Keeping up with Diclegis®: a story of rumors, scandal and fame

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January 15, 2016
Keeping up with Diclegis®: a story of rumors,
scandal and fame
Objectives
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To define and understand nausea and vomiting of pregnancy (NVP)
To review current treatment guidelines for NVP
To discuss pharmacological and pharmaceutical characteristics of Diclegis®
To understand why Diclegis® is first-line by examining the available evidence and history
To evaluate the safety and efficacy of Diclegis®
To define and discuss the determinants of a teratogenic medication
To explore the social and legal aspects of the scandal behind Diclegis®’ predecessor, Bendectin®
Diclegis: a story of rumors, scandal and fame
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January 15, 2016
Introduction
“OMG. Have you heard about this? As you guys know my #morningsickness has been pretty bad. I tried changing
things about my lifestyle, like my diet, but nothing helped, so I talked to my doctor. He prescribed me #Diclegis, and I
felt a lot better and most importantly, it’s been studied and there was no increased risk to the baby. I’m so excited
and happy with my results that I’m partnering with Duchesnay USA to raise awareness about treating morning
sickness. If you have morning sickness, be safe and sure to ask your doctor about the pill with the pregnant woman
on it and find out more www.diclegis.com; www.DiclegisImportantSafetyInfo.com.”
Background1,2,3,4
Definition of nausea and vomiting of pregnancy (NVP)
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Nausea and vomiting of pregnancy (NVP), also known as “morning sickness,” is a common condition that
affects the health of the pregnant woman and her fetus.
It can diminish the woman’s quality of life and contributes to health care costs and time lost from work.
Symptoms can happen at any time of the day but are most common in the mornings. They are manifested
before 9 weeks of gestation and usually during the 5th week of gestation and lasts through week 20 with
peak symptoms occurring between weeks 10 and 16 and resolution at weeks 12 and 18.
NVP, if left untreated, can progress to hyperemesis gravidarum (HG), an extreme spectrum of NVP with an
incidence of 0.3-3% of pregnancies. It is the most common indication for hospital admission during the first
trimester and second to preterm labor as the most common reason during the entire pregnancy.
Epidemiology
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Prevalence rates for nausea is 50-80% and for vomiting and retching is 50%.
An estimated 50% of pregnant women have nausea and vomiting, 25% have nausea only, and 25% are
unaffected.
Risk Factors
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Increased placental mass: advanced molar gestation, multiple gestation
Family history or history from previous pregnancy
Etiology
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Manifestation of psychopathology: response to stress
Evolutionary adaptation: protect the woman and fetus from dangerous foods
Hormones: human chorionic gonadotropin (hCG) and estrogen
Diagnosis
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There have been attempts to categorize severity of NVP according to the duration and amount of vomiting
per day, however, they have not been clinically useful.
Diagnosis is dependent on the timing of the initial symptoms and differential diagnosis by ruling out other
possible causes of nausea and vomiting:
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1) Gastrointestinal conditions: gastroenteritis, gastroparesis, hepatitis, peptic ulcer disease, pancreatitis,
appendicitis
2) Genitourinary tract conditions: pyelonephritis, uremia, kidney stones
3) Metabolic conditions: diabetic ketoacidosis, hyperthyroidism
4) Neurologic disorders: pseudomotor cerebri, vestibular lesions, migraine
5) Miscellaneous conditions: drug toxicity or intolerance, psychologic conditions
6) Pregnancy-related conditions: acute fatty liver of pregnancy, preeclampsia
Treatment Guidelines2,3
The woman’s perception of the severity of her symptoms, her desire for treatment, and the potential effect of
treatment on her fetus are more influential when making clinical decisions.
Early treatment of NVP is recommended to prevent progression to hyperemesis gravidarum.
Prevention
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Women taking multivitamins at the time of conception were less likely to need medical attention for
vomiting in two studies
Taking prenatal vitamins for 3 months before conception may reduce the incidence and severity of NVP
Non-pharmacologic Treatment
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Rest and avoidance of sensory stimuli such as odors, heat, humidity, noise
Frequent, small meals every 1-2 hours
Avoiding spicy or fatty foods
Eating bland or dry foods, high-protein snacks, and crackers in the morning
Ginger has been found to significantly improve symptoms in some studies
Pharmacologic Treatment
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First-line agents: pyridoxine (vitamin B6) or pyridoxine plus doxylamine (Diclegis®)
[Diclegis® - pyridoxine plus doxylamine]
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Components:
Doxylamine: H1-receptor antagonist of the ethanolamine class [which other ones are in this class?]
