol
tablets may be started using either a Day 1 start or a Sunday start (see
Table 1). For the first cycle of a Sunday Start regimen, an additional
method of contraception should be used until after the first 7 consecutive
days of administration.
2.2 How to Take Norgestimate and Ethinyl Estradiol Tablets
Table 1: Instructions for Administration of Norgestimate and Ethinyl
Estradiol Tablets
Complete instructions to facilitate patient counseling on proper tablet
usage are located in the FDA-Approved Patient Labeling.
Starting Norgestimate and Ethinyl Estradiol Tablets after Abortion or Miscarriage
First-trimester
•
After a first-trimester abortion or miscarriage, norgestimate and ethinyl
estradiol tablets may be started immediately. An additional method of
contraception is not needed if norgestimate and ethinyl estradiol tablets
are started immediately.
•
If norgestimate and ethinyl estradiol tablets are not started within 5 days
after termination of the pregnancy, the patient should use additional nonhormonal contraception (such as condoms and spermicide) for the first
seven days of her first cycle pack of norgestimate and ethinyl estradiol
tablets.
Day 1 Start:
• Take first active tablet without
regard to meals on the first day of
menses.
• Take subsequent active tablets
once daily at the same time each
day for a total of 21 days.
Starting COCs in women not
currently
using
hormonal
contraception (Day 1 Start or
Sunday Start)
Important:
Consider
the
possibility
of
ovulation and conception prior to
initiation of this product.
• Take one green inactive tablet
daily for 7 days and at the same
time of day that active tablets were
taken.
• Begin each subsequent pack on
the same day of the week as the
first cycle pack (i.e., on the day
after taking the last inactive tablet)
Sunday Start:
•
Norgestimate and ethinyl
estradiol active tablets are
white (Day 1 to Day 7), light
yellow (Day 8 to Day 14) and
yellow (Day 15 to Day 21).
• Take first active tablet without
regard to meals on the first Sunday
after the onset of menses. Due to
the potential risk of becoming
pregnant, use additional nonhormonal contraception (such
as condoms and spermicide)
for the first seven days of
the patient’s first cycle pack
of norgestimate and ethinyl
estradiol tablets.
•
Norgestimate and ethinyl
estradiol inert tablets are
green (Day 22 to Day 28).
• Take subsequent active tablets
once daily at the same time each
day for a total of 21 days.
Tablet Color:
• Take one green inactive tablet
daily for the following 7 days and
at the same time of day that active
tablets were taken.
Switching to norgestimate and
ethinyl estradiol tablets from
another oral contraceptive
Second-trimester
•
Do not start until 4 weeks after a second-trimester abortion or miscarriage,
due to the increased risk of thromboembolic disease. Start norgestimate
and ethinyl estradiol tablets, following the instructions in Table 1 for Day
1 or Sunday start, as desired. If using Sunday start, use additional nonhormonal contraception (such as condoms and spermicide) for the first
seven days of the patient’s first cycle pack of norgestimate and ethinyl
estradiol tablets. [See Contraindications (4), Warnings and Precautions
(5.1), and FDA-Approved Patient Labeling.]
Starting Norgestimate and Ethinyl Estradiol Tablets after Childbirth
•
Do not start until 4 weeks after delivery, due to the increased risk of
thromboembolic disease. Start contraceptive therapy with norgestimate
and ethinyl estradiol tablets following the instructions in Table 1 for women
not currently using hormonal contraception.
•
Norgestimate and ethinyl estradiol tablets are not recommended for use
in lactating women [see Use in Specific Populations (8.3)].
•
If the woman has not yet had a period postpartum, consider the possibility
of ovulation and conception occurring prior to use of norgestimate and
ethinyl estradiol tablets. [See Contraindications (4), Warnings and
Precautions (5.1), Use in Specific Populations (8.1 and 8.3), and FDAApproved Patient Labeling.]
Blister pack:
SET THE DAY:

Sunday Start: The blister is printed with days starting with SUN
(Sunday) after start arrow.

Day 1 Start: Paste day start sticker label on the printed days (if your
period starts on Tuesday, paste the sticker label “TUE” on the printed
day above pill 1 after start arrow and so on).
• Begin each subsequent pack on
the same day of the week as the
first cycle pack (i.e., on the Sunday
after taking the last inactive tablet)
and additional non-hormonal
contraceptive is not needed.
Pill “1” is ready to be taken. Always begin the pill cycle with pill “1” after start
arrow, as shown on the blister pack.
Start on the same day that a new pack
of the previous oral contraceptive
would have started.
When blister pack is empty start a new blister pack on the day after the blister
pack is empty. The first pill in every refill will always be taken on the same day
of the week, no matter when the patient’s next period starts.
Remove pill “1” by pushing through the blister. The pill will come out through
the blister pack.
Wait 24 hours to take the next pill. Continue to take one pill each day until all
the pills have been taken.
Page 2 of 10
2.3
Missed Tablets
Table 2: Instructions for Missed Norgestimate and Ethinyl Estradiol
Tablets
• If one active tablet is missed in
Take the tablet as soon as possible.
Weeks 1, 2, or 3
Continue taking one tablet a day
until the pack is finished.
• If two active tablets are
missed in Week 1 or Week 2
• If two active tablets are missed
in the third week or three or
more active tablets are missed
in a row in Weeks 1, 2, or 3
2.4
Take the two missed tablets as soon
as possible and the next two active
tablets the next day. Continue taking
one tablet a day until the pack is
finished. Additional non-hormonal
contraception (such as condoms
and spermicide) should be used
as back-up if the patient has
sex within 7 days after missing
tablets.
Day 1 start: Throw out the rest of the
pack and start a new pack that same
day.
Sunday start: Continue taking
one tablet a day until Sunday,
then throw out the rest of the pack
and start a new pack that same
day. Additional non-hormonal
contraception (such as condoms
and spermicide) should be used
as back-up if the patient has
sex within 7 days after missing
tablets.
Advice in Case of Gastrointestinal Disturbances
 Women over age 35 with any migraine headaches [see Warnings
and Precautions (5.6)]
•
Liver tumors, benign or malignant, or liver disease [see Warnings and
Precautions (5.2)]
•
Undiagnosed abnormal uterine bleeding [see Warnings and Precautions
(5.7)]
•
Pregnancy, because there is no reason to use COCs during pregnancy
[see Warnings and Precautions (5.8) and Use in Specific Populations
(8.1)]
•
Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.10)]
5
5.1 Thromboembolic Disorders and Other Vascular Problems
•
Stop norgestimate and ethinyl estradiol tablets if an arterial thrombotic
event or venous thrombotic (VTE) event occurs.
•
Stop norgestimate and ethinyl estradiol tablets if there is unexplained
loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Evaluate for retinal vein thrombosis immediately [see Adverse Reactions
(6.2)].
•
If feasible, stop norgestimate and ethinyl estradiol tablets at least 4 weeks
before and through 2 weeks after major surgery or other surgeries known
to have an elevated risk of VTE as well as during and following prolonged
immobilization.
•
Start norgestimate and ethinyl estradiol tablets no earlier than 4 weeks
after delivery, in women who are not breastfeeding. The risk of postpartum
VTE decreases after the third postpartum week, whereas the risk of
ovulation increases after the third postpartum week.
•
The use of COCs increases the risk of VTE. However, pregnancy
increases the risk of VTE as much or more than the use of COCs. The risk
of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years.
The risk of VTE is highest during the first year of use of COCs and when
restarting hormonal contraception after a break of 4 weeks or longer. The
risk of thromboembolic disease due to COCs gradually disappears after
use is discontinued.
•
Use of COCs also increases the risk of arterial thromboses such as
strokes and myocardial infarctions, especially in women with other risk
factors for these events. COCs have been shown to increase both the
relative and attributable risks of cerebrovascular events (thrombotic and
hemorrhagic strokes). This risk increases with age, particularly in women
over 35 years of age who smoke.
•
Use COCs with caution in women with cardiovascular disease risk factors.
In case of severe vomiting or diarrhea, absorption may not be complete and
additional contraceptive measures should be taken. If vomiting or diarrhea
occurs within 3 to 4 hours after taking an active tablet, handle this as a missed
tablet [see FDA-Approved Patient Labeling].
3
Norgestimate and ethinyl estradiol tablets are available in blister packs. Each
blister pack contains 28 tablets in the following order:
•
7 white, round, flat-faced, beveled edge tablets debossed with “234” on
one side of the tablet and plain on the other side, each containing 0.18 mg
norgestimate and 0.025 mg ethinyl estradiol
•
7 light yellow, round, flat-faced, beveled edge tablets debossed with “235”
on one side of the tablet and plain on the other side, each containing
0.215 mg norgestimate and 0.025 mg ethinyl estradiol
•
7 yellow, round, flat-faced, beveled edge tablets debossed with “236” on
•
7 green, round, flat-faced, beveled edge tablets (non-hormonal placebo)
debossed with “295” on one side of the tablet and plain on the other side,
each containing inert ingredients
Do not use norgestimate and ethinyl estradiol tablets in women with liver
disease, such as acute viral hepatitis or severe (decompensated) cirrhosis
of liver [see Contraindications (4)]. Acute or chronic disturbances of liver
function may necessitate the discontinuation of COC use until markers of liver
function return to normal and COC causation has been excluded. Discontinue
norgestimate and ethinyl estradiol tablets if jaundice develops.
4
CONTRAINDICATIONS
Liver Tumors
Do not prescribe norgestimate and ethinyl estradiol tablets to women who are
known to have the following conditions:
•
A high risk of arterial or venous thrombotic diseases. Examples include
women who are known to:
o
Smoke, if over age 35 [see Boxed Warning and Warnings and
Precautions (5.1)]
o
Have deep vein thrombosis or pulmonary embolism, now or in the
past [see Warnings and Precautions (5.1)]
o
Have inherited or acquired hypercoagulopathies [see Warnings and
Precautions (5.1)]
o
Have cerebrovascular disease [see Warnings and Precautions (5.1)]
o
Have thrombogenic valvular or thrombogenic rhythm diseases of
the heart (for example, subacute bacterial endocarditis with valvular
disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]
o
Have uncontrolled hypertension [see Warnings and Precautions
(5.3)]
o
Have diabetes mellitus with vascular disease [see Warnings and
Precautions (5.5)]
o
Have headaches with focal neurological symptoms or migraine
headaches with aura [see Warnings and Precautions (5.6)]
o
Have coronary artery disease [see Warnings and Precautions (5.1)]
5.2 Liver Disease
Impaired Liver Function
Norgestimate and ethinyl estradiol tablets are contraindicated in women
with benign and malignant liver tumors [see Contraindications (4)]. Hepatic
adenomas are associated with COC use. An estimate of the attributable risk
is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause
death through intra-abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma
in long-term (greater than 8 years) COC users. However, the risk of liver
cancers in COC users is less than one case per million users.
5.3 High Blood Pressure
with uncontrolled hypertension or hypertension with vascular disease [see
Contraindications (4)]. For women with well-controlled hypertension, monitor
blood pressure and stop norgestimate and ethinyl estradiol tablets if blood
pressure rises significantly.
An increase in blood pressure has been reported in women taking COCs,
and this increase is more likely in older women with extended duration of use.
The incidence of hypertension increases with increasing concentrations of
progestin.
5.4 Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder
disease among COC users. Use of COCs may worsen existing gallbladder
disease. A past history of COC-related cholestasis predicts an increased
risk with subsequent COC use. Women with a history of pregnancy-related
cholestasis may be at an increased risk for COC related cholestasis.
Page 3 of 10
5.5 Carbohydrate and Lipid Metabolic Effects
5.12Monitoring
Carefully monitor prediabetic and diabetic women who take norgestimate and
ethinyl estradiol tablets. COCs may decrease glucose tolerance.
A woman who is taking COCs should have a yearly visit with her healthcare
provider for a blood pressure check and for other indicated healthcare.
Consider alternative contraception for women with uncontrolled dyslipidemia.
A small proportion of women will have adverse lipid changes while on COCs.
5.13Hereditary Angioedema
Women with hypertriglyceridemia, or a family history thereof, may be at an
increased risk of pancreatitis when using COCs.
5.6Headache
If a woman taking norgestimate and ethinyl estradiol tablets develops new
headaches that are recurrent, persistent, or severe, evaluate the cause and
discontinue norgestimate and ethinyl estradiol tablets if indicated.
Consider discontinuation of norgestimate and ethinyl estradiol tablets in the
case of increased frequency or severity of migraine during COC use (which
may be prodromal of a cerebrovascular event).
5.7 Bleeding Irregularities and Amenorrhea
Unscheduled Bleeding and Spotting
Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes
occur in patients on COCs, especially during the first three months of use. If
bleeding persists or occurs after previously regular cycles, check for causes
such as pregnancy or malignancy. If pathology and pregnancy are excluded,
bleeding irregularities may resolve over time or with a change to a different
contraceptive product.
In the clinical trial of norgestimate and ethinyl estradiol tablets, the frequency
and duration of unscheduled bleeding and/or spotting was assessed in 1,673
women (11,015 evaluable cycles). A total of 3 (0.2%) women discontinued
norgestimate and ethinyl estradiol tablets, at least in part, due to bleeding or
spotting. Based on data from the clinical trials, 7% to 17% of women
using norgestimate and ethinyl estradiol tablets experienced unscheduled
bleeding per cycle in the first year. The percent of women who experienced
unscheduled bleeding tended to decrease over time.
Amenorrhea and Oligomenorrhea
Women who use norgestimate and ethinyl estradiol tablets may experience
amenorrhea. Some women may experience amenorrhea or oligomenorrhea
after discontinuation of COCs, especially when such a condition was preexistent.
If scheduled (withdrawal) bleeding does not occur, consider the possibility of
pregnancy. If the patient has not adhered to the prescribed dosing schedule
(missed one or more active tablets or started taking them on a day later than
she should have), consider the possibility of pregnancy at the time of the first
missed period and take appropriate diagnostic measures. If the patient has
adhered to the prescribed regimen and misses two consecutive periods, rule
out pregnancy.
5.8 COC Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth
defects in women who have used oral contraceptives prior to pregnancy.
Studies also do not suggest a teratogenic effect, particularly in so far as cardiac
anomalies and limb reduction defects are concerned, when oral contraceptives
are taken inadvertently during early pregnancy. Discontinue norgestimate and
ethinyl estradiol tablets use if pregnancy is confirmed.
Administration of COCs to induce withdrawal bleeding should not be used as a
test for pregnancy [see Use in Specific Populations (8.1)].
5.9Depression
Carefully observe women with a history of depression and discontinue
norgestimate and ethinyl estradiol tablets if depression recurs to a serious
degree.
5.10Carcinoma of Breast and Cervix
•
who currently have or have had breast cancer because breast cancer
may be hormonally sensitive [see Contraindications (4)].
There is substantial evidence that COCs do not increase the incidence
of breast cancer. Although some past studies have suggested that COCs
might increase the incidence of breast cancer, more recent studies have
not confirmed such findings.
•
Some studies suggest that COC use has been associated with an increase
in the risk of cervical cancer or intraepithelial neoplasia. However, there
continues to be controversy about the extent to which such findings may
be due to differences in sexual behavior and other factors.
5.11Effect on Binding Globulins
The estrogen component of COCs may raise the serum concentrations of
thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding
globulin. The dose of replacement thyroid hormone or cortisol therapy may
need to be increased.
In women with hereditary angioedema, exogenous estrogens may induce or
exacerbate symptoms of angioedema.
5.14Chloasma
Chloasma may occasionally occur, especially in women with a history of
chloasma gravidarum. Women with a tendency to chloasma should avoid
exposure to the sun or ultraviolet radiation while taking norgestimate and
ethinyl estradiol tablets.
6
ADVERSE REACTIONS
The following serious adverse reactions with the use of COCs are discussed
elsewhere in labeling:
•
Serious cardiovascular events and stroke [see Boxed Warning and
Warnings and Precautions (5.1)]
•
Vascular events [see Warnings and Precautions (5.1)]
•
Liver disease [see Warnings and Precautions (5.2)]
Adverse reactions commonly reported by COC users are:
•
Irregular uterine bleeding
•
Nausea
•
Breast tenderness
•
Headache
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the
rates observed in clinical practice.
The safety of norgestimate and ethinyl estradiol tablets was evaluated in 1,723
subjects who participated in a randomized, partially blinded, multicenter,
active-controlled clinical trial of norgestimate and ethinyl estradiol tablets for contraception. This trial examined healthy, nonpregnant, volunteers
aged 18 to 45 (nonsmoker if 35 to 45 years of age), who were sexually active
with regular coitus. Subjects were followed for up to 13 28-day cycles.
