All rights r Copyright © 2009 McMahon Publishing Gr eserved. Repr

This Special Report
is supported by
a grant from
BROUGHT
TO
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BY
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DISCLAIMER:
This monograph is designed
to be a summary of information. While it is detailed, it is
not an exhaustive clinical
review. McMahon Publishing,
Takeda, and the authors
neither affirm nor deny the
accuracy of the information
contained herein. No liability
will be assumed for the use of
this special report, and the
absence of typographical
errors is not guaranteed.
Readers are strongly urged to
consult any relevant primary
literature. Copyright © 2009,
McMahon Publishing, 545
West 45th Street, New York,
NY 10036. Printed in the USA.
All rights reserved, including
the right of reproduction, in
whole or in part, in any form.
Susan Lucak, MD
Assistant Professor of Clinical Medicine
Division of Digestive and Liver Disease
Columbia University Medical Center
New York, New York
d.
John F. Johanson, MD, MSc, FACP, FACG
Beloit Clinic
Beloit, Wisconsin
Clinical Associate Professor of Medicine
University of Illinois College of Medicine
Rockford, Illinois
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Distributed by
McMahon Publishing
Management of
Irritable Bowel
Syndrome With
Constipation in
Adult Women
Introduction
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Irritable bowel syndrome (IBS) is a multisymptomatic disorder characterized by abdominal pain associated with altered bowel habits.1 According to the Rome III
diagnostic criteria, IBS consists of recurrent abdominal
pain or discomfort that is associated with 2 or more of
the following characteristics: improvement with defecation, onset associated with a change in stool frequency, or onset associated with a change in stool form.
Symptoms must have occured at least 3 or more days
per month in the last 3 months with symptom onset ≥6
months prior to diagnosis. In this article, we will discuss means of enhancing management of constipation-predominant IBS (IBS-C) in adult women, including
improvement of the clinician–patient relationship, as
well as treatment with an FDA-approved option for management of global symptoms of IBS-C.2 Global symptoms include “abdominal discomfort/pain,” “bowel
habits,” and “other IBS symptoms.”
IBS-C is one of 3 subtypes of IBS designated by
the Rome III criteria for Functional Bowel Disorders
and is defined as IBS plus the occurrence of hard or
lumpy stools in ≥25% of bowel movements and loose
or watery stools in <25% of bowel movements in the
absence of the use of antidiarrheals or laxatives (Figure 1).1 In addition to the symptoms of abdominal pain
and altered bowel habits, more than 60% of patients
may also present with non-GI symptoms.3
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In the absence of an identified biologic marker for
IBS-C, diagnostic assessment relies on recognition of
the symptoms of abdominal pain, bowel habits, and
stool form and their timing in relation to each other.1,5
The American Gastroenterological Association recommends a thorough history and physical examination,
identifying patients with symptoms outlined in the Rome
III Criteria, and then ruling out other potential causes of
the symptoms.6 Patients should be screened for alarm
signs such as anemia, weight loss, and a family history of colon cancer, inflammatory bowel disease, or celiac disease, as any of these may indicate the presence
of other disease states.6,7 In addition to the history and
physical examination, asking the patient to maintain a
symptom diary may aid in the diagnosis of IBS-C.6
In the absence of alarm signs and symptoms, constipation is a prominent and defining feature of IBS-C, and
it may be challenging to differentiate between IBS-C and
chronic constipation (CC). The characteristics of the 2
conditions are somewhat similar, with symptoms varying in intensity along a spectrum of abdominal pain/
discomfort and stool frequency. Abdominal pain is the
primary differentiating factor, being more pronounced
in IBS-C than in CC.8 Frequency of bowel movements
is more likely to be reduced in patients with CC than in
patients with IBS-C, whereas Rome III defines IBS-C by
stool form rather than reduced frequency.1,8
With symptom-defined conditions such as IBS-C, the
importance of an effective clinician–patient relationship cannot be overstated. A patient-centered model
of communication engages the patient in open-ended
dialogue and includes him or her in a collaborative process regarding disease management. Reviews of literature on patient-centered communication have found
this model may help improve patient outcomes, including patient satisfaction, adherence to treatment, and
patient health.9,10 The patient-centered model is also
associated with increased efficiency of care in terms of
fewer diagnostic tests and referrals.11 Thus, it is recommended that such an approach be adopted when interacting with patients, especially those who may suffer
from functional bowel disorders such as IBS-C.
