Doxylamine Succinate and Pyridoxine HCl Delayed-Release Tablets (Diclegis®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a fixed combination of doxylamine succinate and pyridoxine for the treatment of nausea and vomiting due to pregnancy. This is a reintroduction of a product widely used between 1956 and 1983. Then marketed as bendectin, the product was voluntarily withdrawn by the manufacturer due to lawsuits related to birth defects, although evidence of risk was not supported by scientific evidence. Doxylamine and pyridoxine is marketed by Duchesnay Inc. as Diclegis.
Doxylamine and pyridoxine is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.1
The recommended dose is two tablets at bedtime. If the response is inadequate, the dose may be increased to a maximum of four tablets daily (one in the morning, one mid-afternoon, and two at bedtime).1 The tablets should be taken on an empty stomach with a glass of water. Each tablet contains 10 mg of doxylamine succinate and 10 mg of pyridoxine.
Doxylamine and pyridoxine provide an alternative to manage nausea and vomiting during pregnancy.
Doxylamine is contraindicated in combination with monoamine oxidase inhibitors. It can intensify the side effects of anticholinergic drugs.1
The efficacy and safety of doxylamine/pyridoxine was evaluated in a double-blind, randomized, placebo-controlled, 15-day study involving pregnant women with nausea and vomiting due to pregnancy (n = 256).1,2 The subjects were ≥ 18 years of age, 7-14 weeks of gestation, not responsive to conservative dietary/lifestyle management, and had a pregnancy unique quantification of emesis (PUQE) score ≥ 6. The PUQE score is based on the duration of nauseated or sick feeling at one’s stomach, number of vomiting episodes, and number of retching or dry heaves over a 24-hour period. Subjects were randomized to placebo or doxylamine/pyridoxine (two at bedtime with an additional tablet taken on day 3 and day 4 if symptoms were not adequately controlled). The primary efficacy endpoint was the mean change in PUQE score from baseline. Secondary endpoints included day-by-day area under the curve for change in PUQE score from baseline, time lost from employment, number of subjects who continued with the study medication, and the number who reported concurrent use of alternative therapies. Analysis was based on intent-to-treat and last observation carried forward. On day 15, doxylamine/pyridoxine had a mean change of -4.8 ± 2.7 from a mean baseline of 9.0 ± 2.1, compared to -3.9 ± 2.6 from a baseline of 8.8 ± 2.1. The net treatment difference (95% confidence interval [CI]) was -0.7 (-1.2, -0.2), an effect size of 35%. The mean area under the curve was 61.5 ± 36.9 for doxylamine/pyridoxine and 53.5 ± 37.5 for placebo (P < 0.0001). More subjects preferred the study drug (48.9% vs 32.8% for placebo, P = 0.009). Fewer subjects on the study drug used alternative therapies (36% vs 23.7%, P = 0.04). Time loss to employment was numerically greater with placebo, but did not reach statistical difference (2.37 ± 10.23 vs 0.92 ± 3.86, P = 0.06). Somnolence was the most common adverse event. The risk of birth defects that resulted in the withdrawal of bendectin was never substantiated. A meta-analysis of 16 cohort and 11 case-control studies estimated that the relative risk of any malformation in the first trimester was 0.95 (95% CI, 0.88-1.04).3 An ecological analysis that assessed the temporal relationship (1970-1992) between bendectin usage and birth defect rates in the United States found no evidence of teratogenic effect.4 "In the same time period of bendectin withdrawal, the authors found that the birth defect rate remained steady but the hospitalization rate for nausea and vomiting due to pregnancy doubled."
Nausea and vomiting of pregnancy is a very common condition, affecting up to 80% of pregnant women. Management generally involves diet, avoidance of triggers, non-pharmacologic interventions, and complementary and alternative medicine (e.g., ginger).5 There are currently no FDA-approved drugs for this condition, although ondansetron has been used off label. A recently published Danish propensity score-matched analysis reported no difference in any major birth defect between those exposed to ondansetron compared to those not exposed.5 In a case-control study using data from the National Birth Defects Prevention Study, a possible increase in risk of cleft palate was associated with ondansetron exposure (adjusted odds ratio = 2.87; 95% CI, 1.03-7.97).6 The re-introduction of doxylamine and pyridoxine provides an alternative for the management of nausea and vomiting due to pregnancy.
1. Diclegis Prescribing Information. Rosemont, PA: Duchesnay Inc.; April 2013.
2. Koren G, 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-e7.
3. McKeigue PM, et al. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994;50:27-37.
4. Kutcher JS, et al. Bendectin and birth defects. II: Ecological analyses. Birth Defects Res A Clin Mol Teratol 2003;67:88-97.
5. http://www.uptodate.com/contents/treatment-and-outcome-of-nausea-and-vomiting-of-pregnancy. Accessed April 28, 2013.
6. Pasternak B, et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med 2013;368:814-823.
7. Anderka M, et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol 2012;94: 22-30.