Until the early 1980s, the combination of the antihistamine doxylamine succinate and the vitamin B6 analog pyridoxine hydrochloride was marketed in the United States as Bendectin to treat nausea and vomiting of pregnancy – the same combination that was approved by the Food and Drug Administration in April and is being marketed as Diclegis.
Bendectin was taken off the U.S. market, not due to an FDA decision to remove the drug, but because of the lawsuits filed against the manufacturer alleging that the drug had caused birth defects. Despite periodic reaffirmations by the FDA that there was no evidence that it was teratogenic, women in the United States have been left without an FDA-approved drug for morning sickness for over 30 years.
Soon after Bendectin was taken off the market, a study found the rate of hospitalizations for severe morning sickness in the United States increased threefold (Can. J. Public Health 1995;86:66-70).
Dr. Gideon Koren
So clearly, the removal of a drug taken by up to 40% of pregnant women in the United States during the late 1970s was not warranted, and women have suffered as a result. Because it was off-patent, a Canadian company, Duchesnay, began manufacturing the drug and marketed it as Diclectin in Canada, where it remained available and has been widely used, with a solid safety profile and no evidence of an increased risk of congenital malformations/teratogenicity.
Overall, there has been no evidence of an increased malformation risk in over 250,000 women treated during pregnancy – far more than any other drug used in pregnancy. In addition, more studies have confirmed the fetal safety of the combination, including three meta-analyses of studies of over 200,000 women that found no increased risk of congenital malformations in general, or specific malformations in particular, associated with prenatal exposure to Bendectin (Drug Intell. Clin. Pharm. 1988;22:813-24).
Another meta-analysis published in 1994 of 16 cohort and 11 case-control studies found no difference in the risk of birth defects among the babies exposed to Bendectin in the first trimester and those with no such exposure (Teratology 1994;50:27-37).
In another study that followed the neurodevelopment of children whose mothers had called Motherisk about nausea and vomiting of pregnancy (NVP) while pregnant, we found no evidence of an adverse effect of Diclectin exposure on neurodevelopment up through age 7 years (J. Pediatr. 2009;155:45-50, 50.e1-2).
The U.S. approval of doxylamine-pyridoxine in April 2013 is a major milestone, particularly because it is indicated for use in pregnancy and the FDA has labeled it a pregnancy category A drug – the strongest evidence of fetal safety. For approval, the FDA required a new phase III placebo-controlled study conducted in the United States. The study, in which I was an investigator, enrolled over 200 adult women at 7-14 weeks’ gestation experiencing NVP, at medical centers in Galveston, Pittsburgh, and Washington, D.C. It found that treatment with the doxylamine-pyridoxine combination was significantly superior at improving symptoms over placebo, and that it improved quality of life, after 2 weeks of treatment. Women on the drug required fewer alternative treatments, more asked to continue treatment than did those on placebo, and they missed less time from work (Am. J. Obstet. Gynecol. 2010;203:571.e1-571.e7).
Older antihistamines such as doxylamine tend to cause CNS depression, but in the U.S. study, those who received the active drug did not have more sedation than those on placebo. The experience in Canada has been similar.
After 30 years of experience in Canada, quite a few Canadian physicians give more than the four tablets recommended in the label, which may be necessary to achieve the therapeutic effects for women who have severe symptoms, are overweight, or are obese. In a study, my colleagues and I found no increased risk of malformations or developmental issues associated with prenatal exposure to the higher-than-standard doses, more than four tablets a day (J. Clin. Pharmacol. 2001;41:842-5).
We recently published a study showing the benefits of preemptive treatment with Diclectin in women who had experienced severe nausea and vomiting during a previous pregnancy: Those who commenced treatment with Diclectin before symptoms started had significantly fewer cases of moderate to severe NVP than those who started treatment once they started to experience symptoms (Obstet. Gynecol. Int. 2013 [doi: 10.1155/2013/809787]).
In summary, the introduction of Diclegis in the United States is a major victory for American women and their health care providers, after being orphaned from this FDA-approved medication for NVP for 30 years.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, has participated in other studies of Diclectin, and has served as a consultant to Duchesnay. E-mail him at obnews@frontlinemedcom.com.