BENDECTIN

RTC: 1035
CAS Registry: 8064-77-5
Last Updated: October 01, 2001



Copyright © 1994-2003, Reproductive Toxicology Center
Cross-references:

Bendectin is the brand name for a combination of doxylamine (a sedative-antihistamine (1461)) and pyridoxine (vitamin B6) (1190), which was available in the US prior to 1983 for the treatment of nausea and vomiting of pregnancy (1). Between 1956 and 1976, the drug also contained dicyclomine (1139), an antispasmodic. Dicyclomine was removed from the product after clinical studies were unable to demonstrate that it was effective in the treatment of nausea and vomiting (12). Bendectin sales in the US were discontinued in 1983. An identical product remains available in Canada under the name Diclectin. There have been many investigations regarding whether this drug or its components have the potential for embryotoxicity. In general, the available animal and epidemiologic data on Bendectin and on doxylamine alone show no association with adverse pregnancy outcome. Of the animal experiments, the study by Tyl et al. (13) is regarded as definitive, showing no teratogenic effects of this drug even at the maternally toxic dose of 800 mg/kg/d, which is 2 to 3 orders of magnitude higher than the usual human dose. The finding of minor skeletal variations, such as a shortened 13th rib, only at the toxic high doses is consistent with general toxicity. The large body of available epidemiologic research, including both case-control and cohort studies involving thousands of births, includes isolated studies that raise questions about individual types of defects; however, the inconsistent findings, the study designs, and the failure to confirm these occasional findings with other well-controlled studies lead to the conclusion that there is no Bendectin or doxylamine-associated increase in the risk of major congenital malformations, including heart disease, cleft palate, cleft lip with or without cleft palate, or limb-reduction defects (2- 8,15,17,18). Two case control studies, based on a small number of cases, have also suggested a possible association between first trimester use of Bendectin and pyloric stenosis in exposed newborns (3,9). The continuing investigation of this putative effect was expanded to include exposure to all antihistamine- containing drugs (10). Because an increased risk of pyloric stenosis was not uncovered in much larger case-control studies (7) and because animal models using massive doses of Bendectin or doxylamine are inconsistent with a teratogenic mechanism of action, the possibility of an association between this anomaly and Bendectin or doxylamine is unlikely. The authors of one of the studies suggested that the apparent association may be due to a confounder such as an increase in nausea in pregnant women with a genetic predisposition to gastrointestinal malformations (3). One other report involves a cluster of cases of congenital lung hypoplasia in three infants born to mothers who used Bendectin (11). As is true with all case studies, no conclusion as to causation is possible without controlled investigations of this association. Of particular interest are two articles employing meta- analysis in the evaluation of the epidemiologic reports on Bendectin (14,16). Both of these papers confirm the overall conclusion that Bendectin use during pregnancy is not associated with an increased incidence of birth defects in the offspring. Finally, a case-control investigation from the Northern California Kaiser Permanente Birth Defects Study concluded no causal association between Bendectin use and birth defects in spite of an association between drug use and three subclasses of birth defect (microcephaly, cataract, and lung malformations). The authors correctly point out that any agent, even if perfectly safe, will be associated by chance alone with some subclasses of birth defects, and that the number of such associations for Bendectin did not exceed those expected by chance alone (15).

Selected References

  1. PDR for Nonprescription Drugs, Medical Economics Co. Oradell, NJ 6th Edition, 1985.
  2. Cordero JF et al: Is Bendectin a teratogen? J Am Med Assoc 245:2307-10, 1981.
  3. Eskenazi B, Bracken MB: Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 144:919-924, 1982.
  4. Holmes LB: Teratogen update: Bendectin. Teratology 27:277- 281, 1983.
  5. McCredie J et al: The innocent bystander: Doxylamine / dicyclomine / pyridoxine and congenital limb defects. Med J Aust 141:546-547, 1984.
  6. Michaelis J et al: Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformation. Teratology 27:57-64, 1983.
  7. Mitchell AA et al: Birth defects in relation to Bendectin use in pregnancy. Am J Obstet Gynecol 147:737-742, 1983.
  8. Morelock S et al: Bendectin and fetal development: a study at Boston City Hospital. Am J Obstet Gynecol 142:209-13, 1982.
  9. Aselton P et al: Pyloric stenosis and maternal Bendectin exposure. Am J Epidemiol 120:251-6, 1984.
  10. Aselton P et al: Re: Pyloric stenosis and maternal antihistamine exposure at group health cooperative. Am J Epidemiol 122:197, 1985.
  11. Grodofsky MP, Wilmott RW: Possible association of use of Bendectin during early pregnancy and congenital lung hypoplasia. N Engl J Med 311:732, 1984.
  12. Merrell-Dow Pharmaceuticals Inc: Efficacy of the Ingredients of Bendectin alone and in combination versus placebo for nausea and vomiting of pregnancy. Feb. 14, 1977. 8p.
  13. Tyl RW et al: Developmental toxicity evaluation of Bendectin in CD rats. Teratology 37:539-52, 1988.
  14. Einarson TR et al: A method for meta-analysis of epidemiology studies. Drug Intell Clin Pharm 22:813-24, 1988.
  15. Shiono PH, Klebanoff M: Bendectin and human congenital malformations. Teratology 40:151-5, 1989.
  16. McKeigue PM, Lamm SH, Linn S, Kutcher JS: Bendectin and birth defects: I. A meta-analysis of epidemiologic studies. Teratology 50:27-37, 1994.
  17. Brent RL: Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol 1995;9:337-49.
  18. Boneva RS, Moore CA, Botto L, et al: Nausea during pregnancy and congenital heart defects: A population-based case-control study. Am J Epidemiol 149:717-725, 1999.

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