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Figure 1. Rome III diagnostic criteria for IBS-C.
The Importance of the Clinician–Patient
Relationship
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• Recurrent abdominal pain or discomfort associated with ≥2 of the following:
• Improvement with defecation
• Onset associated with a change in stool
frequency
• Onset associated with a change in stool form
(appearance)
• Symptoms occurring ≥3 days per month in the
last 3 months; symptom onset ≥6 months prior to
diagnosis
• Hard or lumpy stools in ≥25% of bowel movements
• Loose or watery stools in <25% of bowel
movements
2
Recognition of IBS-C
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Rome III Diagnostic Criteria for IBS-C
Adapted from Longstreth GW, et al.1
According to one community survey, 4.3% of the US
population is diagnosed with IBS-C, while 15% of individuals have IBS-C without being formally diagnosed.4
A
Developing this collaborative relationship may be
complicated, given that patients do not always describe
their symptoms clearly and effectively. Consequently,
it can be helpful if the clinician not only listens closely
during the patient history, but also encourages discussion. This may involve asking specific questions about
what led the patient to seek treatment at this particular point, how the symptoms are affecting the patient’s
ability to function and participate in daily activities, and
what expectations the patient has from the clinician.10
At a minimum, it is recommended that the clinician
acknowledge the patient’s pain, provide empathy, and
educate the patient about the condition, including possible triggers and available treatment options, in order
to determine an appropriate treatment approach for
his or her symptoms. Education about the condition
should be provided in a manner that allows patients to
assertively discuss their symptoms and related issues
with their clinician. The patient experience is likely to be
significantly improved if the patient is included in the
discussion of available treatment options and establishment of realistic therapeutic goals. Furthermore, a
long-term relationship with appropriate follow-up care
is recommended.10
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AMITIZA for Treatment of IBS-C in Adult Women
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AMITIZA is a selective chloride channel activator
approved by the FDA for treatment of IBS-C in women
≥18 years of age at a dose of 8 mcg twice daily taken
with food and water.2 AMITIZA is contraindicated in
patients with known or suspected mechanical gastrointestinal obstruction. Patients with symptoms suggestive of mechanical gastrointestinal obstruction should
be evaluated prior to initiating AMITIZA therapy.
The mechanism of action of AMITIZA in the treatment of IBS-C is not fully understood, but a relationship
between chloride channel activation and restoration of
tight junctions of gastrointestinal epithelial cells has
been hypothesized based on animal studies. AMITIZA
selectively activates type 2 chloride channels, leading
to the secretion of chloride into the intestinal lumen,
which is followed by sodium ions and water.2,13 Tight
junctions between cells act as gatekeepers for solutes and macromolecules passing between the apical and basolateral regions of the gut.14 Damaged or
compromised tight junctions are associated with leaking of luminal contents through the mucosal barrier.14,15
Activation of type 2 chloride channels by AMITIZA has
been shown to stimulate recovery of mucosal barrier function via the restoration of tight junction protein
complexes in an isolated ischemic porcine intestine
model.2,14 It is important to note, however, that the role
of tight junctions in IBS-C is unclear at this time.
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Treatment Options for IBS-C
C-2 chloride channel activators/AMITIZA® (lubiprostone) (Grade 1B); psychological therapies (Grade 1C);
and diet, fiber, bulking agents, laxatives, antispasmodics, peppermint oil, and probiotic therapy (Grade 2C).