Common Adverse Reactions (greater than or equal to 2% of subjects): The
most common adverse reactions reported by at least 2% of the 1,723 women
using the 28-day regimen were the following in order of decreasing incidence:
headache/migraine (30.5%), nausea/vomiting (16.3%); breast issues
(including tenderness, pain, enlargement, swelling, discharge, discomfort,
cyst, and nipple pain) (10.3%), abdominal pain (9.2%), menstrual disorders
(including dysmenorrhea, menstrual discomfort, menstrual disorder) (9.2%),
mood disorders (including depression, mood altered, mood swings and
depressed mood) (7.6%); acne (5.1%), vulvovaginal infection (3.5%),
abdominal distension (2.8%), weight increased (2.4%) , fatigue (2.1%).
Adverse Reactions Leading to Study Discontinuation: In the
clinical trial of norgestimate and ethinyl estradiol tablets 4% of subjects
discontinued the trial due to an adverse reaction. The most common adverse
reactions leading to discontinuation were headache/migraine (1.2%), nausea/
vomiting (0.7%), cervical dysplasia (0.7%), abdominal pain (0.4%), ovarian
cyst (0.3%), acne (0.2%), flatulence (0.2%) and depression (0.2%).
Serious Adverse Reactions: carcinoma of the cervix in situ (1 subject) and
cervical dysplasia (1 subject).
The following additional adverse drug reactions have been reported from
worldwide postmarketing experience with norgestimate/ethinyl estradiol.
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Infections and Infestations: Urinary tract infection
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps):
Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular
hyperplasia, breast cyst
Immune System Disorders: Hypersensitivity
Metabolism and Nutrition Disorders: Dyslipidemia
Psychiatric Disorders: Anxiety, insomnia
Nervous System Disorders: Syncope, convulsion, paresthesia, dizziness
Eye Disorders: Visual impairment, dry eye, contact lens intolerance
Ear and Labyrinth Disorders: Vertigo
Cardiac Disorders: Tachycardia, palpitations
Vascular Events: Deep vein thrombosis, pulmonary embolism, retinal vascular
thrombosis, hot flush
Page 4 of 10
Arterial Events: Arterial
cerebrovascular accident
thromboembolism,
myocardial
infarction,
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
Gastrointestinal Disorders: Pancreatitis, abdominal distension, diarrhea,
constipation
Hepatobiliary Disorders: Hepatitis
Skin and Subcutaneous Tissue Disorders: Angioedema, erythema nodosum,
hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria,
pruritus, acne
Musculoskeletal, Connective Tissue, and Bone Disorders: Muscle spasms,
pain in extremity, myalgia, back pain
Reproductive System and Breast Disorders: Ovarian cyst, suppressed
lactation, vulvovaginal dryness
General Disorders and Administration Site Conditions: Chest pain, asthenic
conditions.
7
DRUG INTERACTIONS
Consult the labeling of concurrently used drugs to obtain further information
about interactions with hormonal contraceptives or the potential for enzyme
alterations.
No drug-drug interaction studies were conducted with norgestimate and ethinyl
estradiol tablets.
7.1
Effects of Other Drugs on Combined Oral Contraceptives
8
8.1 Pregnancy
There is little or no increased risk of birth defects in women who inadvertently
use COCs during early pregnancy. Epidemiologic studies and meta-analyses
have not found an increased risk of genital or non-genital birth defects
(including cardiac anomalies and limb reduction defects) following exposure to
low dose COCs prior to conception or during early pregnancy.
Do not administer COCs to induce withdrawal bleeding as a test for pregnancy.
Do not use COCs during pregnancy to treat threatened or habitual abortion.
8.3
Nursing Mothers
Advise the nursing mother to use other forms of contraception, when
possible, until she has weaned her child. COCs can reduce milk production in
breastfeeding mothers. This is less likely to occur once breastfeeding is wellestablished; however, it can occur at any time in some women. Small amounts
of oral contraceptive steroids and/or metabolites are present in breast milk.
8.4
Pediatric Use
Safety and efficacy of norgestimate and ethinyl estradiol tablets have been
established in women of reproductive age. Efficacy is expected to be the same
for post-pubertal adolescents under the age of 18 and for users 18 years and
older. Use of this product before menarche is not indicated.
8.5
Geriatric Use
Norgestimate and ethinyl estradiol tablets have not been studied in
postmenopausal women and are not indicated in this population.
Substances Decreasing the Plasma Concentrations of COCs
8.6
Drugs or herbal products that induce certain enzymes, including cytochrome
P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs
and potentially diminish the effectiveness of COCs or increase breakthrough
bleeding. Some drugs or herbal products that may decrease the effectiveness
of COCs include phenytoin, barbiturates, carbamazepine, bosentan, felbamate,
griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide,
aprepitant and products containing St. John’s wort. Interactions between
COCs and other drugs may lead to breakthrough bleeding and/or contraceptive
failure. Counsel women to use an alternative method of contraception or a
back-up method when enzyme inducers are used with COCs, and to continue
back-up contraception for 28 days after discontinuing the enzyme inducer to
ensure contraceptive reliability.
The pharmacokinetics of norgestimate and ethinyl estradiol tablets have not
been studied in subjects with hepatic impairment. However, steroid hormones
may be poorly metabolized in patients with hepatic impairment. Acute or
chronic disturbances of liver function may necessitate the discontinuation of
COC use until markers of liver function return to normal and COC causation
has been excluded. [See Contraindications (4) and Warnings and Precautions
(5.2).]
Colesevelam: Colesevelam, a bile acid sequestrant, given together with a
COC, has been shown to significantly decrease the AUC of ethinyl estradiol
(EE). The drug interaction between the contraceptive and colesevelam was
decreased when the two drug products were given 4 hours apart.
Substances Increasing the Plasma Concentrations of COCs
Co-administration of atorvastatin or rosuvastatin and certain COCs containing
EE increase AUC values for EE by approximately 20% to 25%. Ascorbic acid
and acetaminophen may increase plasma EE concentrations, possibly by
inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole,
fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone
concentrations.
Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease
Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors
Significant changes (increase or decrease) in the plasma concentrations of
estrogen and/or progestin have been noted in some cases of co-administration
with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/
ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir]
or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors
(decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse
transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g.,
etravirine]).
8.7
COCs containing EE may inhibit the metabolism of other compounds (e.g.,
cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole)
and increase their plasma concentrations.
•
COCs have been shown to decrease plasma concentrations of
acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and
lamotrigine. Significant decrease in plasma concentration of lamotrigine
has been shown, likely due to induction of lamotrigine glucuronidation.
This may reduce seizure control; therefore, dosage adjustments of
lamotrigine may be necessary.
Women on thyroid hormone replacement therapy may need increased doses of
thyroid hormone because the serum concentration of thyroid-binding globulin
increases with use of COCs.
7.3 Interference with Laboratory Tests
The use of contraceptive steroids may influence the results of certain
laboratory tests, such as coagulation factors, lipids, glucose tolerance, and
binding proteins.
Renal Impairment
The pharmacokinetics of norgestimate and ethinyl estradiol tablets have not
been studied in women with renal impairment.
10
OVERDOSAGE
There have been no reports of serious ill effects from overdosage of oral
contraceptives, including ingestion by children. Overdosage may cause
withdrawal bleeding in females and nausea.
11
DESCRIPTION
Norgestimate and ethinyl estradiol tablets are combination oral contraceptive
containing the progestational compound norgestimate and the estrogenic
compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17α)-(+)-) and
ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne3,17-diol).
•
Each active white tablet contains 0.18 mg of norgestimate and 0.025
mg of ethinyl estradiol. Inactive ingredients include anhydrous lactose,
croscarmellose sodium, magnesium stearate, microcrystalline cellulose
and pregelatinized starch (corn).
•
Each active light yellow tablet contains 0.215 mg of norgestimate and
0.025 mg of ethinyl estradiol. Inactive ingredients include anhydrous
lactose, croscarmellose sodium, magnesium stearate, microcrystalline
cellulose, pregelatinized starch (corn) and ferric oxide yellow.
•
Each active yellow tablet contains 0.25 mg of norgestimate and 0.025
mg of ethinyl estradiol. Inactive ingredients include anhydrous lactose,
croscarmellose sodium, magnesium stearate, microcrystalline cellulose,
pregelatinized starch (corn) and ferric oxide yellow.
•
Each green placebo tablet contains only inert ingredients, as follows:
anhydrous lactose, croscarmellose sodium, FD&C Blue No. 1 Aluminum
Lake, magnesium stearate, microcrystalline cellulose, pregelatinized
starch (corn) and ferric oxide yellow.
7.2 Effects of Combined Oral Contraceptives on Other Drugs
•
Hepatic Impairment
CH3
OH
OCOCH3
CH2
C
CH3
C
CH
CH
H
H
H
H
H
H
H
HO
HON
12
Norgestimate
Ethinyl Estradiol
COCs lower the risk of becoming pregnant primarily by suppressing ovulation.
Other possible mechanisms may include cervical mucus changes that inhibit
Page 5 of 10
sperm penetration and endometrial changes that reduce the likelihood of
implantation. .
No specific pharmacodynamic studies were conducted with norgestimate
and ethinyl estradiol tablets.
Absorption
Norgestimate (NGM) and EE are rapidly absorbed following oral
administration. NGM is rapidly and completely metabolized by first pass
(intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and
norgestrel (NG), which are the major active metabolites of NGM.
Mean pharmacokinetic parameters for NGMN, NG and EE during three
cycles of administration of norgestimate and ethinyl estradiol tablets are
summarized in Table 3.
Peak serum concentrations of NGMN and EE were generally reached
by 2 hours after administration of norgestimate and ethinyl estradiol tablets.
Accumulation following multiple dosing of the 0.18 mg NGM/0.025 mg EE
dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold
for EE compared with single dose administration, in agreement with that
predicted based on linear kinetics of NGMN and EE. The pharmacokinetics
of NGMN is dose proportional following NGM doses of 0.18 mg to 0.25 mg.
Steady-state conditions for NGMN following each NGM dose and for EE
were achieved during the three cycle study. Non-linear accumulation (4.5 to
14.5 fold) of NG was observed as a result of high affinity binding to SHBG,
which limits its biological activity.
Table 3 Summary of NGMN, NG and EE pharmacokinetic parameters.
Mean (SD) Pharmacokinetic Parameters of Norgestimate and
Ethinyl Estradiol Tablets During a Three Cycle Study
Analyte1
NGMN
(2-4)
(2-4)
NG
(2,3,5)
EE
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
1
1
0.91
(0.27)
1.8 (1)
5.86
(1.54)
NC
3
7
1.42
(0.43)
1.8
(0.7)
11.3
(3.2)
NC
14
1.57
(0.39)
1.8
(0.7)
13.9
(3.7)
NC
21
1.82
(0.54)
1.5
(0.7)
16.1
(4.8)
28.1
(10.6)
1
1
0.32
(0.14)
2.0
(1.1)
2.44
(2.04)
NC
3
7
1.64
(0.89)
1.9
(0.9)
27.9
(18.1)
NC
14
2.11
(1.13)
4.0
(6.3)
40.7
(24.8)
NC
21
2.79
(1.42)
1.7
(1.2)
49.9
(27.6)
36.4
(10.2)
1
55.6
(18.1)
1.7
(0.5)
421
(118)
NC
7
91.1
(36.7)
1.3
(0.3)
782
(329)
NC
14
96.9
(38.5)
1.3
(0.3)
796
(273)
NC
21
95.9
(38.9)
1.3
(0.6)
771
(303)
17.7
(4.4)
1
3
1
NGMN = Norelgestromin, NG = norgestrel, EE = ethinyl estradiol
Cmax = peak serum concentration, tmax = time to reach peak serum
concentration, AUC0-24h = area under serum concentration vs. time curve
from 0 to 24 hours, t1/2 = elimination half-life.
Distribution
NGMN and NG are highly bound (greater than 97%) to serum proteins. NGMN is
bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is
extensively bound (greater than 97%) to serum albumin and induces an increase
in the serum concentrations of SHBG.
Metabolism
NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal
tract and/or liver. NGM’s primary active metabolite is NGMN. Subsequent hepatic
metabolism of NGMN occurs and metabolites include NG, which is also active
and various hydroxylated and conjugated metabolites. Although NGMN and its
metabolites inhibit a variety of P450 enzymes in human liver microsomes, under
the recommended dosing regimen, the in vivo concentrations of NGMN and its
metabolites, even at the peak serum levels, are relatively low compared to the
inhibitory constant (Ki). EE is also metabolized to various hydroxylated products
and their glucuronide and sulfate conjugates.
Excretion
Following 3 cycles of administration of norgestimate and ethinyl estradiol tablets,
the mean (± SD) elimination half-life values, at steady-state, for NGMN, NG
and EE were 28.1 (± 10.6) hours, 36.4 (± 10.2) hours and 17.7 (± 4.4) hours,
respectively (Table 2). The metabolites of NGMN and EE are eliminated by
renal and fecal pathways.
Use in Specific Populations
Effects of Body Weight, Body Surface Area, and Age
The effects of body weight, body surface area, age and race on the
pharmacokinetics of NGMN, NG and EE were evaluated in 79 healthy women
using pooled data following single dose administration of NGM 0.18 mg or 0.25
mg/ EE 0.025 mg tablets in four pharmacokinetic studies. Increasing body
weight and body surface area were each associated with decreases in Cmax
and AUC0-24h values for NGMN and EE and increases in CL/F (oral clearance)
for EE. Increasing body weight by 10 kg is predicted to reduce the following
parameters: NGMN Cmax by 9% and AUC0-24h by 19%, NG Cmax by 12%
and AUC0-24h by 46%, EE Cmax by 13% and AUC0-24h by 12%. These
changes were statistically significant. Increasing age was associated with slight
decreases (6% with increasing age by 5 years) in Cmax and AUC0-24h for
NGMN and were statistically significant, but there was no significant effect for
NG or EE. Only a small to moderate fraction (5% to 40%) of the overall variability
in the pharmacokinetics of NGMN and EE following norgestimate and ethinyl
estradiol tablets may be explained by any or all of the above demographic
parameters.
13
[See Warnings and Precautions (5.2, 5.10) and Use in Specific Populations (8.1).]
14
units for all analytes; h = hours
4
units for NGMN and NG – Cmax = ng/mL, AUC0-24h = h•ng/mL
5
units for EE only – Cmax = pg/mL, AUC0-24h = h•pg/mL
NC = not calculated
Food Effect
The effect of food on the pharmacokinetics of norgestimate and ethinyl
estradiol tablets has not been studied.
CLINICAL STUDIES
In an active controlled clinical trial lasting 12 months, 1,673 women, 18
to 45 years old completed 11,003 cycles of norgestimate and ethinyl estradiol
tablets use and a total of 20 pregnancies were reported in norgestimate and ethinyl
estradiol tablets users. The racial demographic of those treated with norgestimate
and ethinyl estradiol tablets was: Caucasian (86%), African-American (6%), Asian
(2%), and Other (6%). There were no exclusions on the basis of weight; the
weight range for women treated was 90 lbs to 240 lbs, with a mean weight of about
142 lbs. The pregnancy rate in women aged 18 to 35 years was approximately 2.6
pregnancies per 100 woman-years of use.
16
16.1 How Supplied
Norgestimate and ethinyl estradiol tablets USP, 0.18 mg/0.025 mg, 0.215
mg/0.025 mg and 0.25 mg/0.025 mg are available in carton of 3 pouches (NDC
0378-7277-53); each pouch contains a blister pack of 28 tablets.
Each blister pack contains 28 tablets in the following order:
•
7 white, round, flat-faced, beveled edge tablets debossed with “234” on
•
7 light yellow, round, flat-faced, beveled edge tablets debossed with “235” on
•
7 yellow, round, flat-faced, beveled edge tablets debossed with “236” on
•
7 green, round, flat-faced, beveled edge tablets (non-hormonal placebo)
debossed with “295” on one side of the tablet and plain on the other side,
each containing inert ingredients
2
3
Keep this and all medications out of the reach of children.
16.2 Storage Conditions
•
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room
Temperature.]
•
Protect from light.
Page 6 of 10
See FDA-approved patient labeling (Patient Information and Instruction for
Use).
Counsel patients about the following information:
•
Cigarette smoking increases the risk of serious cardiovascular events
from COC use, and that women who are over 35 years old and smoke
should not use COCs [see Boxed Warning].
