Clinical Context

For many years, the 2 components of the combination formulation have been available for clinical use: pyridoxine is a form of vitamin B₆, and doxylamine is an antihistamine. For the last 9 years, the American Congress of Obstetricians and Gynecologists guidelines have recommended this combination as first-line pharmacotherapy for morning sickness.

Despite concerns and litigation regarding birth defects, ongoing research has not supported these claims. The newly approved combination is an extended-release formulation, allowing longer duration of action. A generic version of the drug is currently available in Canada, and the US product should be available in May.

Study Synopsis and Perspective

The US Food and Drug Administration (FDA) approved the combination of doxylamine and pyridoxine (Diclegis) to treat pregnant women with nausea and vomiting whose condition has not adequately responded to dietary and lifestyle changes, the agency has announced.

Conservative management of "morning sickness" includes dividing up big meals into smaller ones, eating low-fat bland foods that are easy to digest, and avoiding smells that trigger nausea. Often, however, these nonmedical measures are not enough, said Hylton Joffe, MD, director of the Division of Reproductive and Urologic Products in the FDA's Center for Drug Evaluation and Research. "Diclegis is now the only FDA-approved treatment for nausea and vomiting due to pregnancy, providing a therapeutic option for pregnant women seeking relief from these symptoms."

The FDA recommends a starting dose every day at bedtime and on an empty stomach. The dose can be boosted to a maximum of 4 doses per day — one in the morning, one in midafternoon, and 2 at bedtime — if need be.

The doxylamine-pyridoxine combination was previously sold in the United States under the brand name Bendectin between 1956 and 1983, but it was pulled from the market because of litigation about birth defects. Although ongoing research has shown that the concerns were unsupported, the drug's previous maker declined to keep making the drug because of the high costs of defending it.

Edward McCabe, MD, medical director for the March of Dimes, told the Associated Press that the birth defect rate was the same among women who used the drug as in those in the general population, creating the false impression that the drug caused the birth defects. "Nothing better has come along" to treat morning sickness in the 30 years since it was taken off the market, Dr. McCabe said. The FDA at the time continued to call the drug safe.

In fact, physicians have been prescribing the 2 active ingredients of the drug for years. Pyridoxine is a form of vitamin B₆, and doxylamine is an antihistamine. The benefit of the newly approved combination is its extended-release formulation, so that it prevents morning sickness before it starts.

The combination has been recommended as a first-line pharmacotherapy by the American Congress of Obstetricians and Gynecologists guidelines for the last 9 years.

The FDA established the efficacy of doxylamine-pyridoxine on the basis of a clinical trial involving 261 pregnant women experiencing nausea and vomiting. Those women randomly assigned to receive doxylamine-pyridoxine for 2 weeks experienced greater improvement in their symptoms than those who were assigned a placebo. The drug's active ingredients also did not pose any increased risk for harm to the fetus in epidemiologic studies.

The most common adverse event associated with doxylamine-pyridoxine is drowsiness, which can be severe.

The drug combination is expected to be available by the end of May.

More information on the announcement on doxylamine-pyridoxine is available at the FDA Web site.

Clinical Implications

• The FDA has approved a doxylamine-pyridoxine combination formulation to treat "morning sickness," or nausea and vomiting during pregnancy, in women whose condition has not responded sufficiently to dietary and lifestyle changes. It is now the only FDA-approved treatment of this condition.
• The starting dose of the doxylamine-pyridoxine combination formulation is once daily at bedtime, on an empty stomach. If needed, the dose can be increased to not more than 4 doses per day: 1 in the morning, 1 in midafternoon, and 2 at bedtime. Conservative management of morning sickness should include eating smaller, more frequent meals; consuming low-fat, bland foods that are easy to digest; and avoiding smells that trigger nausea.
• A randomized efficacy trial leading to FDA approval of doxylamine-pyridoxine for pregnant women with nausea and vomiting showed that women assigned to receive doxylamine-pyridoxine for 2 weeks had greater symptomatic relief than those who were assigned placebo. Drowsiness, which is sometimes severe, is the most common adverse event associated with doxylamine-pyridoxine.

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