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Doxylamine; Pyridoxine
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2 tablets PO (on an empty stomach) at bedtime, on day 1; if dose controls symptoms the next day, continue taking 2 tablets PO daily at bedtime. If symptoms persist on the afternoon of day 2, continue 2 tablets PO at bedtime, then take 3 tablets PO starting on day 3 (1 tablet in the morning and 2 tablets at bedtime); if symptoms are controlled, continue regimen. If symptoms persist, on day 4 take 4 tablets PO (1 tablet in the morning, 1 tablet mid-afternoon, and 2 tablets at bedtime). Do not exceed 4 tablets/day PO. Tablets are taken on a daily basis not on an "as needed" basis; reassess continued need for therapy as pregnancy progresses.[54146] Doxylamine; pyridoxine is a first-line pharmacologic agent in the ACOG treatment algorithm for nausea and vomiting due to pregnancy.[66066]
Safety and efficacy have not been established in pregnant adolescents.[54146]
1 tablet PO (on an empty stomach) at bedtime on day 1; if dose controls symptoms the next day, continue taking 1 tablet PO daily at bedtime only. If symptoms persist on day 2, increase the daily dose to 1 tablet in the morning and 1 tablet at bedtime approximately 12 hours apart. Max: 2 tablets/day PO. Tablets are taken on a daily basis not on an "as needed" basis; reassess continued need for therapy as pregnancy progresses.[61433] Doxylamine; pyridoxine is a first-line pharmacologic agent in the ACOG treatment algorithm for nausea and vomiting due to pregnancy.[66066]
Safety and efficacy have not been established in pregnant adolescents.[61433]
4 tablets/day PO for delayed-release tablets (e.g., Diclegis); 2 tablets/day PO for extended-release tablets (e.g., Bonjesta).
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Not indicated.
Not indicated.
Dosage reduction may be warranted for patients with hepatic impairment but no quantitative guidelines are available; doxylamine is extensively metabolized in the liver.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
† Off-label indication
Doxylamine; Pyridoxine is a combination drug product indicated for the treatment of pregnancy-induced nausea/vomiting (n/v) in women who do not respond to conservative management (i.e., diet and lifestyle modifications).[54146][63316] Doxylamine is a sedating antihistamine (H-1 receptor antagonist) of the ethanolamine class; pyridoxine is also known as vitamin B6. The efficacy and safety of doxylamine; pyridoxine for pregnancy-induced n/v were evaluated in controlled clinical trials. Study subjects (n = 261) were at least 18 years of age and were in their 7 to 14th week of pregnancy. Women were randomized to receive 2 weeks of active treatment or placebo. Women taking doxylamine; pyridoxine experienced greater improvement in n/v compared with those taking placebo. Epidemiological studies have shown no increase risk of teratogenicity with combined use of doxylamine and pyridoxine. Clinical evaluation of doxylamine; pyridoxine was limited to pregnancy within 14 weeks; it is important to reassess continued need for therapy as pregnancy progresses. Doxylamine may cause marked drowsiness or sleepiness. Therefore, women taking doxylamine; pyridoxine should avoid using this product when engaging in activities requiring mental alertness, such as driving or operating heavy machinery, until cleared to do so by their health care provider.[54146][63316] Doxylamine; pyridoxine is a first-line pharmacologic agent to consider in the American College of Obstetrics and Gynecology (ACOG) treatment algorithm for nausea/vomiting due to pregnancy.[66066]
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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]
NOTE: Doxylamine; pyridoxine has not been studied in pregnant women with hyperemesis gravidarum.[54146][61433]
Doxylamine; pyridoxine is contraindicated in patients with known hypersensitivity to doxylamine succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation.[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]
The mechanism of action of doxylamine; pyridoxine for the treatment of pregnancy-induced nausea/vomiting is unknown.[54146]
Doxylamine: Doxylamine does not prevent the release of histamine, but it competes with free histamine for binding at the H1-receptor sites. Like other antihistamines, doxylamine competitively antagonizes the effects of histamine on H1-receptors in the GI tract, uterus, large blood vessels, and bronchial muscle. Blockade of H1-receptors also suppresses the formation of edema, flare, and pruritus that result from histaminic activity. Unlike second generation antihistamines such as loratadine and cetirizine which selectively block peripheral H1-receptors, first generation antihistamines such as doxylamine bind non-selectively to H1-receptors centrally and peripherally. Thus, sedative effects are more likely to occur with first generation antihistamines, especially the ethanolamine group. Doxylamine belongs to the ethanolamine group. Following prolonged use, tolerance can occur, but this may be beneficial, dependent on the indication for drug use, because of reduced sedative effects.