•
Increased risk of VTE compared to non-users of COCs is greatest after
initially starting a COC or restarting (following a 4-week or greater pill-free
interval) the same or a different COC [see Warnings and Precautions
(5.1)].
•
Norgestimate and ethinyl estradiol tablets do not protect against HIV
infection (AIDS) and other sexually transmitted infections.
•
Norgestimate and ethinyl estradiol tablets are not to be used during
pregnancy; if pregnancy occurs during use of norgestimate and ethinyl
estradiol tablets instruct the patient to stop further use [see Warnings and
Precautions (5.8)].
•
Take one tablet daily by mouth at the same time every day. Instruct
patients what to do in the event tablets are missed [see Dosage and
Administration (2.2)].
•
Use a back-up or alternative method of contraception when enzyme
inducers are used with norgestimate and ethinyl estradiol tablets [see
•
COCs may reduce breast milk production; this is less likely to occur if
breastfeeding is well established [see Use in Specific Populations (8.3)].
•
Women who start COCs postpartum, and who have not yet had a period,
should use an additional method of contraception until they have taken a
white tablet for 7 consecutive days [see Dosage and Administration (2.2)].
•
Amenorrhea may occur. Consider pregnancy in the event of amenorrhea
at the time of the first missed period. Rule out pregnancy in the event
of amenorrhea in two or more consecutive cycles [see Warnings and
Precautions (5.7)].
Who should not take norgestimate and ethinyl estradiol tablets?
Do not take norgestimate and ethinyl estradiol tablets if you:
•
smoke and are over 35 years of age
Patient Information
•
had blood clots in your arms, legs, lungs, or eyes
Norgestimate and Ethinyl Estradiol Tablets USP, 0.18 mg/0.025 mg, 0.215
mg/0.025 mg and 0.25 mg/0.025 mg
•
had a problem with your blood that makes it clot more than normal
•
have certain heart valve problems or irregular heart beat that increases
your risk of having blood clots
What is the most important information I should know about norgestimate
and ethinyl estradiol tablets?
Do not use norgestimate and ethinyl estradiol tablets if you smoke
cigarettes and are over 35 years old. Smoking increases your risk of serious
cardiovascular side effects from hormonal birth control pills, including death
from heart attack, blood clots or stroke. This risk increases with age and the
number of cigarettes you smoke.
What are norgestimate and ethinyl estradiol tablets?
Norgestimate and ethinyl estradiol tablets are birth control pills (oral
contraceptive) used by women to prevent pregnancy.
How do norgestimate and ethinyl estradiol tablets work for contraception?
Your chance of getting pregnant depends on how well you follow the directions
for taking your birth control pills. The better you follow the directions, the less
chance you have of getting pregnant.
Based on the results from the clinical study, about 3 out of 100 women may
get pregnant during the first year they use norgestimate and ethinyl estradiol
tablets.
The following chart shows the chance of getting pregnant for women who use
different methods of birth control. Each box on the chart contains a list of birth
control methods that are similar in effectiveness. The most effective methods
are at the top of the chart. The box on the bottom of the chart shows the chance
of getting pregnant for women who do not use birth control and are trying to
get pregnant.
•
had a stroke
•
had a heart attack
•
have high blood pressure that cannot be controlled by medicine
•
have diabetes with kidney, eye, nerve, or blood vessel damage
•
have certain kinds of severe migraine headaches with aura, numbness,
weakness or changes in vision, or any migraine headaches if you are
over 35 years of age
•
have liver problems, including liver tumors
•
have any unexplained vaginal bleeding
•
are pregnant
•
had breast cancer or any cancer that is sensitive to female hormones
If any of these conditions happen while you are taking norgestimate and
ethinyl estradiol tablets, stop taking norgestimate and ethinyl estradiol
tablets right away and talk to your healthcare provider. Use non-hormonal
contraception when you stop taking norgestimate and ethinyl estradiol
tablets.
What should I tell my healthcare provider before taking norgestimate and
ethinyl estradiol tablets?
Tell your healthcare provider if you:
•
are pregnant or think you may be pregnant
•
are depressed now or have been depressed in the past
•
had yellowing of your skin or eyes (jaundice) caused by pregnancy
(cholestasis of pregnancy)
•
are breastfeeding or plan to breastfeed. Norgestimate and ethinyl
estradiol tablets may decrease the amount of breast milk you make.
A small amount of the hormones in norgestimate and ethinyl estradiol
tablets may pass into your breast milk. Talk to your healthcare provider
about the best birth control method for you while breastfeeding.
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins and herbal supplements.
Norgestimate and ethinyl estradiol tablets may affect the way other medicines
work, and other medicines may affect how well norgestimate and ethinyl
estradiol tablets work.
Know the medicines you take. Keep a list of them to show your healthcare
provider and pharmacist when you get a new medicine.
Page 7 of 10
How should I take norgestimate and ethinyl estradiol tablets?
Read the Instructions for Use at the end of this Patient Information.
What are the possible serious side effects of norgestimate and ethinyl
estradiol tablets?
•
Like pregnancy, norgestimate and ethinyl estradiol tablets may
cause serious side effects, including blood clots in your lungs, heart
attack, or a stroke that may lead to death. Some other examples of
serious blood clots include blood clots in the legs or eyes.
Serious blood clots can happen especially if you smoke, are obese, or are
older than 35 years of age. Serious blood clots are more likely to happen when
you:
•
first start taking birth control pills
•
restart the same or different birth control pills after not using them for a
month or more
Call your healthcare provider or go to a hospital emergency room right
away if you have:
o
leg pain that will not go away
o
sudden change in vision or blindness
o
a sudden, severe headache unlike your usual headaches
o
trouble speaking
o
sudden severe shortness of breath
o
chest pain
o
weakness or numbness in your arm or leg
•
liver problems, including:
o
o
rare liver tumors
jaundice (cholestasis), especially if you previously had cholestasis
of pregnancy. Call your healthcare provider if you have yellowing of
your skin or eyes.
•
high blood pressure. You should see your healthcare provider for a
yearly check of your blood pressure.
•
gallbladder problems
•
changes in the sugar and fat (cholesterol and triglycerides) levels
in your blood
•
new or worsening headaches including migraine headaches
•
irregular or unusual vaginal bleeding and spotting between your
menstrual periods, especially during the first 3 months of taking
norgestimate and ethinyl estradiol tablets.
•
depression
•
possible cancer in your breast and cervix
•
swelling of your skin especially around your mouth, eyes, and in
your throat (angioedema). Call your healthcare provider if you have a
swollen face, lips, mouth tongue or throat, which may lead to difficulty
swallowing or breathing. Your chance of having angioedema is higher is
you have a history of angioedema.
•
dark patches of skin around your forehead, nose, cheeks and around
your mouth, especially during pregnancy (chloasma). Women who
tend to get chloasma should avoid spending a long time in sunlight,
tanning booths, and under sun lamps while taking norgestimate and
ethinyl estradiol tablets. Use sunscreen if you have to be in the sunlight.
What are the most common side effects of norgestimate and ethinyl
estradiol tablets?
•
headache (including migraine)
•
nausea and vomiting
•
breast problems
•
o
tenderness, pain and discomfort
o
discharge
o
enlargement and swelling
o
nipple pain
stomach pain
•
pain with your periods (menstrual cycle)
•
mood changes, including depression
•
acne
•
vaginal infections
•
bloating
•
weight gain
•
fatigue
These are not all the possible side effects of norgestimate and ethinyl estradiol
tablets. For more information, ask your healthcare provider or pharmacist.
You may report side effects to the FDA at 1-800-FDA-1088.
What else should I know about taking norgestimate and ethinyl estradiol
tablets?
•
If you are scheduled for any lab tests, tell your healthcare provider you
are taking norgestimate and ethinyl estradiol tablets. Certain blood tests
may be affected by norgestimate and ethinyl estradiol tablets.
•
Norgestimate and ethinyl estradiol tablets do not protect against HIV
infection (AIDS) and other sexually transmitted infections.
How should I store norgestimate and ethinyl estradiol tablets?
•
Store at 20o to 25oC (68o to 77oF). [See USP Controlled Room
Temperature.]
•
Keep norgestimate and ethinyl estradiol tablets and all medications out of
the reach of children.
•
Protect from light.
General information about the safe and effective use of norgestimate and
ethinyl estradiol tablets.
a Patient Information leaflet. Do not use norgestimate and ethinyl estradiol
tablets for a condition for which it was not prescribed. Do not give norgestimate
and ethinyl estradiol tablets to other people, even if they have the same
symptoms that you have.
This Patient Information summarizes the most important information about
norgestimate and ethinyl estradiol tablets. You can ask your pharmacist or
healthcare provider for information about norgestimate and ethinyl estradiol
tablets that is written for health professionals.
(1-877-4-INFO-RX).
Do birth control pills cause cancer?
Birth control pills do not seem to cause breast cancer. However, if you have
breast cancer now, or have had it in the past, do not use birth control pills
because some breast cancers are sensitive to hormones.
Women who use birth control pills may have a slightly higher chance of getting
cervical cancer. However, this may be due to other reasons such as having
more sexual partners.
What if I want to become pregnant?
You may stop taking the pill whenever you wish. Consider a visit with your
healthcare provider for a pre-pregnancy checkup before you stop taking the
pill.
What should I know about my period when taking norgestimate and
ethinyl estradiol tablets?
Your periods may be lighter and shorter than usual. Some women may miss
a period. Irregular vaginal bleeding or spotting may happen while you are
taking norgestimate and ethinyl estradiol tablets, especially during the first few
months of use. This usually is not a serious problem. It is important to continue
taking your pills on a regular schedule to prevent a pregnancy.
What are the ingredients in norgestimate and ethinyl estradiol tablets?
Active ingredients: Each white, light yellow and yellow pill contains
norgestimate and ethinyl estradiol.
Inactive ingredients:
White pills: anhydrous lactose, croscarmellose sodium, magnesium stearate,
microcrystalline cellulose and pregelatinized starch (corn).
Light yellow pills: anhydrous lactose, croscarmellose sodium, magnesium
stearate, microcrystalline cellulose, pregelatinized starch (corn) and ferric
oxide yellow.
Yellow pills: anhydrous lactose, croscarmellose sodium, magnesium stearate,
microcrystalline cellulose, pregelatinized starch (corn) and ferric oxide yellow.
Green pills: anhydrous lactose, croscarmellose sodium, FD&C Blue No. 1
Aluminum Lake, magnesium stearate, microcrystalline cellulose, pregelatinized
starch (corn) and ferric oxide yellow.
Instructions For Use
Norgestimate and Ethinyl Estradiol Tablets USP, 0.18 mg/0.025 mg, 0.215
mg/0.025 mg and 0.25 mg/0.025 mg
Important Information about taking Norgestimate and Ethinyl Estradiol
Tablets
•
Take 1 pill every day at the same time. Take the pills in the order directed
on your pill pack.
•
Do not skip your pills, even if you do not have sex often. If you miss pills
(including starting the pack late) you could get pregnant. The more pills
you miss, the more likely you are to get pregnant.
Page 8 of 10
•
If you have trouble remembering to take norgestimate and ethinyl
estradiol tablets, talk to your healthcare provider. When you first start
taking norgestimate and ethinyl estradiol tablets, spotting or light bleeding
in between your periods may occur. Contact your healthcare provider if
this does not go away after a few months.
•
You may feel sick to your stomach (nauseous), especially during the first
few months of taking norgestimate and ethinyl estradiol tablets. If you feel
sick to your stomach, do not stop taking the pill. The problem will usually
go away. If your nausea does not go away, call your healthcare provider.
•
Missing pills can also cause spotting or light bleeding, even when you
take the missed pills later. On the days you take 2 pills to make up for
missed pills (see What should I do if I miss any norgestimate and
ethinyl estradiol tablets? below), you could also feel a little sick to your
stomach.
•
It is not uncommon to miss a period. However, if you miss a period and
have not taken norgestimate and ethinyl estradiol tablets according to
directions, or miss 2 periods in a row, or feel like you may be pregnant,
call your healthcare provider. If you have a positive pregnancy test, you
should stop taking norgestimate and ethinyl estradiol tablets.
•
If you have vomiting or diarrhea within 3 to 4 hours of taking your pill, take
another pill of the same color from your extra blister pack. If you do not
have an extra blister pack, take the next pill in your blister pack. Continue
taking all your remaining pills in order. Start the first pill of your next blister
pack the day after finishing your current blister pack. This will be 1 day
earlier than originally scheduled. Continue on your new schedule.
•
If you have vomiting or diarrhea for more than 1 day, your birth control
pills may not work as well. Use an additional birth control method, like
condoms and a spermicide, until you check with your healthcare provider.
•
Stop taking norgestimate and ethinyl estradiol tablets at least 4 weeks
before you have major surgery and do not restart after the surgery
without asking your healthcare provider. Be sure to use other forms of
contraception (like condoms and spermicide) during this time period.
Before you start taking norgestimate and ethinyl estradiol tablets:
•
Decide what time of day you want to take your pill. It is important to take
it at the same time every day and in the order as directed on your blister
pack.
Keep a calendar to track your period:
If this is the first time you are taking birth control pills, read, “When should
I start taking norgestimate and ethinyl estradiol tablets?” above. Follow
these instructions for either a Sunday Start or a Day 1 Start.
Sunday Start:
You will use a Sunday Start if your healthcare provider told you to take your
first pill on a Sunday.
•
Take pill 1 on the Sunday after your period starts.
•
If your period starts on a Sunday, take pill “1” that day and refer to Day 1
Start instructions below.
•
Take 1 pill every day in the order on the blister pack at the same time each
day for 28 days.
•
After taking the last pill on Day 28 from the blister pack, start taking the
first pill from a new pack, on the same day of the week as the first pack
(Sunday). Take the first pill in the new pack whether or not you are having
your period.
•
Use non-hormonal back-up contraception such as condoms and
spermicide for the first 7 days of the first cycle that you take norgestimate
and ethinyl estradiol tablets.
Day 1 Start:
You will use a Day 1 Start if your doctor told you to take your first pill (Day 1)
on the first day of your period.
•
Take 1 pill every day in the order of the blister pack, at the same time each
day, for 28 days.
•
After taking the last pill on Day 28 from the blister pack, start taking the
first pill from a new pack, on the same day of the week as the first pack.
Take the first pill in the new pack whether or not you are having your
period.
Norgestimate and ethinyl estradiol tablets are available in carton of three
pouches; each pouch contains a blister pack of 28 tablets.
Instructions for using your blister pack:
Each blister pack has 28 pills.
•
7 white pills with hormone, for Days 1 to 7
•
7 light-yellow pills with hormone, for Days 8 to 14
When should I start taking norgestimate and ethinyl estradiol tablets?
•
7 yellow pills with hormones, for Days 15 to 21
If you start taking norgestimate and ethinyl estradiol tablets and you
have not used a hormonal birth control method before:
•
7 green pills (without hormones), for Days 22 to 28.
•
Have backup contraception (condoms and spermicide) available and if
possible, an extra full pack of pills as needed.
•
There are 2 ways to start taking your birth control pills. You can either
start on a Sunday (Sunday Start) or on the first day (Day 1) of your natural
menstrual period (Day 1 Start). Your healthcare provider should tell you
when to start taking your birth control pill.
•
If you use the Sunday Start, use non-hormonal back-up contraception
such as condoms and spermicide for the first 7 days that you take
norgestimate and ethinyl estradiol tablets. You do not need back-up
contraception if you use the Day 1 Start.
Step 1. SET THE DAY:
Sunday Start: The blister is printed with days starting with SUN (Sunday) after
start arrow.
If you start taking norgestimate and ethinyl estradiol tablets and you are
switching from another birth control pill:
•
Start your new norgestimate and ethinyl estradiol tablets pack on the
same day that you would start the next pack of your previous birth control
method.
•
Do not continue taking the pills from your previous birth control pack.
If you start taking norgestimate and ethinyl estradiol tablets and
previously used a vaginal ring or transdermal patch:
•
Start using norgestimate and ethinyl estradiol tablets on the day you
would have reapplied the next ring or patch.
switching from a progestin-only method such as an implant or injection:
•
Start taking norgestimate and ethinyl estradiol tablets on the day of
removal of your implant or on the day when you would have had your
next injection.
Day 1 Start: Paste day start sticker label on the printed days (if your period
starts on Tuesday, paste the sticker label “TUE” on the printed day above pill 1
after start arrow and so on).
switching from an intrauterine device or system (IUD or IUS):
•
Start taking norgestimate and ethinyl estradiol tablets on the day of
removal of your IUD or IUS.
