Pyridoxine/doxylamine

Pyridoxine/doxylamine, sold under the brand name Diclectin among others, is a combination of pyridoxine hydrochloride (vitamin B6) and doxylamine succinate. It is generally used for nausea and vomiting of pregnancy (morning sickness); even though its efficacy has not been proven [1] [2]

Pyridoxine/doxylamine
Combination of
PyridoxineVitamin
DoxylamineAntihistamine
Clinical data
Trade namesDiclegis, Bendectin, Debendox, Lenotan, Merbental, Diclectin, others
Pregnancy
category
  • Compatible
Routes of
administration		By mouth
Legal status
Legal status
  • CA: Approved
  • US: Approved
  • Prescription only; approved drug in Israel
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
  (verify)

Medical uses

The combination of pyridoxine, more commonly referred to as vitamin B6 and doxylamine is effective for the management of nausea and vomiting of pregnancy.[3] A 2018 review, however, found the benefit was small.[1]

Doxylamine and pyridoxine are pregnancy compatible drugs,[4] consistent with FDA's safety assessment of the combination product. They have 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.[5]

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.[6] 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.[7] 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”.[8]

The Motherisk Program, at the Hospital for Sick Children in Toronto, recommends the combination of doxylamine and of pyridoxine as first-line therapy for the management of nausea and vomiting of pregnancy.[9]

Adverse effects

Pyridoxine is a water-soluble vitamin and is generally recognized as having no adverse effects.[10][11]

The most commonly reported adverse reaction of doxylamine is drowsiness.[12] Other adverse drug reactions associated with doxylamine succinate may include: vertigo, nervousness, epigastric pain, headache, palpitation, diarrhea, disorientation, irritability, convulsions, urinary retention or insomnia.[11]

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.[11][12] 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.[11][12]

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.[11]

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[4] (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.[13][14] No epidemiological studies have found any teratogenic effect.[14]

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.[15][16] The initial meta-analysis, published in 1988, combined data from 12 cohort and 5 case-control studies,[15] and the subsequent meta-analysis, published in 1994, combined data from 16 cohort studies and 11 case control studies.[16] These studies included over 200,000 Bendectin-exposed pregnancies and did not observe an increased risk for major malformations.[15][16] 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.[16]

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).[17] 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”.[17]

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.[18]

History

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.[19]:317 Bendectin (doxylamine/vitamin 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.[20] 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.[20] The most famous case involving the drug is Daubert v. Merrell Dow Pharmaceuticals (1993). These suits were led by celebrity plaintiff attorney Melvin Belli .[21] 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.[22][23]

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.[24]

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.[25][26][27][28][29]

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.[30] 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.[31][32][33]

Society and culture

The Bendectin case, and the subsequent removal of the drug from the US market, has had a number of consequences.[34] Firstly, there was an immediate increase in the rates of hospitalization for nausea and vomiting in pregnancy.[35] 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 form, called hyperemesis gravidarum, could be both life-threatening and cause women to terminate their pregnancy.[36] 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.[34][37][38] Thirdly, it has been claimed that subsequent to the Bendectin experience, drug companies stayed away from developing medications for pregnant patients.[39] As a result, only a few medications were approved by the FDA for obstetrical indications in the past several decades.[40] Lastly, the perception that all medications are teratogenic increased among pregnant women and healthcare professionals.[41] The unfounded fear of using medications during pregnancy has precluded many women from receiving the treatment they require.[41]

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.[42]