H1-antagonists are structurally similar to anticholinergic agents and therefore possess anticholinergic properties of varying degrees. Ethanolamine derivatives such as doxylamine have greater anticholinergic activity than do other antihistamines and commonly produce side effects such as dry mouth, blurred vision, constipation and urinary retention. These anticholinergic actions appear to be due to a central antimuscarinic effect which also may be responsible for the antiemetic effects seen with this class, although the exact mechanism is unknown.
Pyridoxine:Vitamin B6 is composed of pyridoxine, pyridoxal, and pyridoxamine, and foods usually contain all three forms. Pyridoxine is converted in erythrocytes to the active moiety, pyridoxal phosphate (requiring riboflavin for the conversion), while pyridoxamine is converted into pyridoxamine phosphate. These active forms act as coenzymes for no fewer than 60 metabolic processes including the metabolism of fat, protein, and carbohydrate. Their role in protein metabolism includes decarboxylation of amino acids, conversion of tryptophan to niacin or serotonin, deamination, and transamination of amino acids. In carbohydrate metabolism, it is necessary for the conversion of glycogen to glucose-1-phosphate. Pyridoxine is essential for synthesis of gamma aminobutyric acid (GABA) in the CNS and synthesis of heme.
Revision Date: 03/28/2024, 01:48:00 AMDoxylamine; pyridoxine is administered orally. Pyridoxine is highly protein bound, primarily to albumin. Its main active metabolite, pyridoxal 5'-phosphate (PLP) accounts for at least 60% of circulating vitamin B6 concentrations. Doxylamine is biotransformed in the liver by N-dealkylation to the principle metabolites N-desmethyldoxylamine and N, N-didesmethyldoxylamine. Pyridoxine is a prodrug primarily metabolized in the liver. The principle metabolites of doxylamine are excreted by the kidney. The terminal elimination half-life of doxylamine and pyridoxine are 12.5 hours and 0.5 hours, respectively.[54146]
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: none
The pharmacokinetics of doxylamine 10 mg; pyridoxine 10 mg delayed-release tablets have been studied following oral administration of single-dose (2 tablets) and multiple-dose (4 tablets/day). Doxylamine and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum. The time to reach peak concentrations (Tmax) of doxylamine and pyridoxine are within 7.5 and 5.5 hours, respectively. Multiple-dose administration results in increased concentrations of doxylamine (including Cmax and an increased AUC). The time to reach the maximum concentration (Tmax) for doxylamine is not affected by multiple doses. The mean accumulation index is greater than 1 suggesting that doxylamine accumulates following multiple dosing. Although no accumulation was observed for pyridoxine, the mean accumulation index for each metabolite is greater than 1 after multiple-dose administration of the combination product; the Tmax for pyridoxine is not affected by multiple doses.[54146] The pharmacokinetics of a single-dose of doxylamine 20 mg; pyridoxine 20 mg extended-release tablets have been studied in a crossover clinical trial in 48 healthy, premenopausal women under fasting conditions. One doxylamine 20 mg; pyridoxine 20 mg extended-release tablet was bioequivalent to 2 combination tablets of 10 mg doxylamine and 10 mg pyridoxine based on the AUC and Cmax of doxylamine and baseline corrected pyridoxal 5'-phosphate (PLP). In a multiple-dose, crossover clinical trial conducted in 31 healthy, premenopausal women, 1 doxylamine 20 mg; pyridoxine 20 mg extended-release tablet given twice daily for 11 days was bioequivalent to 1 combination tablet of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride given 3 times daily (1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime), based on the AUC and Cmax of doxylamine and baseline corrected PLP.[61433] The administration of food delays the absorption of both doxylamine and pyridoxine.[54146][61433]
The pharmacokinetic profile of doxylamine; pyridoxine has not been studied in hepatically impaired patients.[54146]
The pharmacokinetic profile of doxylamine; pyridoxine has not been studied in renally impaired patients.[54146]
The effect of ethnic differences on the pharmacokinetic profile of doxylamine; pyridoxine has not been studied.[54146]
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.
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