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

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January 15, 2016

Diclegis: a story of rumors, scandal and fame 1

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

Objectives

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®

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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)

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

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

Increased placental mass: advanced molar gestation, multiple gestation

Family history or history from previous pregnancy

Etiology

Manifestation of psychopathology: response to stress

Evolutionary adaptation: protect the woman and fetus from dangerous foods

Hormones: human chorionic gonadotropin (hCG) and estrogen

Diagnosis

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:

http://www.diclegis.com/

http://www.diclegisimportantsafetyinfo.com/

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January 15, 2016


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

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

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

First-line agents: pyridoxine (vitamin B6) or pyridoxine plus doxylamine (Diclegis®)

[Diclegis® - pyridoxine plus doxylamine] Components:

Doxylamine: H1-receptor antagonist of the ethanolamine class [which other ones are in this class?]

Vitamin B6 or pyridoxine: water-soluble vitamin and prodrug metabolized in the liver

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January 15, 2016


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

History2,5

Bendectin®: the predecessor

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

Drug MOA SideEffects PregnancyCategory Comments

Metoclopramide

Blocksdopamineand

serotoninreceptorsin

chemoreceptortriggerzone

ofCNS

Tardivedyskinesia,drowsiness,

xerostomia,persistent

ketonuriamorecommonthan

ondansetron B

Somestudiesshowsimilarefficacyin

reducingnauseaandvomitingsymptoms

whencomparedtoondansetron

Ondansetron Selective5-HT3-receptor

antagonist

Headache,drowsiness,fatigue,

constipation,QTprolongation

B;possibleassociationtooral

cleftsandcardiacanomalies

duringfirsttrimester

Betteratcontrollingvomitingthan

metoclopramideandmoreeffectivethan

doxylaminepluspyridoxine

Methylprednisolone

Regulategeneexpression

afterbindingtointracellular

receptorsandtranslocating

tothenucleus

Numerousendocrine,

metabolic,cardiovascular,CNS,

GIsideeffects

C;threestudieswith

confirmedassociationtooral

clefts

Dosingregimen:16mgTIDPO/IVfor3days

andtaperdoseover2weeks;reservedas

last-resorttreatment

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January 15, 2016


Bendectin®: courtroom drama

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

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:

To conduct a meta-analysis of the 16 cohort and 11 case-control studies that report birth defects from Bendectin®-exposed pregnancies

Inclusion criteria:

Studies that reported the birth defect information for live births in groups with reported Bendectin® use

Definitions:

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:

A 2x2 table was developed for each study on the distribution of malformations among the Bendectin®-exposed and unexposed births

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January 15, 2016


Table 1: 2x2 Table Template for Each Study Exposed Unexposed

Malformations (A) Malformed at birth and exposed to Bendectin®

(B) Malformed at birth and not exposed to Bendectin®

No malformations (C) Not malformed at birth and 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)

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]:

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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January 15, 2016


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 Pooled Odds Ratio 95% CI P Value

Cardiac 0.9 0.77-1.05 0.15

Central Nervous System 1 0.83-1.20 0.2

Neural Tube 0.99 0.76-1.29 0.14

Limb Reduction 1.12 0.83-1.48 0.63

Genital Tract 0.98 0.79-1.22 0.29

Oral Cleft 0.81 0.64-1.03 0.009

Pyloric Stenosis 1.04 0.85-1.29 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


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:

To evaluate the effectiveness of Diclectin® as compared with placebo for nausea and vomiting of pregnancy

Methods:

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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January 15, 2016


At the end, patients were offered compassionate use of the product they were assigned to

Inclusion Criteria:

≥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:

Women treated with other antiemetics

Chronic medical conditions

Could not communicate in either English or Spanish

Primary Endpoint:

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:

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:

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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January 15, 2016


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:

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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January 15, 2016


Significantly more women on placebo resorted to alternate therapies for NVP symptoms

The use of Diclectin® was not associated with an increased rate of any AEs as compared with the placebo

group


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:

To evaluate the maternal safety of Diclegis® in treating NVP compared to placebo

Methods: 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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January 15, 2016


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]:

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

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

• 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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January 15, 2016


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/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM457961.pdf. Accessed November 4, 2015.

2. U.S. Government Publishing Office. Electronic Code of Regulations. http://www.ecfr.gov/cgi-bin/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&Sectionid=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.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM457961.pdf



http://www.ecfr.gov/cgi-bin/text-idx?SID=a4d6997375d19c2ba29066bbb1407767&mc=true&node=pt21.4.202&rgn=div5



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