•
You do not need back-up contraception if your IUD or IUS is removed on
the first day (Day 1) of your period. If your IUD or IUS is removed on any
other day, use non-hormonal back-up contraception such as condoms
and spermicide for the first 7 days that you take norgestimate and ethinyl
estradiol tablets.
Page 9 of 10
Step 2. New blister pack: You are ready to take pill “1”. You should always
begin your pill cycle with pill “1”, after start arrow, as shown on the blister pack.
Step 3. Remove pill “1” by pushing through the blister. The pill will come out
through the blister pack.
Step 4. Swallow the pill. You will take 1 pill every day, at the same time each
day.
Step 5. Wait 24 hours to take your next pill. Continue to take 1 pill each day
until all the pills have been taken.
Step 6. Take your pill at the same time every day. It is important to take the
correct pill each day and not miss any pills.
To help you remember, take your pill at the same time as another daily activity,
like turning off your alarm clock or brushing your teeth.
Step 7. When your blister pack is empty. You will start a new blister pack on
the day after your blister pack is empty.
Step 8. The first pill in every blister pack will always be taken on the same day
of the week, no matter when your next period starts.
What should I do if I miss any norgestimate and ethinyl estradiol pills?
If you miss 1 pill in Weeks 1, 2, or 3, follow these steps:
•
Take it as soon as you remember. Take the next pill at your regular time.
This means you may take 2 pills in 1 day.
•
Then continue taking 1 pill every day until you finish the pack.
•
You do not need to use a back-up birth control method if you have sex.
If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps:
•
Take the 2 missed pills as soon as possible and the next 2 pills the next
day.
•
Then continue to take 1 pill every day until you finish the pack.
•
Use a non-hormonal birth control method (such as a condom and
spermicide) as a back-up if you have sex during the first 7 days after
missing your pills.
If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a row
during Weeks 1, 2, or 3 of the pack, follow these steps:
•
•
If you are a Day 1 Starter:
o
Throw out the rest of the pill pack and start a new pack that same
day.
o
You may not have your period this month but this is expected.
However, if you miss your period 2 months in a row, call your
healthcare provider because you might be pregnant.
o
You could become pregnant if you have sex during the first 7 days
after you restart your pills. You MUST use a non-hormonal birth
control method (such as a condom and spermicide) as a back-up
if you have sex during the first 7 days after you restart your pills.
If you are a Sunday Starter:
o
Keep taking 1 pill every day until Sunday. On Sunday, throw out the
rest of the pack and start a new pack of pills that same day.
o
Use a non-hormonal birth control method (such as a condom and
spermicide) as a back-up if you have sex during the first 7 days after
you restart your pills.
If you have any questions or are unsure about the information in this
leaflet, call your healthcare provider.
This Patient Information and Instructions for Use has been approved by the
U.S. Food and Drug Administration.
Manufactured for:
Jai Pharma Ltd.
Ahmedabad - 382 213, Gujarat, India
200004870-011 REVISED: SEPTEMBER 2015
FC:OT:7277:R3
Page 10 of 10
These highlights do not include all the information needed to use paliperidone extended-release tablets
safely and effectively. See full prescribing information for paliperidone extended-release tablets.
PALIPERIDONE extended-release tablets, for oral use
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Paliperidone extended-release tablets are not approved for use in patients
with dementia-related psychosis. (5.1)
--------------------------------------- INDICATIONS AND USAGE --------------------------------------Paliperidone extended-release tablets are an atypical antipsychotic agent indicated for
Treatment of schizophrenia (1.1)
• Adults: Efficacy was established in three 6-week trials and one maintenance trial. (14.1)
• Adolescents (ages 12 to 17): Efficacy was established in one 6-week trial. (14.1)
Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or
antidepressants. (1.2)
• Efficacy was established in two 6-week trials in adult patients (14.2)
------------------------------------ DOSAGE AND ADMINISTRATION -----------------------------------Initial Dose
Recommended Dose Maximum Dose
Schizophrenia – adults (2.1)
6 mg/day
3 to 12 mg/day
12 mg/day
Schizophrenia
Weight < 51 kg
3 mg/day
3 to 6 mg/day
6 mg/day
– adolescents (2.1) Weight ≥ 51 kg
3 mg/day
3 to 12 mg/day
12 mg/day
Schizoaffective disorder – adults (2.2)
6 mg/day
3 to 12 mg/day
12 mg/day
• Tablet should be swallowed whole and should not be chewed, divided, or crushed. (2.3)
------------------------------------ DOSAGE FORMS AND STRENGTHS ---------------------------------Tablets: 1.5 mg, 3 mg, 6 mg and 9 mg (3)
----------------------------------------- CONTRAINDICATIONS ----------------------------------------Known hypersensitivity to paliperidone, risperidone, or to any components in the formulation. (4)
------------------------------------ WARNINGS AND PRECAUTIONS -----------------------------------• Cerobrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions
(e.g., stroke, transient ischemic attack, including fatalities) has been seen in elderly patients with
dementia-related psychoses treated with atypical antipsychotics. (5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3)
• QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and
in patients with risk factors for prolonged QT interval. (5.4)
• Tardive Dyskinesia: Discontinue drug if clinically appropriate. (5.5)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes
that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.6)
 Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with
diabetes or at risk for diabetes. (5.6)
 Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical
WARNINGS – INCREASED MORTALITY IN ELDERLY PATIENTS WITH
DEMENTIA-RELATED PSYCHOSIS
1.1 Schizophrenia
1.2 Schizoaffective Disorder
2.1 Schizophrenia
2.3 Administration Instructions
2.4 Use with Risperidone
2.5 Dosage in Special Populations
4 CONTRAINDICATIONS
5.1 Increased Mortality in Elderly Patients with DementiaRelated Psychosis
5.2 Cerebrovascular Adverse Reactions, Including Stroke,
in Elderly Patients with Dementia-Related Psychosis
5.4 QT Prolongation
5.7 Hyperprolactinemia
5.8 Potential for Gastrointestinal Obstruction
5.9 Orthostatic Hypotension and Syncope
5.10 Leukopenia, Neutropenia, and Agranulocytosis
5.11 Potential for Cognitive and Motor Impairment
5.12 Seizures
5.13 Dysphagia
5.14 Suicide
5.15 Priapism
6
7
8
antipsychotics. (5.6)
Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.6)
• Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.7)
• Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal
disease. (5.8)
• Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or
cerebrovascular disease and patients predisposed to hypotension. (5.9)
• Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including
paliperidone extended-release tablets. Patients with a history of a clinically significant low white
blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood
count (CBC) monitored frequently during the first few months of therapy and discontinuation of
paliperidone extended-release tablets should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.10)
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.11)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the
seizure threshold. (5.12)
• Suicide: Closely supervise high-risk patients. (5.14)
----------------------------------------- ADVERSE REACTIONS ----------------------------------------Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were (6)
• Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia.
• Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia.
• Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679
(1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
----------------------------------------- DRUG INTERACTIONS ----------------------------------------• Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. (7.1)
• Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with paliperidone extended-release tablets. (7.1)
• Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of
paliperidone extended-release tablets when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine) is co-administered. Conversely, on discontinuation of the strong inducer, it may be
necessary to decrease the dose of paliperidone extended-release tablets. (7.2)
• Co-administration of divalproex sodium increased Cmax and AUC of paliperidone extendedrelease tablets by approximately 50%. Adjust dose of paliperidone if necessary based on clinical assessment. (7.2)
------------------------------------- USE IN SPECIFIC POPULATIONS ---------------------------------• Renal Impairment: Dosing must be individualized according to renal function status. (2.5)
• Elderly: Same as for younger adults (adjust dose according to renal function status). (2.4)
• Nursing Mothers: The benefits of breastfeeding should be weighed against the unknown risks of
infant exposure to paliperidone. (8.3)
• Pediatric Use: Safety and effectiveness in the treatment of schizophrenia not established in
patients less than 12 years of age. Safety and effectiveness in the treatment of schizoaffective disorder not established in patients less than 18 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION.
REVISED FEBRUARY 2015
PALIER:R2

5.16 Thrombotic Thrombocytopenic Purpura (TTP)
5.17 Body Temperature Regulation
5.18 Antiemetic Effect
5.19 Use in Patients with Concomitant Illness
5.20 Monitoring: Laboratory Tests
ADVERSE REACTIONS
6.1 Overall Adverse Reaction Profile
6.2 Commonly-Observed Adverse Reactions in DoubleBlind, Placebo-Controlled Clinical Trials – Schizophrenia in Adults and Adolescents
6.3 Commonly-Observed Adverse Reactions in DoubleBlind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder in Adults
6.4 Discontinuations Due to Adverse Reactions
6.5 Dose-Related Adverse Reactions
6.6 Demographic Differences
6.7 Extrapyramidal Symptoms (EPS)
6.8 Laboratory Test Abnormalities
6.9 Other Adverse Reactions Observed During Premarketing
Evaluation of Paliperidone Extended-Release Tablets
6.11 Adverse Reactions Reported with Risperidone
DRUG INTERACTIONS
7.1 Potential for Paliperidone Extended-Release Tablets to
Affect Other Drugs
7.2 Potential for Other Drugs to Affect Paliperidone
Extended-Release Tablets
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
9
10
11
12
13
14
16
17
9.2 Abuse
9.3 Dependence
OVERDOSAGE
10.1 Human Experience
DESCRIPTION
11.1 Delivery System Components and Performance
CLINICAL STUDIES
14.1 Schizophrenia
17.1 Orthostatic Hypotension
17.3 Pregnancy
17.4 Nursing
17.5 Concomitant Medication
17.6 Alcohol
17.7 Heat Exposure and Dehydration
17.8 Administration
*Sections or subsections omitted from the full prescribing information are
not listed.
Page 1 of 10
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks),
largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated
patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course
of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%,
compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death)
or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical
antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The
extent to which the findings of increased mortality in observational studies may be attributed to
the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Paliperidone extended-release tablets are not approved for the treatment of patients with dementiarelated psychosis. [See Warnings and Precautions (5.1).]
1
1.1 Schizophrenia
Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical
Studies (14.1)].
The efficacy of paliperidone extended-release tablets in schizophrenia was established in three 6-week
trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults.
Paliperidone extended-release tablets are indicated for the treatment of schizoaffective disorder as
monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)].
The efficacy of paliperidone extended-release tablets in schizoaffective disorder was established in two
6-week trials in adults.
2
2.1 Schizophrenia
Adults: The recommended dose of paliperidone extended-release tablets for the treatment of schizophrenia in adults is 6 mg administered once daily. Initial dose titration is not required. Although it has
not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase
in adverse reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some
patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made
only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose
increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose
is 12 mg/day.
In a longer-term study, paliperidone extended-release tablets have been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone extended-release
tablets for 6 weeks [see Clinical Studies (14)]. Paliperidone extended-release tablets should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically re-evaluate the long-term usefulness of the drug in individual patients.
Adolescents (12 to 17 years of age): The recommended starting dose of paliperidone extended-release
tablets for the treatment of schizophrenia in adolescents 12 to 17 years of age is 3 mg administered
once daily. Initial dose titration is not required. Dose increases, if considered necessary, should be made
only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than
5 days. Prescribers should be mindful that, in the adolescent schizophrenia study, there was no clear
enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg
for subjects weighing 51 kg or greater, while adverse events were dose-related.
The recommended dose of paliperidone extended-release tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. Initial dose titration is not required. Some patients may
benefit from lower or higher doses within the recommended dose range of 3 mg to 12 mg once daily. A
general trend for greater effects was seen with higher doses. This trend must be weighed against doserelated increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical
reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days.
When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.
2.3 Administration Instructions
Paliperidone extended-release tablets can be taken with or without food.
Paliperidone extended-release tablets must be swallowed whole with the aid of liquids. Tablets should
not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed
to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
2.4 Use with Risperidone
Concomitant use of paliperidone extended-release tablets with risperidone has not been studied. Since
paliperidone is the major active metabolite of risperidone, consideration should be given to the additive
paliperidone exposure if risperidone is co-administered with paliperidone extended-release tablets.
2.5 Dosage in Special Populations
Renal Impairment: Dosing must be individualized according to the patient’s renal function status. For
patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min), the recommended initial dose of paliperidone extended-release tablets is 3 mg once daily. The dose may then be
increased to a maximum of 6 mg once daily based on clinical response and tolerability. For patients with
moderate to severe renal impairment (creatinine clearance ≥ 10 mL/min to < 50 mL/min), the recommended initial dose of paliperidone extended-release tablets is 1.5 mg once daily, which may be
increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone extendedrelease tablets have not been studied in patients with creatinine clearance below 10 mL/min, use is not
recommended in such patients. [See Clinical Pharmacology (12.3).]
Hepatic Impairment: For patients with mild to moderate hepatic impairment, (Child-Pugh Classification
A and B), no dose adjustment is recommended [see Clinical Pharmacology (12.3)]. Paliperidone extended-release tablets have not been studied in patients with severe hepatic impairment.
Elderly: Because elderly patients may have diminished renal function, dose adjustments may be
required according to their renal function status. In general, recommended dosing for elderly patients
with normal renal function is the same as for younger adult patients with normal renal function. For
patients with moderate to severe renal impairment (creatinine clearance 10 mL/min to < 50 mL/min),
the maximum recommended dose of paliperidone extended-release tablets is 3 mg once daily [see Renal
Impairment above].
3
Paliperidone extended-release tablets are available in the following strengths and colors: 1.5 mg
(brown), 3 mg (white), 6 mg (light beige), and 9 mg (pink). All tablets are round and are imprinted with
M over PD1, M over PD3, M over PD6, or M over PD9, respectively.
4
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in
patients treated with risperidone and paliperidone. Paliperidone is a metabolite of risperidone and is
therefore contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone,
or to any of the excipients in paliperidone extended-release tablets.
5
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
increased risk of death. Paliperidone extended-release tablets are not approved for the treatment
of dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with DementiaRelated Psychosis
In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with
dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents
and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone
extended-release tablets were not marketed at the time these studies were performed. Paliperidone
extended-release tablets are not approved for the treatment of patients with dementia-related psychosis
[see also Boxed Warning and Warnings and Precautions (5.1)].
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has
been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of
NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may
include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is
important to identify cases in which the clinical presentation includes both serious medical illness (e.g.,
pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and
symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other
drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring;
and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of
drug therapy should be closely monitored, since recurrences of NMS have been reported.
5.4 QT Prolongation
Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should
be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g.,
quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or
any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in
patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden
death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2)
hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and
(4) presence of congenital prolongation of the QT interval.
The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective
disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with
schizophrenia.
In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n = 50) showed a mean
placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at
1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended
12 mg dose of paliperidone extended-release tablets (Cmax,ss = 113 ng/mL and 45 ng/mL, respectively,
when administered with a standard breakfast). In this same study, a 4 mg dose of the immediaterelease oral formulation of paliperidone, for which Cmax,ss = 35 ng/mL, showed an increased placebosubtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects
had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.
For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG)
Page 2 of 10
measurements taken at various time points showed only one subject in the paliperidone extendedrelease tablets 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of
62 msec). No subject receiving paliperidone extended-release tablets had a QTcLD exceeding 500 msec
at any time in any of these three studies.
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the
elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome.
Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to
increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered
to the patient increase, but the syndrome can develop after relatively brief treatment periods at low
doses, although this is uncommon.
There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress
(or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying
process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
Given these considerations, paliperidone extended-release tablets should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should
generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration
of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with paliperidone extendedrelease tablets, drug discontinuation should be considered. However, some patients may require treatment with paliperidone extended-release tablets despite the presence of the syndrome.
Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body
weight gain. While all of the drugs in the class have been shown to produce some metabolic changes,
each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme
and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients
treated with all atypical antipsychotics. These cases were, for the most part, seen in postmarketing
clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of
hyperglycemia or diabetes in trial subjects treated with paliperidone extended-release tablets.
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is
complicated by the possibility of an increased background risk of diabetes mellitus in patients with
schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given
these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related
adverse events is not completely understood. However, epidemiological studies suggest an increased
risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because paliperidone extended-release tablets were not marketed at the time
these studies were performed, it is not known if paliperidone extended-release tablets are associated with this increased risk.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics
should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes
mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics
should undergo fasting blood glucose testing at the beginning of treatment and periodically during
treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of
hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.