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Vitamin B6 or pyridoxine: water-soluble vitamin and prodrug metabolized in the liver
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Pharmacokinetics:
Half-life: 12.5 hours and 0.5 hours for doxylamine and pyridoxine, respectively
Tmax: 7.5 hours and 5.5 hours for doxylamine and pyridoxine, respectively (not affected by multiple dosing)
Absorbed in the jejunum
Administration of food delays absorption of both compounds
Both metabolized in the liver and excreted by the kidney
Indication:
For the treatment of pregnancy-induced nausea/vomiting unresponsive to lifestyle modifications and other
conservative methods in adult females
For early pregnancy, up to 14 weeks
Not studied in females younger than 18 years old
Dosing:
Each tablet contains 10mg of doxylamine and 10mg of pyridoxine
Day 1: two tablets by mouth on an empty stomach at bedtime, continue same regimen if NVP controlled
Day 2 (if symptoms persist): two tablets at bedtime
Day 3 (if symptoms persist): one tablet in the morning and two tablets at bedtime, continue this regimen if
NVP controlled
Day 4 (if symptoms uncontrolled): one tablet in the morning, one in the mid-afternoon and two at bedtime
Do not exceed 4 tablets a day
Do not take them as needed; must be taken on a daily basis
Hepatic adjustment may be needed since doxylamine is extensively metabolized in the liver
No renal adjustment needed
Alternative agents (limited safety and efficacy evidence):
Comparison and Characteristics
Drug
Metoclopramide
Ondansetron
Methylprednisolone
MOA
Side Effects
Blocks dopamine and
Tardive dyskinesia, drowsiness,
serotonin receptors in
xerostomia, persistent
chemoreceptor trigger zone ketonuria more common than
of CNS
ondansetron
Pregnancy Category
Comments
Some studies show similar efficacy in
reducing nausea and vomiting symptoms
B
when compared to ondansetron
B; possible association to oral
Better at controlling vomiting than
Headache, drowsiness, fatigue, clefts and cardiac anomalies metoclopramide and more effective than
constipation, QT prolongation
during first trimester
doxylamine plus pyridoxine
Selective 5-HT3-receptor
antagonist
Regulate gene expression
after binding to intracellular
Numerous endocrine,
C; three studies with
Dosing regimen: 16mg TID PO/IV for 3 days
receptors and translocating metabolic, cardiovascular, CNS, confirmed association to oral and taper dose over 2 weeks; reserved as
to the nucleus
GI side effects
clefts
last-resort treatment
History2,5
Bendectin®: the predecessor
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1956: first available in the market as a triple combination of doxylamine, dicyclomine and pyridoxine
1976: dicyclomine removed from the combination due to lack of efficacy as an antiemetic
1983: voluntary withdrawal by the manufacturer over allegation of possible teratogenicity
From 1958-1983, 25-30% of all pregnant women received it
Analysis from this period indicates hospital admissions due to hyperemesis gravidarum decreased and
increased back up as soon as it was discontinued
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Bendectin®: courtroom drama
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What are the characteristics of an agent that is teratogenic in humans?
1) Epidemiology studies consistently demonstrate an increase in the frequency of congenital
malformations, and especially a recognizable syndrome in the exposed population
2) Secular trend analysis reveals that the frequency of congenital malformations is associated with changes
in population exposure
3) An animal model has been developed that is similar to the reports in the human and can be produced
with pharmacokinetically equivalent exposures
4) In the animal model, the frequency and severity of the teratogenesis and/or embryopathology increases
with a dose or exposure that is within the range of human exposures
5) The teratogenic effect is consistent with the basic principles of embryology and teratology and does not
contradict biologic principles or biologic common sense
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Allegations of teratogenic effects
Scientists failed in their role as objective experts; lack of scientific analysis, review or research in support of
their theories
Fraud and partisan testimony
Stewart Newman, one of plaintiff’s experts stated, “Bendectin at a concentration of 10mg/L, drastically
curtails the formation of embryonic cartilage, the tissue that forms the primordial of embryonic cartilage.”
This concentration is 500 times the blood level achieved with Bendectin therapy and abnormal cartilage is
not the cause of limb reduction defects
Primary Literature #1
McKeigue PM, Lamm SH, Linn S, et al. Bendectin and birth defects: a meta-analysis of the epidemiologic
studies. Teratology. 1994;50:27-37.
