Pyridoxine/doxylamine (Returning to the US market as Diclegis; formerly Bendectin in the US; Debendox in the UK; Lenotan and Merbental in other countries and currently available in Canada as Diclectin) is a combination of pyridoxine hydrochloride (vitamin B6) and doxylamine succinate prescribed for the management of nausea and vomiting of pregnancy or morning sickness.
The combination of pyridoxine, more commonly referred to as vitamin B6 and doxylamine, an antihistamine, marketed as Diclectin in Canada and Diclegis in the USA, is prescribed for the management of nausea and vomiting of pregnancy.
A randomized, double-blind, placebo-controlled study demonstrated that the combination of 10 mg of pyridoxine and 10 mg of doxylamine in a delayed-release tablet is effective in reducing symptoms of nausea and vomiting of pregnancy.
Doxylamine and pyridoxine are currently referenced as pregnancy compatible drugs (Drugs in Pregnancy and Lactation 10th Edition), consistent with FDA’s safety assessment of the combination Product. Diclegis(Diclectin) has been categorized by the FDA as a category A drug (no evidence of risk to the fetus). This letter classification system for risk in pregnancy is no longer being utilized and is currently being phased out by the FDA.
Medical organizations’ position
The American Congress of Obstetricians and Gynecologists (ACOG) states that the recommendation of “taking Vitamin B6 or Vitamin B6 plus doxylamine is safe and effective and should be considered a first-line treatment” is based on consistent scientific evidence. This recommendation has been evaluated by the US Department of Health and Human Services’ Agency for Healthcare Research and Quality, who concur that the benefit of implementing the guideline recommendations would be a reduction on nausea and vomiting of pregnancy. The Society of Obstetricians and Gynaecologists of Canada (SOGC) published a Clinical Practice Guideline on the management of nausea and vomiting of pregnancy in which it states that the “doxylamine/pyridoxine combination should be the standard of care, since it has the greatest evidence to support its efficacy and safety”. The Motherisk Program, an internationally recognized teratogen information center located at the Hospital for Sick Children in Toronto, published a Current Practice Update for the treatment of nausea and vomiting of pregnancy. This updated algorithm recommends the combination of 10 mg of doxylamine and 10 mg of pyridoxine as first-line therapy for the management of nausea and vomiting of pregnancy.
Safety in pregnancy
Due to the extensive scientific evidence demonstrating that there is no difference in the risk for birth defects or other adverse pregnancy outcomes between infants whose mothers take pyridoxine/doxylamine during pregnancy and those infants whose mothers do not take this drug combination, the two ingredients of the drug are considered Pregnancy compatible (or category A drugs with the previous pregnancy risk factor classification system).
Since the mid-1950s, over 33 million women have used the combination drug of pyridoxine/doxylamine in pregnancy, and scientific analysis on more than 200,000 exposed pregnancies has been conducted to determine if the combination of pyridoxine and doxylamine is harmful to the unborn baby. No epidemiological studies have found any teratogenic effect.
Two separate meta-analyses have been conducted that have assessed pregnancy outcomes following the use of a combination of pyridoxine and doxylamine with or without dicyclomine during the first trimester of pregnancy. The initial meta-analysis, published in 1988, combined data from 12 cohort and 5 case-control studies, and the subsequent meta-analysis, published in 1994, combined data from 16 cohort studies and 11 case control studies. These studies included over 200,000 Bendectin-exposed pregnancies and did not observe an increased risk for major malformations. Separate analyses were conducted for specific defects including cardiac defects, limb reduction defects, oral clefts, and genital tract malformations; no increased risks for these defects were found.
In 1989, a report on the safety of the drug combination of pyridoxine/doxylamine for use in the management of NVP was prepared by a panel of Canadian and American experts for the Special Advisory Committee on Reproductive Physiology to the Health Protection Branch of Health Canada (currently called the Health Products and Food Branch). These scientific experts concluded that “numerous studies in animals and in humans that have been reported in the scientific and medical literature demonstrate that Bendectin is not a teratogen.The safety of Bendectin/Diclectin in the management of nausea and vomiting of pregnancy has been established by its use in many thousands of pregnant women”.