See also

References
  1. Persaud N, Meaney C, El-Emam K, Moineddin R, Thorpe K (17 January 2018). "Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: Prespecified analyses and reanalysis". PLOS ONE. 13 (1): e0189978. Bibcode:2018PLoSO..1389978P. doi:10.1371/journal.pone.0189978. PMC 5771578. PMID 29342163.
  2. Morning sickness drug Diclectin doesn't work, confidential industry documents reviewed by doctor show — Article published in "CBC news" on 17 January 2018
  3. Madjunkova S, Maltepe C, Koren G (June 2014). "The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy". Paediatric Drugs. 16 (3): 199–211. doi:10.1007/s40272-014-0065-5. PMC 4030125. PMID 24574047.
  4. 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.
  5. "Pregnancy and Lactation Labeling (Drugs) Final Rule". US Food and Drug Administration. 2 March 2020.
  6. American College of Obstetricians and Gynecologists (ACOG). (April 2004). "Nausea and vomiting of pregnancy". ACOG Practice Bulletin. Washington (DC): American College of Obstetricians and Gynecologists (ACOG) (52).
  7. "Guideline Summary NGC-5719. Nausea and vomiting of pregnancy". The National Guideline Clearinghouse. 2007. Archived from the original on 2012-12-19.
  8. Arsenault MY, Lane CA, MacKinnon CJ, Bartellas E, Cargill YM, Klein MC, Martel MJ, Sprague AE, Wilson AK (October 2002). "The management of nausea and vomiting of pregnancy" (PDF). Journal of Obstetrics and Gynaecology Canada. 24 (10): 817–31, quiz 832–3. doi:10.1016/S1701-2163(16)30475-3. PMID 12405123. Archived from the original (PDF) on 29 January 2013.
  9. Einarson A, Maltepe C, Boskovic R, Koren G (December 2007). "Treatment of nausea and vomiting in pregnancy: an updated algorithm". Canadian Family Physician. 53 (12): 2109–11. PMC 2231543. PMID 18077743.
  10. 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. (1998). "Vitamin B6". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press.CS1 maint: multiple names: authors list (link)
  11. Duchesnay Inc. (8 March 2016). Diclectin Product Monograph (PDF) – via Health Canada’s Drug Product Database.
  12. American Society of Health-System Pharmacists (AHFS) Drug Information 2014, Antihistamine Drugs. pgs 1-8.
  13. Koren G, Clark S, Hankins GD, Caritis SN, Miodovnik M, Umans JG, Mattison DR (December 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.e1–7. doi:10.1016/j.ajog.2010.07.030. PMID 20843504.
  14. Kutcher JS, Engle A, Firth J, Lamm SH (February 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. hdl:2027.42/35295. PMID 12769504.
  15. Einarson TR, Leeder JS, Koren G (October 1988). "A method for meta-analysis of epidemiological studies". Drug Intelligence & Clinical Pharmacy. 22 (10): 813–24. doi:10.1177/106002808802201021. PMID 3229352. S2CID 33156399.
  16. McKeigue PM, Lamm SH, Linn S, Kutcher JS (July 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.
  17. Ornstein M, Einarson A, Koren G (1995). "Bendectin/diclectin for morning sickness: a Canadian follow-up of an American tragedy". Reproductive Toxicology. 9 (1): 1–6. doi:10.1016/0890-6238(94)00050-7. PMID 8520127.
  18. Nulman I, Rovet J, Barrera M, Knittel-Keren D, Feldman BM, Koren G (July 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.
  19. Sanders J (January 1992). "The Bendectin Litigation: A Case Study in the Life Cycle of Mass Torts". Hastings Law Journal. 43 (2): 301–418.
  20. Brody JE (1983-06-19). "Shadow of Doubt Wipes Out Bendectin". New York Times.
  21. Korcok M (November 1980). "The Bendectin debate". Canadian Medical Association Journal. 123 (9): 922–8. PMC 1704894. PMID 7437993.
  22. Thalidomide hero found guilty of scientific fraud — Article published in "New Scientist" on 27 February 1991
  23. Thalidomide doctor guilty of medical fraud — Article published in "The Independent" on 20 February 1993
  24. Brent RL (1995). "Bendectin: Review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen" (PDF). Reproductive Toxicology. 9 (4): 337–349. doi:10.1016/0890-6238(95)00020-B. PMID 7496090. Archived from the original (PDF) on 2011-07-16. Retrieved 2010-07-30.
  25. Kroll D (July 31, 2015). "The Kim Kardashian-Endorsed Morning Sickness Drug Is The Real Deal". Forbes. Retrieved 15 October 2015.
  26. "Kim Kardashian drug endorsement may break Canadian law: experts". Yahoo news. 7 Aug 2015. Retrieved 15 October 2015.
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  31. "Un antinauséeux à utiliser avec prudence?".
  32. "Health Canada confidentiality pact forces doctor to withhold drug data". CBC Radio. 15 October 2015.
  33. "Health Canada hands over documents but muzzles doctor | the Star". 14 October 2015.
  34. 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
  35. Kutcher JS, Engle A, Firth J, Lamm SH (February 2003). "Bendectin and birth defects. II: Ecological analyses" (PDF). Birth Defects Research. Part A, Clinical and Molecular Teratology. 67 (2): 88–97. doi:10.1002/bdra.10034. hdl:2027.42/35295. PMID 12769504.
  36. Mazzotta P, Stewart DE, Koren G, Magee LA (March 2001). "Factors associated with elective termination of pregnancy among Canadian and American women with nausea and vomiting of pregnancy". Journal of Psychosomatic Obstetrics and Gynaecology. 22 (1): 7–12. doi:10.3109/01674820109049946. PMID 11317613. S2CID 19503639.
  37. Leeder JS, Spielberg SP, MacLeod SM (November 1983). "Bendectin: the wrong way to regulate drug availability". Canadian Medical Association Journal. 129 (10): 1085–7. PMC 1875483. PMID 6627167.
  38. 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
  39. Wing DA, Powers B, Hickok D (April 2010). "U.S. Food and Drug Administration drug approval: slow advances in obstetric care in the United States". Obstetrics and Gynecology. 115 (4): 825–33. doi:10.1097/AOG.0b013e3181d53843. PMID 20308845.
  40. 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
  41. Koren G, Levichek Z (May 2002). "The teratogenicity of drugs for nausea and vomiting of pregnancy: perceived versus true risk". American Journal of Obstetrics and Gynecology. 186 (5 Suppl Understanding): S248-52. doi:10.1067/mob.2002.122601. PMID 12011895.
  42. McCarthy LS (June 1994). "Life After Daubert v. Merrell Dow: Maine as a Case Law Laboratory for Evidence Rule 702 Without Frye". Maine Law Review. 46 (2).
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