Objective:
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To conduct a meta-analysis of the 16 cohort and 11 case-control studies that report birth defects from
Bendectin®-exposed pregnancies
Inclusion criteria:
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Studies that reported the birth defect information for live births in groups with reported Bendectin® use
Definitions:
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Events under study: most studies included all births or all pregnancies lasting longer than 20-28 weeks but
three studies only included live births
Exposure: consumption of Bendectin® or its local equivalent during the first trimester
Cases: all malformations or all major malformations noted in the birth records
Non-cases: non-malformed births
Methods and Statistics:
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A 2x2 table was developed for each study on the distribution of malformations among the Bendectin®exposed and unexposed births
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Table 1: 2x2 Table Template for Each Study
Exposed
Malformations
(A) Malformed at
birth and exposed to
Bendectin®
No malformations
(C) Not malformed at
birth and exposed to
Bendectin®
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Unexposed
(B) Malformed at birth
and not exposed to
Bendectin®
(D) Not malformed at
birth and not exposed
to Bendectin®
The odds ratio (OR) for the prevalence of malformation in exposed infants compared with unexposed
infants was calculated:
OR = (A)(D) / (B)(C)
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The data from these studies were pooled using the Mantel-Haenszel method and under the assumption that
the studies’ events, definition of exposure and cases were the same
As for the variables for analysis in the studies, the authors chose the alternative least favorable to the drug in
order to avoid failure of detecting association of Bendectin® to any malformations
The tables were tested for heterogeneity of the odds ratios by the Breslow-Day test
Studies that reported data for specific categories of malformation, separate tables were assembled for each
specific malformation (e.g., cardiac defects, central nervous system defects, neural tube defects limb
reduction defects, oral clefts, genital tract malformations)
Confidence intervals for the odds ratios were calculated by the exact method with mid-P adjustment
Tables for specific malformations were tested for heterogeneity of the odds ratios by Zelen’s exact test and
estimated the P values using the Monte Carlo method
Results [REFER TO APPENDIX A FOR INDIVIDUAL CATEGORIES OF ORGAN SYSTEMS]:
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Table 3 is comprised of data from 16 studies from which total malformation rates were calculated
Ten of the studies have OR of less than 1; six of the studies have OR greater than 1
Eleven of the 16 studies have results sufficiently strong to rule out a two-fold risk
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Ten of the studies are able to rule out a two-fold protection
None of the individual studies showed a significant association between Bendectin® exposure and the risk of
all malformations combined
A Breslow-Day test for heterogeneity showed consistency with the assumption that all studies were
measuring the same relative risk
Table 4 is a series of meta-analysis of the data on specific categories of defect
Among the 72 2x2 tables, there were four positive associations and three negative associations
 Cardiac: one positive and one negative
 Oral clefts: one positive and one negative
 Pyloric stenosis: two positive
 Central nervous system defects: one negative
The Zelen test for heterogeneity demonstrated the absence of significant heterogeneity for each
malformation except for oral clefts and pyloric stenosis
Table 2: Pooled Data and Values for Specific Malformations
Defects
Cardiac
Central Nervous System
Neural Tube
Limb Reduction
Genital Tract
Oral Cleft
Pyloric Stenosis
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Pooled Odds Ratio
0.9
1
0.99
1.12
0.98
0.81
1.04
95% CI
0.77-1.05
0.83-1.20
0.76-1.29
0.83-1.48
0.79-1.22
0.64-1.03
0.85-1.29
P Value
0.15
0.2
0.14
0.63
0.29
0.009
0.004
In summary, meta-analysis of the data from the published Bendectin® studies has shown no evidence of any
increased prevalence of birth defect among those who were exposed during the first trimester
Primary Literature #2
Koren G, Clark S, Hankins GD, et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea
and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol 2010;203:571.e1-7.
Objective:
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To evaluate the effectiveness of Diclectin® as compared with placebo for nausea and vomiting of pregnancy
Methods:
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Randomized, double-blind, multicenter placebo controlled trial
Pregnant women suffering from nausea and vomiting of pregnancy, analyzed by intention to treat
Women received Diclectin® (n=131) or placebo (n=125) for 14 days
Symptoms were evaluated daily using the pregnancy unique quantification of emesis (PUQE) scale
Dosing method was the same as Diclegis® mentioned previously
15-day study where telephone contact was made on days 2, 6, 12 and 14 to assess subject diary information,
adverse events (AEs), concomitant medications and compliance
Patients returned to the clinic in the morning prior to their morning dose on day 4, 8 and 15 to collect diary
report and complete all study-related data
A follow-up phone call was conducted 30 days after last dosing to capture any serious AEs for patients
completing the treatment period or early termination
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At the end, patients were offered compassionate use of the product they were assigned to
Inclusion Criteria:
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≥18 years of age
Gestational age range of 7-14 weeks
PUQE score ≥6
Not responded to conservative management consisting of dietary and lifestyle advice
Exclusion Criteria:
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Women treated with other antiemetics
Chronic medical conditions
Could not communicate in either English or Spanish