A study was conducted to determine whether the combination drug of pyridoxine and doxylamine had an effect on the neurodevelopment of children exposed in utero. Results from this study observed no difference in intelligence quotient scores between children who were exposed to pyridoxine/doxylamine in utero and children who were not exposed.
The most commonly reported adverse reaction of doxylamine is drowsiness. Other adverse drug reactions associated with doxylamine succinate may include: vertigo, nervousness, epigastric pain, headache, palpitation, diarrhea, disorientation, irritability, convulsions, urinary retention or insomnia.
It is not recommended to take doxylamine with other medications of the same class, medications that act on the central nervous system (CNS) or with alcohol as this may increase the risk of adverse effects. To minimize the risk of particular adverse effects, doxylamine should not be used when taking any medication classified as a monoamine oxidase inhibitor (MAOI), and should be used with caution, if at all, when certain medical conditions are present.
Because doxylamine is small enough on a molecular weight basis to pass into breastmilk, women should not breastfeed while using products with doxylamine as this may lead to adverse effects in the breastfed infant.
The combination of doxylamine and vitamin B6 was first introduced to the US market as Bendectin in 1956. At that time, Bendectin was a 3 ingredients prescription medication. The third one, dicyclomine, a Pregnancy Category B anticholinergic/antispasmodic, was omitted from the formulation starting in 1976 due to its lack of efficacy. Bendectin (doxylamine/vitamine B6) was voluntarily removed from the market in 1983 by its manufacturer, Merrell Dow Pharmaceuticals, following numerous lawsuits alleging that it caused birth defects, although an FDA panel concluded that no association between Bendectin and birth defects had been demonstrated. In litigation, Bendectin was supposed to cause all kinds of fetal malformations and problems including limb and other musculoskeletal deformities, facial and brain damage, defects of the respiratory, gastrointestinal, cardiovascular and genital-urinary systems, blood disorders and cancer. The most famous case involving the drug is Daubert v. Merrell Dow Pharmaceuticals (1993). These suits were led by celebrity plaintiff attorney Melvin Belli . The star witness for the case against Bendectin, William McBride, was later found to have falsified research on teratogenic effects of the drug, and was struck off the medical register in Australia.
An extensive review of the evidence submitted in legal proceedings regarding Bendectin has been summarized and found no evidence that the drug in clinical use was linked to birth defects.
The FDA, in 1999, published a statement in the Federal Register that summarized their opinion regarding the safety of pyridoxine/doxylamine during pregnancy: “The FDA has determined that the drug product Bendectin, a tablet composed of pyridoxine hydrochloride 10 mg, and doxylamine succinate 10 mg, for the prevention of nausea of pregnancy was not withdrawn from the market for reasons of safety or effectiveness”.
On Monday April 8, 2013, the FDA approved the return of the doxylamine-pyridoxine combination under the new trademark name of Diclegis. The medication is manufactured by Duchesnay Inc.
In July 2015, the drug company came under considerable scrutiny for promoting its drug through the American celebrity Kim Kardashian through the social media platforms Facebook and instagram.
In October 2015, Toronto, Canada physicians Drs. Navindra Persaud, Jessica Chin, and Mark Walker wrote a public letter to the Journal of Obstetrics and Gynaecology of Canada and raised concerns over the risks of Diclectin and recommended reconsidering it as the "first-line pharmacological treatment" against the nausea and vomiting of pregnancy. Dr. Persaud shared with news agencies that his only source of research data for this drug came from Health Canada and claimed he was only able to access the document by signing a confidentiality agreement.
Society and culture
The Bendectin case, and the subsequent removal of the drug from the US market, has had a number of consequences. Firstly, there was an immediate increase in the rates of hospitalization for nausea and vomiting in pregnancy. Secondly, it created a treatment void in terms of having a safe medication that could be used for alleviating morning sickness in US pregnant women, a condition which, in the most severe from, called hyperemesis gravidarum, could be both life-threatening and cause women to teminate their pregnancy.