Table 1a: Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in
Paliperidone Extended-release Tablets
Placebo
3 mg/day 6 mg/day 9 mg/day 12 mg/day
Mean change from baseline (mg/dL)
n = 322
n = 122
n = 212
n = 234
n = 218
Serum Glucose
Change from baseline
0.8
-0.7
0.4
2.3
4.3
Proportion of Patients with Shifts
Serum Glucose
Normal to High
5.1%
3.2%
4.5%
4.8%
3.8%
(< 100 mg/dL to ≥ 126 mg/dL)
(12/236)
(3/93)
(7/156)
(9/187)
(6/157)
In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets
were associated with a mean change in glucose of +3.3 mg/dL at Week 24 (n = 570) and +4.6 mg/dL
at Week 52 (n = 314).
Data from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) with schizophrenia are presented in Table 1b.
Table 1b. Change in Fasting Glucose from a Placebo-Controlled 6-Week Study in Adolescent Subjects
(12 to 17 years of age) with Schizophrenia
Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day
n = 41
n = 44
n = 11
n = 28
n = 32
Serum Glucose
0.8
-1.4
-1.8
-0.1
5.2
Serum Glucose
Normal to High
3%
0%
0%
0%
11%
(< 100 mg/dL to ≥ 126 mg/dL)
(1/32)
(0/34)
(0/9)
(0/20)
(3/27)
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical
antipsychotics.
Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a.
Table 2a: Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in
Placebo
Cholesterol
n = 331
n = 120
n = 216
n = 236
n = 231
-6.3
-4.4
-2.4
-5.3
-4
LDL
n = 322
n = 116
n = 210
n = 231
n = 225
-3.2
0.5
-0.8
-3.9
-2
HDL
n = 331
n = 119
n = 216
n = 234
n = 230
0.3
-0.4
0.5
0.8
1.2
Triglycerides
n = 331
n = 120
n = 216
n = 236
n = 231
-22.3
-18.3
-12.6
-10.6
-15.4
Cholesterol
Normal to High
2.6%
2.8%
5.6%
4.1%
3.1%
(< 200 mg/dL to ≥ 240 mg/dL)
(5/194)
(2/71)
(7/125)
(6/147)
(4/130)
LDL
Normal to High
1.9%
0%
5%
3.7%
0%
(< 100 mg/dL to ≥ 160 mg/dL)
(2/105)
(0/44)
(3/60)
(3/81)
(0/69)
HDL
Normal to Low
22%
16.3%
29.1%
23.4%
20%
(≥ 40 mg/dL to < 40 mg/dL)
(44/200)
(13/80)
(39/134)
(32/137)
(27/135)
Triglycerides
Normal to High
5.3%
11%
8.8%
8.7%
4.3%
(< 150 mg/dL to ≥ 200 mg/dL)
(11/208)
(9/82)
(12/136)
(13/150)
(6/139)
were associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n = 573) and
-1.5 mg/dL at Week 52 (n = 317), (b) triglycerides of -6.4 mg/dL at Week 24 (n = 573) and
-10.5 mg/dL at Week 52 (n = 317); (c) LDL of -1.9 mg/dL at Week 24 (n = 557) and -2.7 mg/dL at Week
52 (n = 297); and (d) HDL of +2.2 mg/dL at Week 24 (n = 568) and +3.6 mg/dL at Week 52 (n = 302).
Data from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) with schizophrenia are presented in Table 2b.
Table 2b. Change in Fasting Lipids from a Placebo-Controlled 6-Week Study in Adolescent Subjects
(12 to 17 years of age) with Schizophrenia
Cholesterol
n = 39
n = 45
n = 11
n = 28
n = 32
-7.8
-3.3
12.7
3
-1.5
LDL
n = 37
n = 40
n=9
n = 27
n = 31
-4.1
-3.1
7.2
2.4
0.6
HDL
n = 37
n = 41
n=9
n = 27
n = 31
-1.9
0
1.3
1.4
0
Triglycerides
n = 39
n = 44
n = 11
n = 28
n = 32
-8.9
3.2
17.6
-5.4
3.9
Cholesterol
Normal to High
7%
4%
0%
6%
11%
(< 170 mg/dL to ≥ 200 mg/dL)
(2/27)
(1/26)
(0/6)
(1/18)
(2/19)
LDL
Normal to High
3%
4%
14%
0%
9%
(< 110 mg/dL to ≥ 130 mg/dL)
(1/32)
(1/25)
(1/7)
(0/22)
(2/22)
HDL
Normal to Low
14%
7%
29%
13%
23%
(≥ 40 mg/dL to < 40 mg/dL)
(4/28)
(2/30)
(2/7)
(3/23)
(5/22)
Triglycerides
Normal to High
3%
5%
13%
8%
7%
(< 150 mg/dL to ≥ 200 mg/dL)
(1/34)
(2/38)
(1/8)
(2/26)
(2/28)
Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of
Page 3 of 10
weight is recommended.
Schizophrenia Trials: Data on mean changes in body weight and the proportion of subjects meeting a
weight gain criterion of ≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a.
Table 3a: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body
Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia
Placebo
n = 323
n = 112
n = 215
n = 235
n = 218
Weight (kg)
-0.4
0.6
0.6
1
1.1
Weight Gain
≥ 7% increase from baseline
5%
7%
6%
9%
9%
were associated with a mean change in weight of +1.4 kg at Week 24 (n = 63) and +2.6 kg at Week 52
(n = 302).
Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind, placebocontrolled study and an open-label extension with a median duration of exposure to paliperidone extended-release tablets of 182 days. Data on mean changes in body weight and the proportion of subjects
meeting a weight gain criterion of ≥ 7% of body weight [see Clinical Studies (14.1)] from the placebocontrolled 6-week study in adolescent subjects (12 to 17 years of age) are presented in Table 3b.
Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body
Weight from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with
Schizophrenia
n = 51
n = 54
n = 16
n = 45
n = 34
Weight (kg)
0
0.3
0.8
1.2
1.5
Weight Gain
≥ 7% increase from baseline
2%
6%
19%
7%
18%
In the open-label long-term study the proportion of total subjects treated with paliperidone extendedrelease tablets with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with paliperidone extended-release tablets, weight gain should be assessed against
that expected with normal growth. When taking into consideration the median duration of exposure to
paliperidone extended-release tablets in the open-label study (182 days) along with expected normal
growth in this population based on age and gender, an assessment of standardized scores relative to
normative data provides a more clinically relevant measure of changes in weight. The mean change from
open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.
Schizoaffective Disorder Trials: In the pooled data from the two placebo-controlled, 6-week studies in
adult subjects with schizoaffective disorder, a higher percentage of paliperidone extended-release
tablets-treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated
subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of
≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.
5.7 Hyperprolactinemia
Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the
elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to
that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.
Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal
steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female
and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin
dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a
patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary
gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have
shown an association between chronic administration of this class of drugs and tumorigenesis in
humans, but the available evidence is too limited to be conclusive.
5.8 Potential for Gastrointestinal Obstruction
Because the paliperidone extended-release tablet is non-deformable and does not appreciably change
in shape in the gastrointestinal tract, paliperidone extended-release tablets should ordinarily not be
administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic,
for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due
to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal
pseudoobstruction, or Meckel’s diverticulum). There have been rare reports of obstructive symptoms in
patients with known strictures in association with the ingestion of drugs in non-deformable controlledrelease formulations. Because of the controlled-release design of the tablet, paliperidone extendedrelease tablets should only be used in patients who are able to swallow the tablet whole [see Dosage and
Administration (2.3) and Patient Counseling Information (17.8)].
A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and
an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or
other causes, would be expected to increase bioavailability. These changes in bioavailability are more
likely when the changes in transit time occur in the upper GI tract.
5.9 Orthostatic Hypotension and Syncope
Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in subjects with
schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with paliperidone extendedrelease tablets (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo.
Paliperidone extended-release tablets should be used with caution in patients with known cardiovascular
disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be
considered in patients who are vulnerable to hypotension.
5.10 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have
been reported temporally related to antipsychotic agents, including paliperidone extended-release
tablets. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)
and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant
low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of paliperidone extendedrelease tablets should be considered at the first sign of a clinically significant decline in WBC in the
absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms
or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue paliperidone extended-release
tablets and have their WBC followed until recovery.
5.11 Potential for Cognitive and Motor Impairment
Somnolence was reported in subjects treated with paliperidone extended-release tablets [see Adverse
Reactions (6.1, 6.2)]. Antipsychotics, including paliperidone extended-release tablets, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle,
until they are reasonably certain that paliperidone therapy does not adversely affect them.
5.12 Seizures
During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-week,
fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22%
of subjects treated with paliperidone extended-release tablets (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of
subjects treated with placebo. Like other antipsychotic drugs, paliperidone extended-release tablets
should be used cautiously in patients with a history of seizures or other conditions that potentially lower
the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients
65 years or older.
5.13 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration
pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Paliperidone extended-release tablets and other antipsychotic drugs should be used cautiously in
patients at risk for aspiration pneumonia.
5.14 Suicide
The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk
patients should accompany drug therapy. Prescriptions for paliperidone extended-release tablets should
be written for the smallest quantity of tablets consistent with good patient management in order to
reduce the risk of overdose.
5.15 Priapism
Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been
reported with paliperidone extended-release tablets during postmarketing surveillance. Severe priapism
may require surgical intervention.
5.16 Thrombotic Thrombocytopenic Purpura (TTP)
No cases of TTP were observed during clinical studies with paliperidone. Although cases of TTP have been
reported in association with risperidone administration, the relationship to risperidone therapy is unknown.
5.17 Body Temperature Regulation
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic
agents. Appropriate care is advised when prescribing paliperidone extended-release tablets to patients
who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g.,
exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic
activity, or being subject to dehydration.
5.18 Antiemetic Effect
An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in
humans, may mask the signs and symptoms of overdosage with certain drugs or of conditions such as
intestinal obstruction, Reye’s syndrome, and brain tumor.
5.19 Use in Patients with Concomitant Illness
Clinical experience with paliperidone extended-release tablets in patients with certain concomitant illnesses is limited [see Clinical Pharmacology (12.3)].
Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion,
obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features
consistent with the neuroleptic malignant syndrome.
Paliperidone extended-release tablets have not been evaluated or used to any appreciable extent in
Page 4 of 10
patients with a recent history of myocardial infarction or unstable heart disease. Patients with these
diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with paliperidone extended-release tablets, caution should be observed in patients with known cardiovascular disease [see Warnings and Precautions (5.9)].
5.20 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
6
ADVERSE REACTIONS
6.1 Overall Adverse Reaction Profile
The following adverse reactions are discussed in more detail in other sections of the labeling:
•
Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and
Warnings and Precautions (5.1)]
•
Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related
psychosis [see Warnings and Precautions (5.2)]
•
Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
•
QT prolongation [see Warnings and Precautions (5.4)]
•
Tardive dyskinesia [see Warnings and Precautions (5.5)]
•
Metabolic changes [see Warnings and Precautions (5.6)]
•
Hyperprolactinemia [see Warnings and Precautions (5.7)]
•
Potential for gastrointestinal obstruction [see Warnings and Precautions (5.8)]
•
Orthostatic hypotension and syncope [see Warnings and Precautions (5.9)]
•
Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.10)]
•
Potential for cognitive and motor impairment [see Warnings and Precautions (5.11)]
•
Seizures [see Warnings and Precautions (5.12)]
•
Dysphagia [see Warnings and Precautions (5.13)]
•
Suicide [see Warnings and Precautions (5.14)]
•
Priapism [see Warnings and Precautions (5.15)]
•
Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.16)]
•
Disruption of body temperature regulation [see Warnings and Precautions (5.17)]
•
Antiemetic effect [see Warnings and Precautions (5.18)]
•
Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.19)]
•
Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings
and Precautions (5.19)]
The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in
5% or more of subjects treated with paliperidone extended-release tablets and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most
common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in
5% or more of subjects treated with paliperidone extended-release tablets and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and
nasopharyngitis.
The most common adverse reactions that were associated with discontinuation from clinical trials in
adult subjects with schizophrenia (causing discontinuation in 2% of paliperidone extended-release
tablets-treated subjects) were nervous system disorders. The most common adverse reactions that were
associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were
gastrointestinal disorders, which resulted in discontinuation in 1% of paliperidone extended-release
tablets-treated subjects. [See Adverse Reactions (6.4)].
The safety of paliperidone extended-release tablets was evaluated in 1,205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects
received paliperidone extended-release tablets at fixed doses ranging from 3 mg to 12 mg once daily.
The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in
which subjects received paliperidone extended-release tablets at daily doses within the range of 3 mg
to 15 mg (n = 104), is also included.
The safety of paliperidone extended-release tablets was evaluated in 150 adolescent subjects 12 to 17
years of age with schizophrenia who received paliperidone extended-release tablets in the dose range of
1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.
The safety of paliperidone extended-release tablets was also evaluated in 622 adult subjects with
schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one
of these trials, 206 subjects were assigned to one of two dose levels of paliperidone extended-release
tablets: 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg
(n = 98) once daily. In the other study, 214 subjects received flexible doses of paliperidone extendedrelease tablets (3 mg to 12 mg once daily). Both studies included subjects who received paliperidone
extended-release tablets either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate
of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were
considered to be reasonably associated with the use of paliperidone extended-release tablets (adverse
drug reactions) based on the comprehensive assessment of the available adverse event information. A
causal association for paliperidone extended-release tablets often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials –
Schizophrenia in Adults and Adolescents
Adult Patients with Schizophrenia: Table 4 enumerates the pooled incidences of adverse reactions
reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred
in 2% or more of subjects treated with paliperidone extended-release tablets in any of the dose groups,
and for which the incidence in paliperidone extended-release tablets-treated subjects in any of the dose
groups was greater than the incidence in subjects treated with placebo.
Table 4: Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablets-Treated Adult
Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*
Placebo
3 mg
6 mg
9 mg
12 mg
once daily once daily once daily once daily
Body System or Organ Class
(N = 355) (N = 127) (N = 235) (N = 246) (N = 242)
Dictionary-Derived Term
Total percentage of subjects
37
48
47
53
59
with adverse reactions
Cardiac disorders
Atrioventricular block first
1
2
0
2
1
degree
Bundle branch block
2
3
1
3
<1
Sinus arrhythmia
0
2
1
1
<1
Tachycardia
7
14
12
12
14
1
1
3
2
2
Dry mouth
1
2
3
1
3
<1
0
<1
1
4
General disorders
Asthenia
1
2
<1
2
2
Fatigue
1
2
1
2
2
Akathisia
4
4
3
8
10
Dizziness
4
6
5
4
5
Extrapyramidal symptoms
8
10
7
20
18
Headache
12
11
12
14
14
Somnolence
7
6
9
10
11
Vascular disorders
Orthostatic hypotension
1
2
1
2
4
* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extendedrelease tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from
three studies; one study included once daily paliperidone extended-release tablets doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg [see Clinical Studies (14)].
Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia
includes the terms tachycardia, sinus tachycardia, and heart rate increased. Adverse reactions for which the paliperidone extended-release tablets incidence was equal to or less than placebo are not listed in the table, but included the
following: vomiting.
Adolescent Patients with Schizophrenia: Table 5 lists the adverse reactions reported in a fixed-dose,
placebo-controlled study in adolescent subjects 12 to 17 years of age with schizophrenia, listing those
that occurred in 2% or more of subjects treated with paliperidone extended-release tablets in any of the
dose groups, and for which the incidence in paliperidone extended-release tablets-treated subjects in
any of the dose groups was greater than the incidence in subjects treated with placebo.
