In safety and efficacy trials, somnolence (drowsiness) was reported in 14.3% of doxylamine; pyridoxine treated women (n = 133) compared to 11.7% of placebo treated women (n = 128).[54146] [61433] CNS depression manifested as drowsiness and/or dizziness can occur during therapy with doxylamine; pyridoxine. Less frequently occurring CNS effects of sedating antihistamines include asthenia/weakness, confusion, dysarthria (slurred speech), myasthenia, fatigue, or headache. There is considerable individual patient response to sedative effects, so patients should be warned of the possible impairment of mental acuity. These side effects may disappear after a few days of medication. Ethanol intake will increase the risk of sedation. If sedation persists or is severe, a dosage reduction may be advisable. The following adverse events have been identified during post-approval use of the doxylamine; pyridoxine combination: disorientation, dizziness, fatigue, headache, malaise, migraine, paresthesias, psychomotor hyperactivity (restlessness), and vertigo.[54146] [61433]

Doxylamine, like other sedating antihistamines (H1-antagonists) possesses a significant degree of anticholinergic effects [54146] [61433], which can result in thickening of bronchial secretions, xerostomia, urinary retention, insomnia, irritability, nervousness, mydriasis, restlessness, xerophthalmia, and/or blurred vision. Dry mouth (xerostomia) is a common complaint in the use of first-generation antihistamines such as doxylamine. The following adverse events have been identified during post-approval use of the combination of doxylamine; pyridoxine: anxiety, insomnia, irritability, nightmares, blurred vision, visual disturbances, dysuria, and urinary retention.[54146] [61433]

Doxylamine; pyridoxine contains a sedating antihistamine (H1-antagonist) which may cause adverse GI effects. The following adverse events have been identified during post-approval use of the combination of doxylamine; pyridoxine: abdominal distension, abdominal pain, constipation, diarrhea.[54146] [61433]

Adverse cardiovascular responses of doxylamine; pyridoxine are likely to be associated with the anticholinergic properties or the quinidine-like anesthetic effects of some antihistamines (H1-antagonists).[54146] [61433] These responses can include sinus tachycardia, extrasystole, palpitations, and/or cardiac arrhythmias. Alpha-adrenergic blockade can lead to symptoms of hypotension. Hypertension can also occur, but is usually not of clinical significance. The following adverse events have been identified during post-approval use of the combination of doxylamine; pyridoxine: chest discomfort, dyspnea, palpitation, and sinus tachycardia.[54146] [61433]

The following adverse events have been identified during post-approval use of the combination of doxylamine; pyridoxine: hyperhidrosis, hypersensitivity, pruritus, rash (unspecified), and maculopapular rash.[54146] [61433]

Doxylamine; pyridoxine may cause somnolence due to the anticholinergic properties of doxylamine, a sedating antihistamine. Women should avoid driving or operating machinery while using doxylamine; pyridoxine until cleared to do so by their healthcare provider. In addition, patients using other central nervous system (CNS) depressants including alcohol are at particular risk for severe drowsiness leading to falls or accidents; ethanol ingestion should be avoided during the use of this drug combination, given its use in the pregnant patient and the potential for additive CNS depression.[54146] [61433]

The anticholinergic effects of doxylamine may be additive with other anticholinergic medications. Also, due to a possible worsening of symptoms, anticholinergic drugs such as doxylamine; pyridoxine should be used with caution in patients with the following conditions: stenosing peptic ulcer disease, GI obstruction (pyloroduodenal obstruction), ileus, urinary bladder obstruction, urinary retention, increased intraocular pressure, and closed-angle glaucoma. Ocular effects resulting from the anticholinergic effects of doxylamine also include dry eyes or blurred vision, which may be of significance in wearers of contact lenses.[54146] [61433]

No clinical or pharmacokinetic studies have been conducted with this drug combination in patients with hepatic disease. Doxylamine is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyldoxylamine and N, N-didesmethyldoxylamine. Pyridoxine is a prodrug primarily metabolized in the liver.[54146] [61433] Therefore, the metabolism of doxylamine; pyridoxine may be reduced in the presence of hepatic impairment.

This drug combination is intended for use during human pregnancy in women who do not respond to conservative management. No increased risk for congenital malformations has been reported with use in pregnant women. Doxylamine; pyridoxine has been evaluated through epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride, with or without dicyclomine hydrochloride. A second meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no statistically significant relationships between fetal abnormalities and the first trimester use of the combination doxylamine and pyridoxine with or without dicyclomine.[54146] [61433] Doxylamine; pyridoxine is a first-line pharmacologic agent for use following conservative management in the ACOG treatment algorithm for nausea and vomiting due to pregnancy.[66066]

According to the manufacturer, doxylamine; pyridoxine is not recommended for use during breast-feeding. Data regarding the transfer of doxylamine into human milk are not available; however, the molecular weight of doxylamine suggests that passage into human breast milk is possible. Maternal exposure to antihistamine (H-1 antagonists) has also been reported to induce irritability or sedation in 9.4% of breast-fed infants.[35545] Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of doxylamine. Pyridoxine hydrochloride is excreted into breast milk. There have been no reports of adverse events in infants presumably exposed to pyridoxine through breast milk and the use of pyridoxine is compatible with breast-feeding.[27500] [54146] [61433] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

Use of doxylamine;pyridoxine is contraindicated in women who are currently on monoamine oxidase inhibitors (MAOI therapy). Monoamine oxidase inhibitors (MAOIs) may prolong and intensify the anticholinergic (drying) effects as well as the central nervous system effects of doxylamine.[54146] [61433]

Administration of doxylamine; pyridoxine may result in laboratory test interference; false positive drug screens for methadone, opiates, and phencyclidine phosphate (PCP) can occur. Confirmatory tests, such as Gas Chromatography Mass Spectrometry (GC-MS), should be used to confirm the identity of the substance in the event of a positive immunoassay result.[61433] [63316]