New molecular entity

July 4, 2013

In April 2013, FDA approved doxylamine succinate 10 mg, pyridoxine hydrochloride 10 mg (Diclegis, Duchesnay) for the treatment of nausea and vomiting in pregnant women who do not respond to conservative management. Diclegis is a delayed-release formulation combining 10 mg of the antihistamine doxylamine succinate and 10 mg of the vitamin B6 analog pyridoxine hydrochloride. This combination was once marketed in the United States as Bendectin. However, legal suits claiming related birth defects forced the manufacturer to withdraw Bendectin from the market in the 1980s. Doxylamine/pyridoxine has not been studied in women with hyperemesis gravidarum.

In April 2013, FDA approved doxylamine succinate 10 mg, pyridoxine hydrochloride 10 mg (Diclegis, Duchesnay) for the treatment of nausea and vomiting in pregnant women who do not respond to conservative management. Diclegis is a delayed-release formulation combining 10 mg of the antihistamine doxylamine succinate and 10 mg of the vitamin B6 analog pyridoxine hydrochloride. This combination was once marketed in the United States as Bendectin. However, legal suits claiming related birth defects forced the manufacturer to withdraw Bendectin from the market in the 1980s. Doxylamine/pyridoxine has not been studied in women with hyperemesis gravidarum.

Efficacy. A randomized trial with 261 pregnant women compared doxylamine/pyridoxine to placebo for 14 days. The mean gestational age was 9.3 weeks (range 7 to 14 weeks). Sixty percent of women were taking 4 tablets daily and the remaining 40% were similarly split between 2 and 3 tablets daily. The Pregnancy Unique-Quantification of Emesis (PUQE) score was used to quantify efficacy, and the change in score from baseline to day 15 was evaluated. The PUQE score encompasses information about daily vomiting episodes and feelings of nausea. There was a significant difference in the change of PUQE score from baseline in the Diclegis group compared to placebo [-0.7 (-1.2 to -0.2)].

Safety. The same randomized trial described above evaluated the safety of doxylamine/pyridoxine. Somnolence was found to be the only adverse event occurring in greater than 5% of participants and of a higher incidence than in the participants receiving placebo. Other adverse events described in the prescribing information include falls or other accidents that can result from the concurrent use of doxylamine/pyridoxine with other central nervous system depressants. Given the risk of somnolence, women should avoid activities such as driving or operation of heavy machinery until medically cleared. Women should also be advised to avoid other depressants of the central nervous system such as alcohol, other antihistamines, narcotics, or sleep aids as these medications may worsen somnolence.

Two meta-analyses based on observational studies from 1963 to 1991 concluded that there was no increased risk of fetal malformation from exposure to doxylamine succinate and pyridoxine hydrochloride in the first trimester. 

The voluntary reporting of post-marketing use of 10 mg of doxylamine plus 10 mg of pyridoxine has provided additional possible side effects that may be related to the drug. The following are listed in the package insert: Dyspnea, palpitation, tachycardia, vertigo, vision blurred, visual disturbances, abdominal distension, abdominal pain, constipation, diarrhea, chest discomfort, fatigue, irritability, malaise, hypersensitivity, dizziness, headache, migraines, paresthesia, psychomotor hyperactivity, anxiety, disorientation, insomnia, nightmares, dysuria, urinary retention, hyperhidrosis, pruritus, rash, and maculo-papular rash. Doxylamine/pyridoxine is contraindicated with monoamine oxidase inhibitors since they can prolong the anticholinergic effects of antihistamines. Avoidance of other sedatives is also recommended. 

Dosing. Doxylamine/pyridoxine  is recognized as a pregnancy Category A drug. The recommended initial dose of doxylamine/pyridoxine is 2 tablets at bedtime on an empty stomach with a glass of water, taken daily and not on an as needed basis. If after 2 nights symptoms are not adequately controlled, the dose may be increased to 1 tablet in the morning and 2 tablets at bedtime. If on the next day symptoms are still inadequately controlled, the dose can be increased to 1 tablet in the morning, 1 tablet mid-morning, and 2 tablets at bedtime. The maximum recommended dose is 4 tablets daily. It is important to take doxylamine/pyridoxine on an empty stomach due to delayed and reduced absorption. Given the delayed-release formulation these tablets should not be crushed, chewed, or split. There are currently no dose recommendations in patients with renal or hepatic dysfunction as no studies have been conducted in these populations.