Table 5. Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-release Tablets-Treated
Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial*
Placebo
1.5 mg
3 mg
6 mg
12 mg
(N = 51)
(N = 54)
(N = 16)
(N = 45)
(N = 35)
Total percentage of subjects
43
37
50
58
74
with adverse reactions
Cardiac disorders
Tachycardia
0
0
6
9
6
Eye disorders
Vision blurred
0
0
0
0
3
Dry mouth
2
0
0
0
3
0
2
6
2
0
Swollen tongue
0
0
0
0
3
Vomiting
10
0
6
11
3
General disorders
Asthenia
0
0
0
2
3
Fatigue
0
4
0
2
3
Infections and infestations
Nasopharyngitis
2
4
0
4
0
Investigations
Weight increased
0
7
6
2
3
Akathisia
0
4
6
11
17
Dizziness
0
2
6
2
3
continued
Page 5 of 10
Table 5. Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-release Tablets-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial*
Placebo
1.5 mg
3 mg
6 mg
12 mg
(N = 51)
(N = 54)
(N = 16)
(N = 45)
(N = 35)
0
4
19
18
23
Headache
4
9
6
4
14
Lethargy
0
0
0
0
3
Somnolence
4
9
13
20
26
Tongue paralysis
0
0
0
0
3
Anxiety
4
0
0
2
9
Reproductive system and breast disorders
Amenorrhea
0
0
6
0
0
Galactorrhea
0
0
0
4
0
Gynecomastia
0
0
0
0
3
Respiratory, thoracic and mediastinal disorders
Epistaxis
0
0
0
2
0
Table 6: Adverse Drug Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablets-Treated
Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials*
Placebo
Paliperidone Paliperidone Paliperidone
ExtendedExtendedExtendedrelease
release
release
Tablets
Tablets
Tablets
3 mg to 6 mg 9 mg to 12 mg 3 mg to 12 mg
once daily
once daily
once daily
fixed-dose
fixed-dose
flexible dose
range
range
(N = 202)
(N = 108)
(N = 98)
(N = 214)
Dysarthria
0
1
4
2
8
20
17
12
Somnolence
5
12
12
8
Sleep disorder
<1
2
3
0
Respiratory, thoracic and
mediastinal disorders
Cough
1
1
3
1
Pharyngolaryngeal pain
<1
0
2
1
* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extendedrelease tablets dose groups and which occurred at greater incidence than in the placebo group. Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus,
bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes the terms somnolence, sedation, and hypersomnia. Insomnia includes the terms insomnia and initial insomnia. Tachycardia includes the
terms tachycardia, sinus tachycardia, and heart rate increased. Hypertension includes the terms hypertension and blood
pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling.
* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extendedrelease tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from
two studies. One study included once daily paliperidone extended-release tablets doses of 6 mg (with the option to
reduce to 3 mg) and 12 mg (with the option to reduce to 9 mg). The second study included flexible once daily doses of
3 mg to 12 mg. Among the 420 subjects treated with paliperidone extended-release tablets, 230 (55%) received
paliperidone extended-release tablets as monotherapy and 190 (45%) received paliperidone extended-release tablets
as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia,
drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the
terms tachycardia, sinus tachycardia, and heart rate increased.
6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials –
Schizoaffective Disorder in Adults
Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled
6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with
paliperidone extended-release tablets and for which the incidence in paliperidone extended-release
tablets-treated subjects was greater than the incidence in subjects treated with placebo.
Table 6: Adverse Drug Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablets-Treated
Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials*
Placebo
Paliperidone Paliperidone Paliperidone
ExtendedExtendedExtendedrelease
release
release
Tablets
Tablets
Tablets
3 mg to 6 mg 9 mg to 12 mg 3 mg to 12 mg
once daily
once daily
once daily
fixed-dose
fixed-dose
flexible dose
range
range
(N = 202)
(N = 108)
(N = 98)
(N = 214)
Total percentage of subjects with
32
48
50
43
adverse reactions
Cardiac disorders
Tachycardia
2
3
1
2
Abdominal discomfort/abdominal
1
1
0
3
pain upper
Constipation
2
4
5
4
Dyspepsia
2
5
6
6
Nausea
6
8
8
5
Stomach discomfort
1
0
1
2
General disorders
Asthenia
1
3
4
<1
Infections and Infestations
Nasopharyngitis
1
2
5
3
Rhinitis
0
1
3
1
Upper respiratory tract infection
1
2
2
2
Investigations
Weight increased
1
5
4
4
Decreased appetite
<1
1
0
2
Increased appetite
<1
3
2
2
Musculoskeletal and connective
tissue disorders
Back pain
1
1
1
3
Myalgia
<1
2
4
1
Akathisia
4
4
6
6
continued
Monotherapy Versus Adjunctive Therapy: The designs of the two placebo-controlled, 6-week, doubleblind trials in adult subjects with schizoaffective disorder included the option for subjects to receive
antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or
lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received paliperidone
extended-release tablets as monotherapy and 190 (45%) subjects received paliperidone extendedrelease tablets as an adjunct to mood stabilizers and/or antidepressants. When comparing these two
subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving
paliperidone extended-release tablets as monotherapy.
6.4 Discontinuations Due to Adverse Reactions
Schizophrenia Trials: The percentages of subjects who discontinued due to adverse reactions in the
three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in
paliperidone extended-release tablets-treated and placebo-treated subjects, respectively. The most
common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone extended-release tablets- and placebo-treated subjects, respectively).
Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with
schizophrenia, only dystonia led to discontinuation (< 1% of paliperidone extended-release tabletstreated subjects).
Schizoaffective Disorder Trials: The percentages of subjects who discontinued due to adverse reactions
in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and < 1% in
paliperidone extended-release tablets- and placebo-treated subjects, respectively. The most common
reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone extendedrelease tablets- and placebo-treated subjects, respectively).
6.5 Dose-Related Adverse Reactions
Schizophrenia Trials: Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose
studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater
than 2% incidence in the subjects treated with paliperidone extended-release tablets, the incidences of
the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia,
dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of
these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.
In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the
adverse reactions that occurred with > 2% incidence in the subjects treated with paliperidone extended-release tablets, the incidences of the following adverse reactions increased with dose: tachycardia,
akathisia, extrapyramidal symptoms, somnolence, and headache.
Schizoaffective Disorder Trials: In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis,
cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of paliperidone extended-release tablets compared with subjects who
received lower doses.
6.6 Demographic Differences
An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in
adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects
with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on
the basis of gender or race alone; there was also no difference on the basis of age [see Use in Specific
Populations (8.5)].
6.7 Extrapyramidal Symptoms (EPS)
Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates
Page 6 of 10
Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from
baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table
7), and (4) incidence of spontaneous reports of EPS (Table 8). For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed
for the 9 mg and 12 mg doses. There was no difference observed between placebo and paliperidone
extended-release tablets 3 mg and 6 mg doses for any of these EPS measures.
Table 7: Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed b Incidence of Ratings
Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults
Placebo
3 mg
6 mg
9 mg
12 mg
EPS Group
(N = 355) (N = 127) (N = 235) (N = 246) (N = 242)
Parkinsonisma
9
11
3
15
14
Akathisiab
6
6
4
7
9
Use of anticholinergic medicationsc
10
10
9
22
22
a For
Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of
items score divided by the number of items)
b For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2
c Percent of patients who received anticholinergic medications to treat emergent EPS
Table 8: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA
Preferred Term – Schizophrenia Studies in Adults
Placebo
3 mg
6 mg
9 mg
12 mg
EPS Group
(N = 355) (N = 127) (N = 235) (N = 246) (N = 242)
Overall percentage of patients with
11
13
10
25
26
EPS-related AE
Dyskinesia
3
5
3
8
9
Dystonia
1
1
1
5
5
Hyperkinesia
4
4
3
8
10
Parkinsonism
2
3
3
7
6
Tremor
3
3
3
4
3
Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia
Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismus
Hyperkinesia group includes: Akathisia, hyperkinesia
Parkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling, hypertonia, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism
Tremor group includes: Tremor
Compared to data from the studies in adult subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and
frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous
reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no doserelated increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the
Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS
reports of hyperkinesia and dystonia and in the use of anticholinergic medications.
Table 9 shows the EPS data from the pooled schizoaffective disorder trials.
Table 9: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA
Preferred Term – Schizoaffective Disorder Studies in Adults
Placebo
3 mg to 6 mg
9 mg to 12 mg 3 mg to 12 mg
once daily
once daily
once daily
fixed-dose range fixed-dose range flexible dose
EPS Group
(N = 202)
(N = 108)
(N = 98)
(N = 214)
Overall percentage of patients
11
23
22
17
with EPS-related AE
Dyskinesia
1
3
1
1
Dystonia
1
2
3
2
Hyperkinesia
5
5
8
7
Parkinsonism
3
14
7
7
Tremor
3
12
11
5
Dyskinesia group includes: Dyskinesia, muscle twitching
Dystonia group includes: Dystonia, muscle spasms, oculogyration
Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness
Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle tightness, musculoskeletal
stiffness, parkinsonian gait, parkinsonism
The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar
dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia,
hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies
(Table 10).
Table 10. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA
Preferred Term – Schizophrenia Studies in Adolescent Subjects
Placebo
1.5 mg
3 mg
6 mg
12 mg
EPS Group
(N = 51)
(N = 54)
(N = 16)
(N = 45)
(N = 35)
Overall percentage of patients
0
6
25
22
40
with EPS-related AE
Hyperkinesia
0
4
6
11
17
Dystonia
0
2
0
11
14
Tremor
0
2
6
7
11
Parkinsonism
0
0
6
2
14
Dyskinesia
0
2
6
2
6
Hyperkinesia group includes: Akathisia
Dystonia group includes: Dystonia, muscle contracture, oculogyric crisis, tongue paralysis, torticollis
Parkinsonism group includes: Cogwheel rigidity, extrapyramidal disorder, muscle rigidity
Dyskinesia group includes: Dyskinesia, muscle contractions involuntary
Dystonia: Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may
occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include:
spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they
occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age
groups.
6.8 Laboratory Test Abnormalities
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with
schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between paliperidone extended-release tablets and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly,
there were no differences between paliperidone extended-release tablets and placebo in the incidence of
discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes
from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, paliperidone extended-release tablets were associated with increases in serum prolactin [see Warnings and Precautions (5.7)].
6.9 Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone Extended-Release Tablets
The following additional adverse reactions occurred in < 2% of paliperidone extended-release tabletstreated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The
following also includes additional adverse reactions reported at any frequency by paliperidone extended-release tablets-treated subjects who participated in other clinical studies.
Cardiac Disorders: bradycardia, palpitations
Eye Disorders: eye movement disorder
Gastrointestinal Disorders: flatulence
General Disorders: edema
Immune System Disorders: anaphylactic reaction
Infections and Infestations: urinary tract infection
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased
Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity
Nervous System Disorders: opisthotonus
Psychiatric Disorders: agitation, insomnia, nightmare
Reproductive System and Breast Disorders: breast discomfort, menstruation irregular, retrograde ejaculation
Respiratory, Thoracic and Mediastinal Disorders: nasal congestion
Skin and Subcutaneous Tissue Disorders: pruritus, rash
Vascular Disorders: hypertension
The safety of paliperidone extended-release tablets was also evaluated in a long-term trial designed to
assess the maintenance of effect with paliperidone extended-release tablets in adults with schizophrenia [see Clinical Studies (14)]. In general, adverse reaction types, frequencies, and severities during the
initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase
of this study were similar in type and severity to those observed in the initial 14-week open-label phase.
The following adverse reactions have been identified during postapproval use of paliperidone extendedrelease tablets, because these reactions were reported voluntarily from a population of uncertain size, it
is not possible to reliably estimate their frequency: angioedema, ileus, priapism, swollen tongue, tardive
dyskinesia, urinary incontinence, urinary retention.
6.11 Adverse Reactions Reported with Risperidone
Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone
can be found in the ADVERSE REACTIONS section of the risperidone package insert.
7
DRUG INTERACTIONS
7.1 Potential for Paliperidone Extended-Release Tablets to Affect Other Drugs
Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], paliperidone extendedrelease tablets should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when
Page 7 of 10
paliperidone extended-release tablets are administered with other therapeutic agents that have this
potential [see Warnings and Precautions (5.9)].
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are
metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that
paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450
isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore,
paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are
available and the clinical relevance is unknown.
Pharmacokinetic interaction between lithium and paliperidone is unlikely.
In a drug interaction study, co-administration of paliperidone extended-release tablets (12 mg once daily
for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not
affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on
valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average
plasma concentrations when paliperidone extended-release tablets 3 to 15 mg/day were added to their
existing valproate treatment.
7.2 Potential for Other Drugs to Affect Paliperidone Extended-Release Tablets
Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with
inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and
CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased
elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro
studies have shown that paliperidone is a P-gp substrate.
Co-administration of paliperidone extended-release tablets 6 mg once daily with carbamazepine, a
strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of
approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to
a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the
amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of paliperidone extended-release tablets should be re-evaluated and increased if
necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone extended-release
tablets should be re-evaluated and decreased if necessary.
Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an
interaction study in healthy subjects in which a single 3 mg dose of paliperidone extended-release
tablets was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor),
paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers.
Higher doses of paroxetine have not been studied. The clinical relevance is unknown.
Co-administration of a single dose of paliperidone extended-release tablets 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately
50% in the Cmax and AUC of paliperidone. Dosage reduction for paliperidone extended-release tablets
should be considered when paliperidone extended-release tablets are co-administered with valproate
after clinical assessment.
Pharmacokinetic interaction between lithium and paliperidone is unlikely.
8
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C: There are no adequate and well controlled studies of
paliperidone extended-release tablets in pregnant women.
Use of first generation antipsychotic drugs during the last trimester of pregnancy has been associated
with extrapyramidal symptoms in the neonate. These symptoms are usually self-limited. It is not known
whether paliperidone, when taken near the end of pregnancy, will lead to similar neonatal signs and
symptoms.
In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and
rabbits were treated during the period of organogenesis with up to 8 times the maximum recommended
human dose of paliperidone (on a mg/m2 basis).
In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and
humans, there were increases in pup deaths seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m2 basis (see risperidone package insert).
Non-Teratogenic Effects: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports
of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these
neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Paliperidone extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be weighed
against the unknown risks of infant exposure to paliperidone.
8.4 Pediatric Use
Safety and effectiveness of paliperidone extended-release tablets in the treatment of schizophrenia were
evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone extended-release tablets in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind,
placebo-controlled trial.
Safety and effectiveness of paliperidone extended-release tablets for the treatment of schizophrenia in
patients < 12 years of age have not been established. Safety and effectiveness of paliperidone extended-release tablets for the treatment of schizoaffective disorder in patients < 18 years of age have not
been studied.
In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a
reversible impairment of performance in a test of learning and memory was seen, in females only, with
a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those
in adolescents. No other consistent effects on neurobehavioral or reproductive development were seen
up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2 to 3 times
those in adolescents.
Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to
paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and
density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of
risperidone plus paliperidone which were similar to those in children and adolescents receiving the maximum recommended human dose of risperidone. In addition, a delay in sexual maturation was seen at
all doses in both males and females. The above effects showed little or no reversibility in females after
a 12-week drug-free recovery period.
The long-term effects of paliperidone extended-release tablets on growth and sexual maturation have
not been fully evaluated in children and adolescents.
8.5 Geriatric Use
The safety, tolerability, and efficacy of paliperidone extended-release tablets were evaluated in a 6-week
placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom
21 were 75 years of age and older). In this study, subjects received flexible doses of paliperidone extended-release tablets (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age
and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects
received fixed doses of paliperidone extended-release tablets (3 mg to 15 mg once daily) [see Clinical
Studies (14)]. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.
Overall, of the total number of subjects in schizophrenia clinical studies of paliperidone extendedrelease tablets (n = 1,796), including those who received paliperidone extended-release tablets or placebo, 125 (7%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall
differences in safety or effectiveness were observed between these subjects and younger subjects, and
other reported clinical experience has not identified differences in response between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with
moderate to severe renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced
doses. Because elderly patients are more likely to have decreased renal function, care should be taken
in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)].
Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration (2.5)].
No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone
extended-release tablets have not been studied in patients with severe hepatic impairment.
9
Paliperidone is not a controlled substance.
9.2 Abuse
Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is
not possible to predict the extent to which a CNS-active drug will be misused, diverted, and/or abused
once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and
such patients should be observed closely for signs of paliperidone extended-release tablets misuse or
abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or
physical dependence.
10 OVERDOSAGE
10.1 Human Experience
While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials, the highest estimated ingestion of paliperidone extended-release tablets was 405 mg.
Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation.
Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.
Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone
can be found in the OVERDOSAGE section of the risperidone package insert.
There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs
and recovery. Multiple drug involvement should also be considered.
In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose
may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately, including continuous electrocardiographic
monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered
in patients with an acute overdose of paliperidone. Similarly the alpha-blocking properties of bretylium
might be additive to those of paliperidone, resulting in problematic hypotension.
Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous
fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of
severe extrapyramidal symptoms, anticholinergic medication should be administered.
Page 8 of 10
11 DESCRIPTION
Paliperidone, the active ingredient in paliperidone extended-release tablets, is a psychotropic agent
belonging to the chemical class of benzisoxazole derivatives. Paliperidone extended-release tablets contain a racemic mixture of (+)- and (-)-paliperidone. The chemical name is (9RS)-3-[2-[4-(6-Fluoro-1,2benzisoxazol-3-yl)piperidin-1-yl]]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O3 and its molecular weight is 426.49. The structural formula is:
O
N
F
O
N
N
N
CH3
OH
Paliperidone is sparingly soluble in 0.1N HCl and methylene chloride; practically insoluble in water, 0.1N
NaOH, and hexane; and slightly soluble in N,N-dimethylformamide.
