Doxylamine succinate with pyridoxine has approval from the U.S. Food and Drug Administration for the first-line treatment of nausea and vomiting of pregnancy (NVP).[1]  NVP affects up to 85% of women during pregnancy—it is the most prevalent medical condition during pregnancy.[2] Most patients with NVP are manageable by making alterations to diet and lifestyle factors; however, more than 30% might need fluids, vitamin supplementation, and additional treatment with an antiemetic such as doxylamine.[3]

Like other antihistamines, it also has utility for the management of allergic rhinitis.[4] Allergic rhinitis is the most prevalent atopic disorder, and symptoms consist of nasal congestion, sneezing, rhinorrhea, and nasal itching.[5] Doxylamine tablets are also available over-the-counter as an approved sleep aid for insomnia.[6] Insomnia is among the most commonly encountered patient concerns, and it can have significant adverse effects on mental and physical health.[7]

As a member of the first-generation class of antihistamines, doxylamine exerts its effects by competitively antagonizing the binding of free histamine at the H1-receptor binding sites. It antagonizes the effects of histamine in the uterus, GI tract, large blood vessels, and bronchial muscles. Doxylamine binds non-selectively to H1-receptors, both centrally and peripherally, contributing to the sedative effects that also make it an effective sleeping aid. However, due to their interactions with receptor residues that remain highly conserved across the aminergic receptors, H1 receptor antagonists can produce several off-target effects, which are anticholinergic. This activity also depresses labyrinthine function, blocks the chemoreceptor trigger zone, and diminishes vestibular stimulation.[8] Furthermore, doxylamine reduces nausea and vomiting by inhibiting histaminergic signaling to the vomiting center in the medulla.[9] The mechanism of action of pyridoxine while treating NVP is unknown.

Doxylamine is often co-administered with pyridoxine (vitamin B6) as an extended-release oral tablet (doxylamine succinate 10 mg/ pyridoxine-HCl 10 mg). The tablets should not be crushed, chewed, or split to maintain the extended-release effects.[10] For NVP, the recommended dose is two tablets before bed with water on an empty stomach. If symptoms continue on the second day, the patient can take one tablet after waking in the morning and two at night. If, on the third day, symptoms are still inadequately controlled with a three tablet regimen, the dose could increase to four tablets per day: one in the morning, one mid-afternoon, and two before bed. The maximum daily limit is four tablets.

Patients should not take doxylamine/pyridoxine as needed while treating NVP. The need for continued therapy requires reassessment throughout the pregnancy.[11][12][13] Doxylamine as a standalone medication is also available as doxylamine succinate 25 mg oral tablets under both brand and generic forms. These serve as a sleep aid, so the medication should be administered 30 minutes before bedtime.[14]

Because doxylamine is available over the counter, the risk of overdose is a concern.[4] Adverse effects due to hypersensitivity to the drug include hypotension, urticaria, and decreased oxygen saturation.[15] Common adverse effects include impaired vigilance, atropine-like effects, and drowsiness during the day—all of which could pose problems for high-risk fall patients and those operating heavy machinery.[16] 

Doxylamine and other first-generation histamine H1 receptor antagonists can bind to and inhibit muscarinic receptor signaling in other organ systems, resulting in systemic anticholinergic effects. This non-selective receptor binding can lead to various adverse effects such as flushing of the skin, anhidrosis, hyperthermia, hallucinations, mydriasis, delirium, and urinary retention.[17] Doxylamine is safe for use in breastfeeding in small, occasional doses. In longer-term or higher doses, doxylamine might decrease lactation, and it could cause drowsiness or other adverse effects on the breastfed infant.[18] Doxylamine is safe for use in pregnancy, as it is not teratogenic.[3]

One contraindication to treatment with doxylamine includes concurrent use of a monoamine oxidase inhibitor (MAOI).[13] Hypersensitivity to doxylamine is a contraindication to its use.[15] Concomitant alcohol use is contraindicated due to its effect of causing pronounced somnolence when combined with doxylamine. Doxylamine contraindications also include patients with the following conditions: elevated intraocular pressure, narrow-angle glaucoma, asthma, stenosing peptic ulcer disease, urinary bladder neck obstruction, gastric outlet obstruction.[11]