The lack of availability of a safe and effective drug for the treatment of nausea and vomiting of pregnancy resulted in the use of other, less studied drugs in pregnancy. Thirdly, it has been claimed that subsequent to the Bendectin experience, drug companies stayed away from developing medications for pregnant patients. As a result, only a few medications were approved by the FDA for obstetrical indications in the past several decades. Lastly, the perception that all medications are teratogenic increased among pregnant women and healthcare professionals. The unfounded fear of using medications during pregnancy has orphaned many women from receiving the appropriate treatment they require. Leaving medical conditions untreated during pregnancy can result in adverse pregnancy outcomes or significant morbidity for both the mother and baby. Ongoing education of physicians and the general public has resulted in improvements in the perception of medication use in pregnancy; however, further advances are required to overcome the devastating effects of the Bendectin saga.
From a legal perspective, the case through Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993) set a new standard for admitting expert testimony in federal courts in lieu of the Frye standard.
- Koren, G.; Clark, S.; Hankins, G. D. V.; Caritis, S. N.; Miodovnik, M.; Umans, J. G.; Mattison, D. R. (2010). "Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: A randomized placebo controlled trial". American Journal of Obstetrics and Gynecology 203 (6): 571.5e1–7. doi:10.1016/j.ajog.2010.07.030. PMID 20843504. edit
- Briggs GG, Freeman RK. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition. 2015. Published by: Wolters Kluwer Health.
- US Food and Drug Administration. Labelling Pregnancy and Lactation Final Rule as seen in : http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm
- American College of Obstetricians and Gynecologists (ACOG). Nausea and vomiting of pregnancy. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2004 Apr. 13 p. (ACOG practice bulletin; no. 52)
- The National Guideline Clearinghouse. Guideline Summary NGC-5719. Nausea and vomiting of pregnancy. 2007. Available at: http://www.guideline.gov/content.aspx?id=10939
- Arsenault MY, Lane CA, MacKinnon CJ, Bartellas E, Cargill YM, Klein MC, Martel MJ, Sprague AE, Wilson AK. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can. 2002 Oct;24(10):817-31; quiz 832-3. Available at: http://www.sogc.org/guidelines/public/120E-CPG-October2002.pdf
- Einarson, A; Maltepe, C; Boskovic, R; Koren, G (Dec 2007). "Treatment of nausea and vomiting in pregnancy: an updated algorithm". Can Fam Physician 53 (12): 2109–11.
- Kutcher, J. S.; Engle, A.; Firth, J.; Lamm, S. H. (2003). "Bendectin and birth defects II: Ecological analyses". Birth Defects Research Part A: Clinical and Molecular Teratology 67 (2): 88–97. doi:10.1002/bdra.10034. PMID 12769504.
- Einarson, T. R.; Leeder, J. S.; Koren, G. (1988). "A method for meta-analysis of epidemiological studies". Drug intelligence & clinical pharmacy 22 (10): 813–824. PMID 3229352.
- McKeigue, P. M.; Lamm, S. H.; Linn, S.; Kutcher, J. S. (1994). "Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies". Teratology 50 (1): 27–37. doi:10.1002/tera.1420500105. PMID 7974252.
- Ornstein, M.; Einarson, A.; Koren, G. (1995). "Bendectin/diclectin for morning sickness: A Canadian follow-up of an American tragedy". Reproductive toxicology (Elmsford, N.Y.) 9 (1): 1–6. doi:10.1016/0890-6238(94)00050-7. PMID 8520127.
- Nulman, I.; Rovet, J.; Barrera, M.; Knittel-Keren, D.; Feldman, B. M.; Koren, G. (2009). "Long-term Neurodevelopment of Children Exposed to Maternal Nausea and Vomiting of Pregnancy and Diclectin". The Journal of Pediatrics 155 (1): 45–50, 50.e1–2. doi:10.1016/j.jpeds.2009.02.005. PMID 19394042.