Paliperidone extended-release tablets are available in 1.5 mg (brown), 3 mg (white), 6 mg (light beige),
and 9 mg (pink) strengths. Paliperidone extended-release tablets utilize osmotic drug-release technology [see Description (11.1)].
Inactive ingredients are butylated hydroxytoluene, cellulose acetate, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polyethylene oxide, red iron oxide, sodium chloride,
sodium stearyl fumarate, talc, titanium dioxide and yellow iron oxide.
The 1.5 mg tablet also contains black iron oxide and polydextrose. The 3 mg tablet also contains polyvinyl
alcohol. The 6 mg tablet also contains black iron oxide, FD&C Blue No. 1 Aluminum Lake and polyvinyl
alcohol. The 9 mg tablet also contains FD&C Blue No. 1 Aluminum Lake and polyvinyl alcohol.
The imprinting ink contains the following: black iron oxide, hypromellose and propylene glycol.
11.1 Delivery System Components and Performance
Paliperidone extended-release tablets contain a bi-layer core tablet that consists of a drug layer containing the entire amount of active ingredient in a hydrophilic polymer matrix and a push layer that contains an osmotic agent in a hydrophilic, swell-able polymer matrix. The bi-layer core tablet is coated with
a release-controlling semi-permeable membrane (SPM). The SPM allows water permeation into the core
without allowing components to quickly dissipate from the core. A laser-drilled aperture is present on the
drug layer side of the SPM-coated tablet and is necessary for delivery. The tablets contain a water soluble cosmetic over-coating that is imprinted with an identifier. Once ingested, the cosmetic over-coating rapidly dissipates in the gastrointestinal tract. The SPM allows water to penetrate into the core as
the osmotic agent in the push layer provides a driving force for water influx. Once hydrated, the swellable polymer matrix in the push layer (high molecular weight polyethylene oxide) expands, exerting a
pressure on the drug layer portion of the core tablet which forces it out of the laser-drilled aperture in a
plug-flow fashion. After an initial lag time (about 2 to 4 hours), water influx into the core reaches a
steady-state and the drug layer is released from the laser-drilled aperture at a constant rate for approximately 20 to 24 hours. As the release rate is controlled by the rate of water influx into the core (SPM permeability), the delivery is independent of pH or gastrointestinal motility. The biologically inert tablet core
(ghost), containing residual push layer components, remains intact and is eliminated in the feces. Drug
absorption is controlled by a combination of drug release from the tablet and subsequent dissolution in
the gastrointestinal tract.
Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as
with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug’s
therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2)
and serotonin Type 2 (5HT2A) receptor antagonism.
Paliperidone is a centrally active dopamine Type 2 (D2) antagonist and with predominant serotonin Type
2 (5HT2A) activity. Paliperidone is also active as an antagonist at α1 and α2 adrenergic receptors and
H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has
no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity
of the (+)- and (-)-paliperidone enantiomers is qualitatively and quantitatively similar in vitro.
Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma
concentration (Cmax) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following paliperidone extended-release tablets administration are dose-proportional within the available dose
range. The terminal elimination half-life of paliperidone is approximately 23 hours.
Steady-state concentrations of paliperidone are attained within 4 to 5 days of dosing with paliperidone
extended-release tablets in most subjects. The mean steady-state peak:trough ratio for a paliperidone
dose of 9 mg was 1.7 with a range of 1.2 to 3.1.
Following administration of paliperidone extended-release tablets, the (+) and (-) enantiomers of
paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady-state.
Absorption and Distribution: The absolute oral bioavailability of paliperidone following paliperidone
extended-release tablets administration is 28%.
Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a
standard high-fat/high-caloric meal gave mean Cmax and AUC values of paliperidone that were
increased by 60% and 54%, respectively, compared with administration under fasting conditions. Clinical trials establishing the safety and efficacy of paliperidone extended-release tablets were carried out
in subjects without regard to the timing of meals. While paliperidone extended-release tablets can be
taken without regard to food, the presence of food at the time of paliperidone extended-release tablets
administration may increase exposure to paliperidone [see Dosage and Administration (2.3)].
Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%.
Metabolism and Elimination: Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the
metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone [see Drug Interactions (7)].
One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone to
five healthy volunteers, 59% (range 51% to 67%) of the dose was excreted unchanged into urine, 32%
(26% to 41%) of the dose was recovered as metabolites, and 6% to 12% of the dose was not recovered.
Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four
primary metabolic pathways have been identified in vivo, none of which could be shown to account for
more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.
Population pharmacokinetic analyses found no difference in exposure or clearance of paliperidone
between extensive metabolizers and poor metabolizers of CYP2D6 substrates.
Special Populations: Renal Impairment: The dose of paliperidone extended-release tablets should be
reduced in patients with moderate or severe renal impairment [see Dosage and Administration (2.5)].
The disposition of a single dose paliperidone 3 mg extended-release tablet was studied in adult subjects
with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal
function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate
(CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal
impairment, corresponding to an average increase in exposure (AUCinf) of 1.5-fold, 2.6-fold, and
4.8-fold, respectively, compared to healthy subjects. The mean terminal elimination half-life of paliperidone was 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min).
Hepatic Impairment: In a study in adult subjects with moderate hepatic impairment (Child-Pugh class
B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although
total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose
adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been
studied in patients with severe hepatic impairment.
Adolescents (12 to 17 years of age): Paliperidone systemic exposure in adolescents weighing ≥ 51 kg
(≥ 112 lbs) was similar to that in adults. In adolescents weighing < 51 kg (< 112 lbs), a 23% higher
exposure was observed; this is considered not to be clinically significant. Age did not influence the
paliperidone exposure.
Elderly: No dosage adjustment is recommended based on age alone. However, dose adjustment may be
required because of age-related decreases in creatinine clearance [see Renal Impairment above and
Dosage and Administration (2.1, 2.5)].
Race: No dosage adjustment is recommended based on race. No differences in pharmacokinetics were
observed in a pharmacokinetic study conducted in Japanese and Caucasians.
Gender: No dosage adjustment is recommended based on gender. No differences in pharmacokinetics
were observed in a pharmacokinetic study conducted in men and women.
Smoking: No dosage adjustment is recommended based on smoking status. Based on in vitro studies
utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore,
not have an effect on the pharmacokinetics of paliperidone.
Carcinogenesis: Carcinogenicity studies of paliperidone have not been performed.
Carcinogenicity studies of risperidone, which is extensively converted to paliperidone in rats, mice, and
humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet
at daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats.
A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas.
The no-effect dose for these tumors was less than or equal to the maximum recommended human dose
of risperidone on a mg/m2 basis (see risperidone package insert). An increase in mammary, pituitary,
and endocrine pancreas neoplasms has been found in rodents after chronic administration of other
antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents in terms of human risk is unknown [see
Mutagenesis: No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo rat micronucleus test.
Impairment of Fertility: In a study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day. However, pre- and postimplantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg,
a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of
0.63 mg/kg, which is half of the maximum recommended human dose on a mg/m2 basis.
The fertility of male rats was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day, although
sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in
Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all
doses tested (0.31 mg/kg to 5 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration. Serum testosterone and sperm parameters partially recovered, but remained
decreased after the last observation (two months after treatment was discontinued).
14 CLINICAL STUDIES
14.1 Schizophrenia
Adults: The acute efficacy of paliperidone extended-release tablets (3 mg to 15 mg once daily) was
established in three placebo-controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in
non-elderly adult subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were
carried out in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these
three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in the morning without regard to meals.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item
inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized
thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also evaluated using
Page 9 of 10
the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that
measures personal and social functioning in the domains of socially useful activities (e.g., work and
study), personal and social relationships, self-care, and disturbing and aggressive behaviors.
In all three studies (n = 1,665), paliperidone extended-release tablets were superior to placebo on the
PANSS at all doses. Mean effects at all doses were fairly similar, although the higher doses in all studies were numerically superior. Paliperidone extended-release tablets were also superior to placebo on the
PSP in these trials.
An examination of population subgroups did not reveal any evidence of differential responsiveness on
the basis of gender, age (there were few patients over 65), or geographic region. There were insufficient
data to explore differential effects based on race.
In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically
responded (defined as PANSS score ≤ 70 or ≤ 4 on pre-defined PANSS subscales, as well as having been
on a stable fixed dose of paliperidone extended-release tablets for the last 2 weeks of an 8-week run-in
phase) were entered into a 6-week open-label stabilization phase where they received paliperidone
extended-release tablets (doses ranging from 3 mg to 15 mg once daily). After the stabilization phase,
patients were randomized in a double-blind manner to either continue on paliperidone extended-release
tablets at their achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia
symptoms. Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales),
hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others.
An interim analysis of the data showed a significantly longer time to relapse in patients treated with
paliperidone extended-release tablets compared to placebo, and the trial was stopped early because
maintenance of efficacy was demonstrated.
Adolescents: The efficacy of paliperidone extended-release tablets in adolescent subjects with schizophrenia was established in a randomized, double-blind, parallel-group, placebo-controlled, 6-week
study using a fixed-dose weight-based treatment group design over the dose range of 1.5 to 12 mg/day.
The study was carried out in the US, India, Romania, Russia, and Ukraine, and involved subjects 12 to
17 years of age meeting DSM-IV criteria for schizophrenia, with diagnosis confirmation using the Kiddie
Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADSPL).
Eligible subjects were randomly assigned to 1 of 4 treatment groups: a placebo group or paliperidone
extended-release tablets Low, Medium, or High dose groups. Doses were administered based on body
weight to minimize the risk of exposing lower-weight adolescents to high doses of paliperidone extended-release tablets. Subjects weighing between 29 kg and less than 51 kg at the baseline visit were randomly assigned to receive placebo or 1.5 mg (Low dose), 3 mg (Medium dose), or 6 mg (High dose) of
paliperidone extended-release tablets daily, and subjects weighing at least 51 kg at the baseline visit
were randomly assigned to receive placebo or 1.5 mg (Low dose), 6 mg (Medium dose), or 12 mg (High
dose) of paliperidone extended-release tablets daily. Dosing was in the morning without regard to meals.
Efficacy was evaluated using PANSS. Overall, this study demonstrated the efficacy of paliperidone
extended-release tablets in adolescents with schizophrenia in the dose range of 3 to 12 mg/day. Doses
within this broad range were shown to be effective, however, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater. Although paliperidone was adequately tolerated within the dose range of 3 to
12 mg/day, adverse events were dose-related.
Adults: The acute efficacy of paliperidone extended-release tablets (3 mg to 12 mg once daily) in the
treatment of schizoaffective disorder was established in two placebo-controlled, 6-week trials in nonelderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed
by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale
(PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at
least 16 on the Young Mania Rating Scale and/or Hamilton Rating Scale for Depression. The population
included subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was
assessed in 211 subjects who received flexible doses of paliperidone extended-release tablets (3 mg to
12 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one
of two dose levels of paliperidone extended-release tablets: 6 mg with the option to reduce to 3 mg
(n = 105) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. Both studies included subjects who received paliperidone extended-release tablets either as monotherapy [no mood stabilizers
and/or antidepressants (55%)] or as an adjunct to mood stabilizers and/or antidepressants (45%). The
most commonly used mood stabilizers were valproate and lithium. The most commonly used antidepressants were SSRIs and SNRIs. Paliperidone extended-release tablets were dosed in the morning without regard to meals. Studies were carried out in the United States, Eastern Europe, Russia, and Asia.
Efficacy was evaluated using the PANSS, a validated multi-item inventory composed of five factors to
evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. As secondary outcomes, mood symptoms were evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and the Young Mania Rating Scale (YMRS).
The paliperidone extended-release tablets group in the flexible-dose study (dosed between 3 and
12 mg/day, mean modal dose of 8.6 mg/day) and the higher dose group of paliperidone extended-release
tablets in the two dose-level study (12 mg/day with option to reduce to 9 mg/day) were each superior to
placebo in the PANSS. Numerical improvements in mood symptoms were also observed, as measured by
the HAM-D-21 and YMRS. In the lower dose group of the two dose-level study (6 mg/day with option to
reduce to 3 mg/day), paliperidone extended-release tablets were not significantly different from placebo as measured by the PANSS.
Taking the results of both studies together, paliperidone extended-release tablets improved the symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region. There were insufficient data to explore differential effects based on race.
ink on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-3978-93
NDC 0378-3978-77
NDC 0378-3978-05
The 3 mg tablets are white, film-coated, round, unscored tablets imprinted with M over PD3 in black ink
on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-3979-93
NDC 0378-3979-77
NDC 0378-3979-05
The 6 mg tablets are light beige, film-coated, round, unscored tablets imprinted with M over PD6 in
black ink on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-3980-93
NDC 0378-3980-77
NDC 0378-3980-05
The 9 mg tablets are pink, film-coated, round, unscored tablets imprinted with M over PD9 in black ink
on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-3981-93
NDC 0378-3981-77
NDC 0378-3981-05
Storage and Handling: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from moisture.
Keep out of reach of children.
Paliperidone Extended-release Tablets are available containing 1.5 mg, 3 mg, 6 mg or 9 mg of paliperidone.
The 1.5 mg tablets are brown, film-coated, round, unscored tablets imprinted with M over PD1 in black
Physicians are advised to discuss the following issues with patients for whom they prescribe paliperidone extended-release tablets.
17.1 Orthostatic Hypotension
Patients should be advised that there is risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)].
As paliperidone extended-release tablets have the potential to impair judgment, thinking, or motor skills,
patients should be cautioned about operating hazardous machinery, including automobiles, until they
are reasonably certain that paliperidone extended-release tablets therapy does not affect them adversely [see Warnings and Precautions (5.11)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with paliperidone extended-release tablets [see Use in Specific Populations (8.1)].
17.4 Nursing
Caution should be exercised when paliperidone extended-release tablets are administered to a nursing
woman. The known benefits of breastfeeding should be weighed against the unknown risks of infant
exposure to paliperidone [see Use in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription
or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking paliperidone extended-release tablets [see Drug
Interactions (7.1)].
17.7 Heat Exposure and Dehydration
Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see
17.8 Administration
Patients should be informed that paliperidone extended-release tablets should be swallowed whole with
the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with
insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool [see Dosage and Administration (2.3)].
REVISED FEBRUARY 2015
PALIER:R2
Page 10 of 10
• Known hypersensitivity to any component of this product (4, 6.2)
-------------------------------- WARNINGS AND PRECAUTIONS ---------------------------------• Products Containing Same Active Ingredient: Patients receiving risedronate sodium
delayed-release tablets should not be treated with risedronate sodium tablets (5.1)
• Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing
instructions. Discontinue use if new or worsening symptoms occur (5.2)
• Hypocalcemia may worsen and must be corrected prior to use (5.3)
• Osteonecrosis of the Jaw has been reported (5.4)
• Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop (5.5,
6.2)
• Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should
be evaluated to rule out a femoral fracture (5.6)
These highlights do not include all the information needed to use risedronate sodium tablets
safely and effectively. See Full Prescribing Information for risedronate sodium tablets.