AMITIZA, a selective type 2 chloride channel activator, is currently the only widely available FDA-approved
option for treatment of IBS-C in women age 18 years of
age and older. AMITIZA was found to be more effective than placebo and received a 1B rating, which is a
strong recommendation with moderate evidence in the
systematic review.
AMITIZA Clinical Trials
In a multicenter, double-blind, placebo-controlled
Phase II dose-ranging study, 195 patients with IBS-C
were randomized to receive placebo, AMITIZA 8 mcg
twice daily, AMITIZA 16 mcg twice daily, or AMITIZA 24
mcg twice daily.16 Levels of improvement in the primary end point of abdominal pain/discomfort were similar
across treatment groups, but a dose–response effect
was noted with regard to the incidence of adverse
events (AEs). The dose of 8 mcg, twice daily was
therefore determined to offer the best combination of
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IBS-C is considered difficult to treat because of
its multiple triggers, variable clinical course, and the
unpredictable nature and severity of its symptoms.12 In
addition, the number of therapies available to manage
the condition is limited.
Traditionally, treatment has included a combination of diet and lifestyle modifications, pharmacologic
agents, and other therapeutic interventions to address
the multitude of symptoms. Efficacy among these treatments varies widely, and although many of these remedies are currently used in clinical practice to treat
IBS-C, they are not approved by the Food and Drug
Administration (FDA) for the treatment of IBS-C.
A systematic review on the management of IBS was
recently published by the American College of Gastroenterology Task Force on IBS.7 Therapies that are frequently used for management of patients with IBS-C
were evaluated based on available published clinical
evidence. Evidence levels were graded according to
the strength of the recommendation and the quality of
evidence: strong and weak recommendations are indicated with a 1 or 2, respectively, and high, moderate,
or low quality of evidence is indicated by an A, B, or
C, respectively. Some examples of the treatment ratings are 5-HT4 receptor agonists (Grade 1A); selective
3
20
Placebo
P=0.029
18
P=0.023
AMITIZA
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(n=193) (n=390)
(n=192) (n=379)
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Phase III-1
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7.8%
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Response Rates (%)
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Phase III-2
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Figure 2. For all populations analyzed, the proportion of overall responders in the
AMITIZA group was significantly greater than the proportion in the placebo group.2
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4
test prior to beginning therapy with AMITIZA and should
be capable of complying with effective contraceptive
measures.
The primary efficacy end point was assessed weekly via electronic diaries based on patient response to a
global symptom relief question.2 Subjects were asked,
“How would you rate your relief of IBS symptoms
(abdominal discomfort/pain, bowel habits, and other
IBS symptoms) over the past week compared to how
you felt before you entered the study?” and responded
based on a 7-point balanced scale from “significantly
worse” to “significantly better.”2,17 The primary efficacy
analysis in the Phase III trials compared the proportion
of “overall responders” in each arm. To be considered
an overall responder, subjects were required to meet
the criteria for being designated a monthly responder
in at least 2 of the 3 months while on study. Monthly
responder was defined as a patient who had reported
“significantly relieved” for at least 2 weeks of the month
or at least “moderately relieved” in all 4 weeks of that
month. Patients were considered nonresponders for
the monthly evaluation period if they reported “moderately worse” or “significantly worse” relief, reported an
increased use of rescue medication, or if they discontinued due to a lack of efficacy.
Figure 2 represents the overall responder rates in
the two Phase III trials. The percentage of patients in
the Phase III-1 study meeting the criteria for overall
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tolerability and efficacy.