- A Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine. "Front Matter." Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press, 1998
- Diclectin Product Monograph (2011). Available on Health Canada’s Drug Product Database at: http://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp
- American Society of Health-System Pharmacists (AHFS) Drug Information 2014, Antihistamine Drugs. pgs 1-8.
- Jane E. Brody (1983-06-19). "Shadow of Doubt Wipes Out Bendectin". New York Times.
- Korcok M (November 1980). "The Bendectin debate". Canadian Medical Association Journal 123 (9): 922–8. PMC 1704894. PMID 7437993.
- Thalidomide hero found guilty of scientific fraud — Article published in "New Scientist" on 27 February 1991
- Thalidomide doctor guilty of medical fraud — Article published in "The Independent" on 20 February 1993
- Brent RL. "Bendectin: Review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen" (PDF). Reproductive Toxicology, Vol. 9, No. 4, pp. 337-349, 1995.
- Kroll, David (July 31, 2015). "The Kim Kardashian-Endorsed Morning Sickness Drug Is The Real Deal". Forbes. Retrieved 15 October 2015.
- "Kim Kardashian drug endorsement may break Canadian law: experts". Yahoo news. 7 Aug 2015. Retrieved 15 October 2015.
- Rinkunas, Susan (19 July 2015). "How Safe Is the Morning-Sickness Drug Diclegis?". New York Magazine. Retrieved 15 October 2015.
- Blackwell, Tom (11 August 2015). "FDA lashes out at drug company for promoting Canadian morning-sickness pill on Kardashian Instagram feed". National Post. Retrieved 15 October 2015.
- "Kim Kardashian's social media posts for morning-sickness violate drug promotion rules: FDA". Canadian Broadcasting Corporation. The Associated Press. 11 August 2015. Retrieved 15 October 2015.
- Persaud, N; Chin, J; Walker, M (April 2014). "Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy?". Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC 36 (4): 343–8. doi:10.1016/s1701-2163(15)30611-3. PMID 24798673.
- Brent R. "Medical, social, and legal implications of treating nausea and vomiting of pregnancy" Am J Obstet Gynecol 2002 May;186(5 Suppl Understanding):S262-6
- Kutcher, JS; Engle, A; Firth, J; Lamm, SH (2003). "Bendectin and birth defects. II: Ecological analyses". Birth Defects Research 67 (2): 88–97. doi:10.1002/bdra.10034. PMID 12769504.
- Mazzotta, P; Stewart, DE; Koren, G; Magee, LA (Mar 2001). "Factors associated with elective termination of pregnancy among Canadian and American women with nausea and vomiting of pregnancy". J Psychosom Obstet Gynaecol 22 (1): 7–12. doi:10.3109/01674820109049946.
- Leeder, JS; Spielberg, SP; MacLeod, SM (Nov 1983). "Bendectin: the wrong way to regulate drug availability". Can Med Assoc J. 129 (10): 1085–7.
- Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S; National Birth Defects Prevention Study. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008" Am J Obstet Gynecol 2011 Jul;205(1):51.e1-8
- Wing, DA; Powers, B; Hickok, D (2010). "U.S. Food and Drug Administration Drug Approval: Slow Advances in Obstetric Care in the United States". Obstetrics & Gynecology 115 (4): 825–33. doi:10.1097/AOG.0b013e3181d53843. PMID 20308845.
- Centerwatch. FDA Approved Drugs for Obstetrics/Gynecology (Women’s Health); as seen in: https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic-area/11/obstetrics-gynecology-womens-health
- Koren, G; Levichek, Z (May 2002). "The teratogenicity of drugs for nausea and vomiting of pregnancy: perceived versus true risk". Am J Obstet Gynecol 186 (5 Suppl): S248–52.
- FDA FederalRegister/Vol. 64, No. 152/August 9,1999/Determination That Bendectin Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness
- FDA approves Diclegis for pregnant women experiencing nausea and vomiting, April 8, 2013
- About Morning Sickness from MOTHERISK at the Hospital for Sick Children in Toronto