Primary Endpoint:
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Change from baseline in the 2 domains of the PUQE score (number of daily vomiting episodes, daily retching,
length of daily nausea in hours, overall score of symptoms rated from 3-15)
Secondary Endpoint:
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Day-by-day area under the curve for change in PUQE from baseline, time loss from employment, number of
women in each arm who continued with compassionate use of their medication
Number of patients who reported concurrent use of alternate therapy for NVP (nutritional modifications,
teas, aromatherapy, massage, yoga)
Statistical Analysis:
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280 patients were enrolled to achieve 200 evaluable patients based on some recent studies testing the
effect of ginger or vitamin B6 on “nausea score”
Intent to treat group differences for continuous demographic variables at baseline were examined by
analysis of variance (ANOVA) for unpaired results or by Mann-Whitney U test
Categorical variables such as race and ethnicity were examined by Pearson’s X2 test or Fisher’s exact test
Primary and secondary endpoints analysis was done using an ANCOVA model
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AEs experienced by the subjects which occurred on or after day 1 through day 15 were compared between
groups using Pearson’s X2 test or Fisher’s exact test
Results:
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After written informed consent, 280 women were randomly assigned to either Diclectin® or placebo
7 subjects assigned to Diclectin® and 12 assigned to placebo withdrew their consent before receiving a single
dose of study medication, leaving 133 and 128 in each group, respectively
The two groups did not differ in any demographic or medical characteristics
Diclectin® led to significantly greater improvement in NVP symptoms as compared with placebo and also
resulted in a larger improvement in the global assessment of well-being score
There was a trend toward more time lost from employment in the placebo group
More women receiving Diclectin® asked to continue compassionate use of their medication
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Significantly more women on placebo resorted to alternate therapies for NVP symptoms
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The use of Diclectin® was not associated with an increased rate of any AEs as compared with the placebo
group
Primary Literature #3
Koren G, Clark S, Hankins GD, et al. Maternal safety of the delayed-release doxylamine and pyridoxine
combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial. BMC Pregnancy
and Childbirth. 2015;15(59):1-6.
Objective:
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To evaluate the maternal safety of Diclegis® in treating NVP compared to placebo
Methods:
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Same as the previous study
The frequency and severity of all AEs were tabulated by treatment group, system organ class, preferred term
severity, and relationship to study drug
Statistical Analysis:
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The available sample size has 80% power to show a doubling in central nervous system (CNS) depression
with alpha of 5%
Results [REFER TO APPENDIX B]:
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The active drug was not associated with increased rates of symptoms known to be associated with
antihistamines, such as sedation, symptoms of CNS depression and gastrointestinal or anticholinergic
symptoms
It was also not associated with either more frequently occurring adverse events or with an increase in
Treatment Emergent Adverse Events (TEAEs)
Conclusion
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Combination product of doxylamine and pyridoxine is the safest and the most studied agent in the
market for the treatment of nausea and vomiting of pregnancy
Recommendation
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Combination product of delayed-release doxylamine and pyridoxine is recommended in mothers
whose symptoms of NVP are not improved with lifestyle modifications alone and this can be
administered safely without any major risk to the infant and the mother
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Appendix A
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Appendix B
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References
1. U.S. Food and Drug Administration, Department of Health & Human Services, Office of Prescription
Drug Promotion. Diclegis NDA 021876 warning letter.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementAc
tivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM457961
.pdf. Accessed November 4, 2015.
2. U.S. Government Publishing Office. Electronic Code of Regulations. http://www.ecfr.gov/cgibin/text-idx?SID=a4d6997375d19c2ba29066bbb1407767&mc=true&node=pt21.4.202&rgn=div5.
Accessed January 8, 2016.
3. Nausea and vomiting of pregnancy. Practice Bulletin No. 153. American College of Obstetricians and
Gynecologists. Obstet Gynecol. 2015;126:e12-24.
4. Diclegis® [package insert]. Bryn Mawr, PA: Duchesnay USA, Inc; 2013.
5. Ward KE, O’Brien BM. Chapter 61. Pregnancy and Lactation: Therapeutic Considerations. In: DiPiro
JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic
Approach, 9e. New York, NY: McGraw-Hill; 2014.
http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=689&Sectioni
d=45310514. Accessed December 24, 2015.
6. Brent RL. Bendectin: review of the medical literature of a comprehensively studied human
nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol. 1995;9(4):337-349.
7. McKeigue PM, Lamm SH, Linn S, et al. Bendectin and birth defects: a meta-analysis of the
epidemiologic studies. Teratology. 1994;50:27-37.
8. Koren G, Clark S, Hankins GD, et al. Effectiveness of delayed-release doxylamine and pyridoxine for
nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol
2010;203:571.e1-7.
9. Koren G, Clark S, Hankins GD, et al. Maternal safety of the delayed-release doxylamine and
pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled
trial. BMC Pregnancy and Childbirth. 2015;15(59):1-6.
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