Two multicenter, double-blind, randomized, controlled
Phase III trials were conducted to evaluate the efficacy
and safety of AMITIZA 8 mcg twice daily for the treatment of IBS-C.2,17 The studies had a total intent-to-treat
population of 1154 men and women aged ≥18 years
who fulfilled modified Rome II criteria for IBS-C. IBS
was defined as abdominal pain or discomfort occurring over at least 6 months with 2 or more of the following: 1) relieved with defecation; 2) onset associated
with a change in stool frequency; and 3) onset associated with a change in stool form. Patients were subtyped as having IBS-C if they also experienced 2 or 3
of the following: 1) <3 spontaneous bowel movements
per week, 2) >25% hard stools, and 3) >25% spontaneous bowel movements associated with straining. After
a 4-week baseline/washout period, patients were randomized to receive placebo or AMITIZA 8 mcg twice
daily for 12 weeks.
The two Phase III controlled trials comprised 97 (8.4%)
male patients, which is insufficient to determine whether men with IBS-C respond differently to AMITIZA than
women.2 For this reason, AMITIZA is indicated for adult
women with IBS-C. The safety of AMITIZA in pregnancy
has not been evaluated in humans. AMITIZA should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who could
become pregnant should have a negative pregnancy
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responder was 13.8% in the AMITIZA-treatment group
compared to 7.8% of the placebo group.2 In the Phase
III-2 study, 12.1% of patients in the AMITIZA-treatment
group were overall responders compared to 5.7% in
the placebo group. The difference was statistically significant in both studies 1 and 2 (P<0.05).
One of the Phase III studies also assessed the
rebound effect from the withdrawal of AMITIZA 8 mcg
twice daily. Following 12 weeks of treatment, withdrawal of AMITIZA did not result in a rebound effect.2
Patients taking AMITIZA may experience nausea.
Concomitant administration of food with AMITIZA may
reduce the occurrence of nausea.3 AMITIZA should not
be prescribed to patients who have severe diarrhea.
Patients should be aware of the possible occurrence of
diarrhea during treatment with AMITIZA. Patients taking AMITIZA may experience dyspnea within 1 hour of
the first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing. Some
patients have discontinued therapy because of dyspnea. Patients on treatment with AMITIZA who experience severe nausea, diarrhea, or dyspnea should
inform their healthcare provider.
In the clinical trials for IBS-C, AMITIZA was generally well tolerated. Table 1 notes the adverse events
that occurred in ≥1% of patients who were treated with
AMITIZA 8 mcg twice daily and that occurred more frequently with AMITIZA than with placebo.2 These data
are compiled from patients enrolled in the Phase II dosefinding study as well as the two Phase III studies: 1011
patients with IBS-C treated with AMITIZA 8 mcg twice
daily for up to 12 months and 435 patients who received
placebo twice daily for up to 16 weeks. These events
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Other Pharmacologic Agents for IBS-C
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only included those possibly or probably related to treatment, as assessed by the investigator. The most common adverse events in the AMITIZA 8 mcg twice-daily
arm versus placebo were nausea (8% vs 4%), diarrhea
(7% vs 4%), and abdominal pain (5% vs 5%).
In the two 12-week studies, 4.7% of patients taking AMITIZA (n=832) discontinued treatment due to
an adverse event compared with 6% of patients taking placebo (n=435).18 In a 36-week open-label safety
study, adverse events reported were similar to those in
Phase III controlled studies. In this study, 4.8% of
patients taking AMITIZA (n=520) discontinued treatment due to an adverse event.
One other agent has been approved by the FDA for
treatment of IBS-C. Zelnorm® (tegaserod) is a 5-HT4
(serotonin) agonist that was demonstrated to be more
effective than placebo in relieving global IBS symptoms in female IBS-C patients.19 Due to postmarketing safety concerns, however, Zelnorm was withdrawn
from the market in 2007 and is now available only for
emergency use through the FDA.20
Emerging Agents for IBS-C
There are 2 investigational drugs currently in clinical
trials for treatment of IBS-C. Linaclotide is a guanylate
cyclase type C agonist in Phase III trials for treatment
of IBS-C and CC.21 Pumosetrag, previously known
as DPP733, is a partial 5-HT3 agonist and is currently being evaluated for treatment of IBS-C in Phase IIb
trials.22
Table 1. Percentage of Patients Experiencing Adverse Reactions
in AMITIZA Phase II/III IBS-C Trials2
Incidence of Adverse Reactions ≥1%
Placebo
n=435 up to 16 weeks
Nausea
8%
4%
Diarrhea
7%
4%
Abdominal pain
5%
5%
Abdominal
distension
3%
2%
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AMITIZA 8 mcg Twice Daily
n=1011 through 1 year*
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Adverse Event
12- to 16-week double-blind studies and a 36-week open-label study.