RISEDRONATE sodium tablets, USP for oral use
------------------------------------ RECENT MAJOR CHANGES ----------------------------------Contraindications (4)
03/2015
Warnings and Precautions (5.4)
04/2015
----------------------------------- INDICATIONS AND USAGE -----------------------------------Risedronate sodium tablets, USP are a bisphosphonate indicated for:
• Treatment and prevention of postmenopausal osteoporosis (1.1)
• Treatment to increase bone mass in men with osteoporosis (1.2)
• Treatment and prevention of glucocorticoid-induced osteoporosis (1.3)
• Treatment of Paget’s disease (1.4)
Limitations of Use
Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use. (1.5)
------------------------------------- ADVERSE REACTIONS -------------------------------------Most common adverse reactions reported in greater than 10% of patients treated with risedronate and with a higher frequency than placebo are: back pain, arthralgia, abdominal pain,
and dyspepsia (6.1)
Hypersensitivity reactions (angioedema, generalized rash, bullous skin reactions, Stevens-Johnson
syndrome, and toxic epidermal necrolysis), and eye inflammation (iritis, uveitis) have been reported
rarely (6.2)
-------------------------------- DOSAGE AND ADMINISTRATION --------------------------------Treatment of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week, 75 mg two consecutive days each month, 150 mg once-a-month (2.1)
Prevention of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week (2.2)
Men with Osteoporosis: 35 mg once-a-week (2.3)
Glucocorticoid-Induced Osteoporosis: 5 mg daily (2.4)
Paget’s Disease: 30 mg daily for 2 months (2.5)
Instruct patients to:
• Swallow tablet whole with 6 to 8 ounces of plain water, at least 30 minutes before the first
food, beverage, or medication of the day
• Avoid lying down for 30 minutes (2)
• Take supplemental calcium and vitamin D if dietary intake is inadequate (2.7)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals, Inc. at
-------------------------------------- DRUG INTERACTIONS -------------------------------------Calcium, antacids, or oral medications containing divalent cations interfere with the absorption of risedronate (7.1)
------------------------------- USE IN SPECIFIC POPULATIONS --------------------------------Risedronate is not recommended for use in patients with severe renal impairment (creatinine
clearance less than 30 mL/min) (5.6, 8.6, 12.3)
Risedronate is not indicated for use in pediatric patients (8.4)
------------------------------- DOSAGE FORMS AND STRENGTHS -------------------------------Tablets: 5 mg, 30 mg, 35 mg, 75 mg and 150 mg (3)
REVISED JUNE 2015
RISE:R4mh/MG:RISE:R1mh
------------------------------------- CONTRAINDICATIONS --------------------------------------• Abnormalities of the esophagus which delay esophageal emptying such as stricture or
achalasia (4, 5.1)
• Inability to stand or sit upright for at least 30 minutes (4, 5.1)
• Hypocalcemia (4, 5.2)
1
2
1.1 Postmenopausal Osteoporosis
1.2 Osteoporosis in Men
1.3 Glucocorticoid-Induced Osteoporosis
1.4 Paget’s Disease
1.5 Important Limitations of Use
2.1 Treatment of Postmenopausal Osteoporosis
2.2 Prevention of Postmenopausal Osteoporosis
2.3 Treatment to Increase Bone Mass in Men with
Osteoporosis
2.4 Treatment and Prevention of GlucocorticoidInduced Osteoporosis
2.5 Treatment of Paget’s Disease
2.7 Recommendations for Calcium and Vitamin D
Supplementation
2.8 Administration Instructions for Missed Doses
5.8
5.9
Glucocorticoid-Induced Osteoporosis
Laboratory Test Interactions
6
ADVERSE REACTIONS
6.1 Clinical Studies Experience
7
DRUG INTERACTIONS
7.1 Calcium Supplements/Antacids
7.2 Hormone Replacement Therapy
7.3 Aspirin/Nonsteroidal Anti-Inflammatory Drugs
7.4 H2 Blockers and Proton Pump Inhibitors (PPIs)
8
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
3
11 DESCRIPTION
4
CONTRAINDICATIONS
5
5.1 Drug Products with the Same Active Ingredient
5.2 Upper Gastrointestinal Adverse Reactions
5.3 Mineral Metabolism
5.4 Jaw Osteonecrosis
5.5 Musculoskeletal Pain
5.6 Atypical Subtrochanteric and Diaphyseal Femoral
Fractures
14 CLINICAL STUDIES
14.1 Treatment of Osteoporosis in Postmenopausal Women
1
14.2
14.3
14.4
14.5
Prevention of Osteoporosis in Postmenopausal Women
Men with Osteoporosis
Glucocorticoid-Induced Osteoporosis
Treatment of Paget’s Disease
*Sections or subsections omitted from the Full Prescribing Information
are not listed.
•
1
1.1 Postmenopausal Osteoporosis
Risedronate sodium tablets, USP are indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, risedronate
reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [see Clinical Studies (14.1, 14.2)].
1.2 Osteoporosis in Men
Risedronate sodium tablets are indicated for treatment to increase bone mass in men with
osteoporosis.
Risedronate sodium tablets are indicated for the treatment and prevention of glucocorticoidinduced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate
amounts of calcium and vitamin D.
1.4 Paget’s Disease
Risedronate sodium tablets are indicated for treatment of Paget’s disease of bone in men and
women.
1.5 Important Limitations of Use
The optimal duration of use has not been determined. The safety and effectiveness of risedronate sodium tablets for the treatment of osteoporosis are based on clinical data of 3 years
duration. All patients on bisphosphonate therapy should have the need for continued therapy
re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for
drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have
their risk for fracture re-evaluated periodically.
•
•
•
•
2
2.1 Treatment of Postmenopausal Osteoporosis
[See Indications and Usage (1.1).]
The recommended regimen is:
•
one 5 mg tablet orally, taken daily or
•
one 35 mg tablet orally, taken once-a-week or
•
one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each
month or
•
one 150 mg tablet orally, taken once-a-month
2.2 Prevention of Postmenopausal Osteoporosis
•
one 5 mg tablet orally, taken daily or
•
one 35 mg tablet orally, taken once-a-week or
•
alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two
tablets each month may be considered or
•
alternatively, one 150 mg tablet orally, taken once-a-month may be considered
2.3 Treatment to Increase Bone Mass in Men with Osteoporosis
•
one 35 mg tablet orally, taken once-a-week
2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
•
one 5 mg tablet orally, taken daily
2.5 Treatment of Paget’s Disease
The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment
may be considered (following post-treatment observation of at least 2 months) if relapse
occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the
dose and duration of therapy are the same as for initial treatment. No data are available on
more than one course of retreatment.
Instruct patients to do the following:
•
Take risedronate sodium tablets at least 30 minutes before the first food or drink of the
day other than water, and before taking any oral medication or supplementation,
including calcium, antacids, or vitamins to maximize absorption and clinical benefit,
[see Drug Interactions (7.1)]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium.
•
Swallow risedronate sodium tablets whole with a full glass of plain water (6 to 8 ounces).
Avoid lying down for 30 minutes after taking the medication [see Warnings and Precautions (5.1)]. Do not chew or suck the tablet because of a potential for oropharyngeal
ulceration.
•
Do not eat or drink anything except plain water, or take other medications for at least
30 minutes after taking risedronate sodium tablets.
2.7 Recommendations for Calcium and Vitamin D Supplementation
Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium tablets.
2.8 Administration Instructions for Missed Doses
Instruct patients about missing risedronate sodium tablet doses as follows:
•
If a dose of risedronate sodium 35 mg once-a-week is missed:
3
•
•
•
•
•
Take 1 tablet on the morning after they remember and return to taking 1 tablet
once-a-week, as originally scheduled on their chosen day.
• Do not take 2 tablets on the same day.
If one or both tablets of risedronate sodium 75 mg on two consecutive days per month
are missed, and the next month’s scheduled doses are more than 7 days away:
• If both tablets are missed, take one risedronate sodium 75 mg tablet in the morning after the day it is remembered and then the other tablet on the next consecutive morning.
• If only one risedronate sodium 75 mg tablet is missed, take the missed tablet in
the morning after the day it is remembered.
• Return to taking their risedronate sodium 75 mg tablets on two consecutive days
per month as originally scheduled.
• Do not take more than two 75 mg tablets within 7 days.
If one or both tablets of risedronate sodium 75 mg on two consecutive days per month
are missed, and the next month’s scheduled doses are within 7 days:
• Wait until their next month’s scheduled doses and then continue taking risedronate
sodium 75 mg tablets on two consecutive days per month as originally scheduled.
If the dose of risedronate sodium 150 mg once-a-month is missed, and the next
month’s scheduled dose is more than 7 days away:
• Take the missed tablet in the morning after the day it is remembered and then
return to taking their risedronate sodium 150 mg tablet once-a-month as originally
scheduled.
• Do not take more than one 150 mg tablet within 7 days.
If the dose of risedronate sodium 150 mg once-a-month is missed, and the next
month’s scheduled dose is within 7 days:
• Wait until their next month’s scheduled dose and then continue taking risedronate
sodium 150 mg tablet once-a-month as originally scheduled.
5 mg tablets are light beige, film-coated, round, unscored tablets debossed with M on
one side of that tablet and 44 on the other side.
30 mg tablets are white, film-coated, round, unscored tablets debossed with M on one
side of the tablet and 114 on the other side.
35 mg tablets are light orange, film-coated, round, unscored tablets debossed with M
on one side of the tablet and 714 on the other side.
75 mg tablets are pink, film-coated, round, unscored tablets debossed with M on one
side of the tablet and 727 on the other side.
150 mg tablets are light blue, film-coated, round, tablets debossed with M over RE on
one side of the tablet and 150 on the other side.
4
CONTRAINDICATIONS
Risedronate sodium tablets are contraindicated in patients with the following conditions:
•
Abnormalities of the esophagus which delay esophageal emptying such as stricture or
achalasia [see Warnings and Precautions (5.1)]
•
Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration
(2), Warnings and Precautions (5.1)]
•
Hypocalcemia [see Warnings and Precautions (5.2)]
•
Known hypersensitivity to risedronate sodium tablets or any of its excipients. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported [see Adverse Reactions (6.2)]
5
5.1 Drug Products with the Same Active Ingredient
Risedronate sodium tablets contain the same active ingredient found in risedronate sodium
delayed-release tablets. A patient being treated with risedronate sodium delayed-release
tablets should not receive risedronate sodium tablets.
5.2 Upper Gastrointestinal Adverse Reactions
Risedronate, like other bisphosphonates administered orally, may cause local irritation of the
upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for
worsening of the underlying disease, caution should be used when risedronate is given to
patients with active upper gastrointestinal problems (such as known Barrett’s esophagus,
dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers) [see Contraindications
(4), Adverse Reactions (6.1), Information for Patients (17.1)].
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation,
have been reported in patients receiving treatment with oral bisphosphonates. In some cases,
these have been severe and required hospitalization. Physicians should therefore be alert to
any signs or symptoms signaling a possible esophageal reaction and patients should be
instructed to discontinue risedronate and seek medical attention if they develop dysphagia,
odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie
down after taking oral bisphosphonates and/or who fail to swallow it with the recommended
full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates after
developing symptoms suggestive of esophageal irritation. Therefore, it is very important that
the full dosing instructions are provided to, and understood by, the patient [see Dosage and
Administration (2)]. In patients who cannot comply with dosing instructions due to mental
disability, therapy with risedronate should be used under appropriate supervision.
There have been postmarketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in
controlled clinical trials.
5.3 Mineral Metabolism
Hypocalcemia has been reported in patients taking risedronate. Treat hypocalcemia and other
2
Table 1. Adverse Events Occurring at a Frequency Greater than or Equal to 5% in Either
Treatment Group Combined Phase 3 Postmenopausal Osteoporosis Treatment Trials
disturbances of bone and mineral metabolism before starting risedronate therapy. Instruct
patients to take supplemental calcium and vitamin D if their dietary intake is inadequate.
Adequate intake of calcium and vitamin D is important in all patients, especially in patients
with Paget’s disease in whom bone turnover is significantly elevated [see Contraindications
(4), Adverse Reactions (6.1), Information for Patients (17.1)].
5.4 Jaw Osteonecrosis
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with
tooth extraction and/or local infection with delayed healing, and has been reported in
patients taking bisphosphonates, including risedronate. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental
implants, boney surgery), diagnosis of cancer, concomitant therapies (for example,
chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid
disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk
assessment.
Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive
care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on
individual benefit/risk assessment [see Adverse Reactions (6.2)].
5.5 Musculoskeletal Pain
In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [see Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had
recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
Consider discontinuing use if severe symptoms develop.
5.6 Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just
below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in
orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal or no trauma to the affected
area. They may be bilateral and many patients report prodromal pain in the affected area,
usually presenting as dull, aching thigh pain, weeks to months before a complete fracture
occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (for example, prednisone) at the time of fracture.
Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain
should be suspected of having an atypical fracture and should be evaluated to rule out an
incomplete femur fracture. Patients presenting with an atypical fracture should also be
assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
Risedronate is not recommended for use in patients with severe renal impairment (creatinine
clearance less than 30 mL/min).
Before initiating risedronate treatment for the treatment and prevention of glucocorticoidinduced osteoporosis, the sex steroid hormonal status of both men and women should be
ascertained and appropriate replacement considered.
5.9 Laboratory Test Interactions
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with risedronate have not been performed.
Body System
Body as a Whole
Infection
Back Pain
Accidental Injury
Pain
Abdominal Pain
Flu Syndrome
Headache
Asthenia
Neck Pain
Chest Pain
Allergic Reaction
Cardiovascular System
Hypertension
Digestive System
Constipation
Diarrhea
Dyspepsia
Nausea
Metabolic & Nutritional Disorders
Peripheral Edema
Musculoskeletal System
Arthralgia
Arthritis
Traumatic Bone Fracture
Joint Disorder
Myalgia
Bone Pain
Nervous System
Dizziness
Depression
Insomnia
Respiratory System
Bronchitis
Sinusitis
Rhinitis
Pharyngitis
Increase Cough
Skin and Appendages
Rash
Special Senses
Cataract
Urogenital System
Urinary Tract Infection
Placebo
N = 1,619
%
5 mg Risedronate
N = 1,613
%
29.9
26.1
16.8
14
9.9
11.6
10.8
4.5
4.7
5.1
5.9
31.1
28
16.9
14.1
12.2
10.5
9.9
5.4
5.4
5
3.8
9.8
10.5
12.6
10
10.6
11.2
12.9
10.8
10.8
10.5
8.8
7.7
22.1
10.1
12.3
5.3
6.2
4.8
23.7
9.6
9.3
7
6.7
5.3
5.7
6.1
4.6
7.1
6.8
5
10.4
9.1
5.1
5
6.3
10
8.7
6.2
6
5.9
7.1
7.9
5.7
6.5
10.4
11.1
Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and risedronate 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10% versus
10.8%), dyspepsia (10.6% versus 10.8%) and gastritis (2.3% versus 2.7%). Duodenitis and
glossitis have been reported uncommonly in the risedronate 5 mg daily group (0.1% to 1%).
In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and risedronate 5 mg daily
groups.
Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and risedronate 5 mg daily groups were: back pain (26.1% versus 28%), arthralgia (22.1% versus
23.7%), myalgia (6.2% versus 6.7%) and bone pain (4.8% versus 5.3%).
Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline
in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory
increases in serum PTH levels (less than 30%) were observed within 6 months in patients in
osteoporosis clinical trials treated with risedronate 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and risedronate 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18
patients, nine (0.5%) in each treatment arm (placebo and risedronate 5 mg once daily).
Serum phosphorus levels below 2 mg/dL were observed in 14 patients, three (0.2%) treated
with placebo and 11 (0.6%) treated with risedronate 5 mg once daily. There have been rare
reports (less than 0.1%) of abnormal liver function tests.
Endoscopic Findings: In the risedronate clinical trials, endoscopic evaluation was encouraged
in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the
blind. Endoscopies were performed on equal numbers of patients between the placebo and
treated groups [75 (14.5%) placebo; 75 (11.9%) risedronate]. Clinically important findings
(perforations, ulcers, or bleeding) among this symptomatic population were similar between
groups (51% placebo; 39% risedronate).
Once-a-Week Dosing: The safety of risedronate 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing risedronate 5 mg daily and risedronate 35 mg once-a-week in postmenopausal
women aged 50 to 95 years. The duration of the trials was one year, with 480 patients
6
ADVERSE REACTIONS
6.1 Clinical Studies Experience
Treatment of Postmenopausal Osteoporosis: Daily Dosing: The safety of risedronate 5 mg
once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85
years with postmenopausal osteoporosis. The duration of the trials was up to 3 years, with
1619 patients exposed to placebo and 1613 patients exposed to risedronate 5 mg. Patients
with pre-existing gastrointestinal disease and concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up
to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at
baseline.
The incidence of all-cause mortality was 2% in the placebo group and 1.7% in the risedronate 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the risedronate 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in
the risedronate 5 mg group. The most common adverse reactions reported in greater than
10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1
lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in
greater than or equal to 5% of patients. Adverse events are shown without attribution of
causality.
3
and 1.4% of patients on risedronate 150 mg once-a-month.
Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with
risedronate 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively).
The risedronate 150 mg once-a-month group resulted in a higher incidence of discontinuation
due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0%) compared
to the risedronate 5 mg daily regimen. All of these events occurred within a few days of the
first dose. The incidence of vomiting that led to discontinuation was the same in both groups
(0.3% versus 0.3%).
Ocular Adverse Events: None of the patients treated with risedronate 150 mg once-a-month
reported ocular inflammation such as uveitis, scleritis, or iritis; two patients treated with risedr

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