5
Conclusion
References
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Management of IBS-C has often been suboptimal
because of a poor understanding of its etiology and
pathophysiology, underdiagnosis of the condition, and
a lack of widely available treatments with indications
specific to IBS-C. In addition to the benefits that may
be achieved through better understanding and awareness of this condition, improvement in the clinician–
patient dialogue regarding symptoms and their impact
on patients’ daily lives will enhance management. Both
clinicians and patients need to recognize the variable
symptoms of IBS-C and develop a collaborative relationship that emphasizes empathy, full disclosure from
both parties, establishment of realistic treatment plans,
and appropriate follow-up care for better management
of symptoms.
Currently, AMITIZA is the only widely available FDAapproved option for management of IBS-C in adult
women. Clinical evidence from controlled Phase III trials
demonstrates that AMITIZA, at a dose of 8 mcg twice
daily, is more effective than placebo in this patient population. In a recent evidence-based, systematic review
on the management of IBS conducted by the American College of Gastroenterology, AMITIZA received
a grade 1B rating, which is a strong recommendation
with moderate evidence. Development of new therapeutic agents may increase the number of therapeutic
options for patients with IBS-C in the future.
1. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller
RC. Functional bowel disorders. Gastroenterology. 2006;130:1480-1491.
2. AMITIZA [package insert]. Bethesda, MD: Sucampo Pharmaceuticals,
Inc.; 2008.
3. Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the alternating
bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol. 2005;100:896-904.
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4. Hungin APS, Chang L, Locke GR, Dennis EH, Barghout V. Irritable bowel
syndrome in the United States: prevalence, symptom patterns and
impact. Aliment Pharmacol Ther. 2005;21:1365-1375.
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5. Lembo TJ, Fink RN. Clinical Assessment of IBS. J Clin Gastroenterol.
2002:35:S31-S36.
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Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based systemic review on the management of irritable bowel syndrome. American
College of Gastroenterology Task Force on IBS. Am J Gastroenterol.
2009;104:S1-S35.
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6. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical
review on irritable bowel syndrome. Gastroenterology. 2002;123:21082131.
8. Brandt LJ, Prather CM, Quigley EMM, Schiller LR, Schoenfeld P, Talley
NJ. Systematic review on the management of chronic constipation in
North America. Am J Gastroenterol. 2005;100:S5-S22.
9. Charlton CR, Dearing KS, Berry JA, Johnson MJ. Nurse practitioners’
communication styles and their impact on patient outcomes: an integrated literature review. J Am Acad Nurse Pract. 2008;20:382-388.
10. Drossman DA. The functional gastrointestinal disorders and the Rome III
process. Gastroenterology. 2006;130:1377-1390.
11. Stewart M, Brown JB, Donner A, et al. The impact of patient-centered
care on outcomes. J Fam Pract. 2000;49:796-804.
12. Frissora CL. Nuances in treating irritable bowel syndrome. Rev Gastroenterol Disord. 2007;7:89-96.
13. Montrose MH, Keely SJ, Barrett KE. Electrolyte secretion and absorption:
small intestine and colon. In: Yamada T, ed. Textbook of Gastroenterology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:308-340.
14. Moeser AJ, Nighot PK, Engelke JK, Ueno R, Bliksglager AT. Recovery of
mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone. Am
J Physiol Gastrointest Liver Physiol. 2007;292:G647-G656.
15. Camilleri M, Gorman H. Intestinal permeability and irritable bowel syndrome. Neurogastroenterol Motil. 2007;19:545-552.
16. Johanson JF, Drossman DA, Panas R, Wahle A, Ueno R. Clinical trial:
phase 2 trial of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2008;27:685-696.
17. Drossman DA, Chey W, Panas R, et al. Lubiprostone significantly
improves symptom relief rates in adults with irritable bowel syndrome
and constipation (IBS-C): Data from two twelve-week, randomized, placebo-controlled, double-blind trials. Gastroenterology. 2007;132:25862587.
18. Sucampo Pharmaceuticals, Inc. Data on file.
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19. Spiller R, Aziz Q, Creed F, et al. Guidelines on the irritable bowel syndrome: Mechanisms and practical management. Gut. 2007;56:17701798.
d.
20. Zelnorm (tegaserod maleate) information page. US Food and Drug
Administration. www.fda.gov/cder/drug/infopage/zelnorm/default.htm.
Accessed January 17, 2009.
21. Gastrointestinal Program. Ironwood Pharmaceuticals. www.ironwoodpharma.com/gastrointestinal.php. Accessed January 17, 2009.
22. Dynogen product pipeline: GI disorders. Dynogen Pharmaceuticals.
www.dynogen.com/pipeline_gi.htm. Accessed January 17, 2009.
6
Indication
Author Disclosure
AMITIZA® (lubiprostone) is indicated for the treatment of Irritable Bowel Syndrome With Constipation (8
mcg twice daily) in women ≥18 years old.
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Important Safety Information
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• AMITIZA is contraindicated in patients with
known or suspected mechanical gastrointestinal obstruction. Patients with symptoms suggestive of mechanical gastrointestinal obstruction
should be thoroughly evaluated by the treating
healthcare provider to confirm the absence of
such an obstruction prior to initiating AMITIZA
treatment.
• The safety of AMITIZA in pregnancy has not
been evaluated in humans. AMITIZA should be
used during pregnancy only if the benefit justifies the potential risk to the fetus. Women who
could become pregnant should have a negative
pregnancy test prior to beginning therapy with
AMITIZA and should be capable of complying
with effective contraceptive measures.
• Patients taking AMITIZA may experience nausea.
If this occurs, concomitant administration of food
with AMITIZA may reduce symptoms of nausea.
Patients who experience severe nausea should
inform their healthcare provider.
• AMITIZA should not be prescribed to patients
that have severe diarrhea. Patients should be
aware of the possible occurrence of diarrhea during treatment and inform their healthcare provider if the diarrhea becomes severe.
• Patients taking AMITIZA may experience dyspnea within an hour of first dose. This symptom
generally resolves within three hours, but may
recur with repeat dosing. Patients who experience dyspnea should inform their healthcare provider. Some patients have discontinued therapy
because of dyspnea.
• In clinical trials of AMITIZA (8 mcg twice daily vs
placebo; N=1,011 vs N=435) in patients with Irritable Bowel Syndrome with Constipation, the most
common adverse reactions (incidence >4%)
were nausea (8% vs 4%), diarrhea (7% vs 4%),
and abdominal pain (5% vs 5%).
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Dr. Lucak has served as a consultant or speaker
for Prometheus Laboratories; Salix; Forest Laboratories; and Takeda Pharmaceuticals North America,
Inc. She has received other financial or material support from Novartis.
Dr. Johanson has served as a consultant or speaker for Boehringer Ingelheim; Epix Pharmaceuticals;
Kellogg’s; Salix; Schering Plough; Sucampo Pharmaceuticals, Inc.; Takeda Pharmaceuticals North
America, Inc.; and Theravance. He has received
other financial support from Sucampo Pharmaceuticals, Inc.
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Please see attached complete Prescribing Information.
AMITIZA is a registered trademark of Sucampo
Pharmaceuticals, Inc.
LUB-02113
7
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d.
SR0897
8