VA Class:AH102

ATC Class:R06AA09

AHFS Class:

• First Generation Antihistamines 4:04

Generic Name(s):

• Doxylamine Succinate

Associated Monographs

• Antihistamines General Statement

Doxylamine is an ethanolamine-derivative, first generation antihistamine.103,105,106

Doxylamine succinate shares the actions and uses of other antihistamines.

Insomnia

Because of its sedative effect, doxylamine succinate is used as a nighttime sleep aid in the short-term management of insomnia. Although the safety and efficacy of doxylamine as a nighttime sleep aid have not been fully established, the FDA states that, pending further accumulation of data, doxylamine-containing nighttime sleep aids that have been approved for this use may continue to be marketed in the US.

Nausea and Vomiting of Pregnancy

Doxylamine succinate is used in fixed combination with pyridoxine hydrochloride for the management of nausea and vomiting of pregnancy in women who have not responded to conservative management.105,106

Safety and efficacy of doxylamine in fixed combination with pyridoxine have been established in a double-blind, randomized, placebo-controlled trial for the treatment of nausea and vomiting of pregnancy in pregnant women at 7-14 weeks' gestation (median: 9 weeks).105,108 Patients were randomized to receive 14 days of treatment with doxylamine and pyridoxine hydochloride in fixed combination or placebo.105,108 Patients in the active treatment group received an initial dosage of doxylamine succinate 20 mg in fixed combination with pyridoxine hydrochloride 20 mg (2 tablets) at bedtime.105,108 If symptoms persisted into the afternoon of the second day, a morning dosage of doxylamine succinate 10 mg in fixed combination with pyridoxine hydrochloride 10 mg (1 tablet) was added beginning on day 3.105,108 If symptoms persisted into day 4, an additional dose of doxylamine succinate 10 mg in fixed combination with pyridoxine hydrochloride 10 mg (1 tablet) was added midafternoon beginning on day 4, for a maximum total daily dosage of 4 tablets (1 in the morning, 1 midafternoon, and 2 at bedtime).105,108 Among patients receiving doxylamine in fixed combination with pyridoxine during the course of the study, 19% of patients continued receiving 2 tablets daily, 21% received 3 tablets daily, and 60% received 4 tablets daily.105 The primary end point in the study was the change from baseline to day 15 in the Pregnancy Unique-Quantification of Emesis (PUQE) score, which incorporates the number of daily vomiting episodes, number of daily heaves, and duration of daily nausea in hours for an overall score of symptoms ranging from 3 (no symptoms) to 15 (most severe).105,108 A greater decrease from baseline in PUQE score was observed in patients receiving doxylamine in fixed combination with pyridoxine compared with those receiving placebo (decrease of 4.8 versus 3.9, respectively).105,108

Clinical management guidelines for the treatment of nausea and vomiting of pregnancy published by the American College of Obstetricians and Gynecologists (ACOG) in 2015 recommend pyridoxine alone or the fixed combination of doxylamine and pyridoxine as first-line drug therapy in patients who do not respond to diet and lifestyle modifications.110 The ACOG guidelines emphasize the importance of early treatment of nausea and vomiting of pregnancy to help prevent progression to hyperemesis gravidarum.110 In addition, the guidelines affirm that evidence from case-control and cohort studies in large numbers of pregnant women have proven the fixed-combination therapy to be safe with respect to fetal effects.110 (See Cautions: Pregnancy and Lactation.)

Some clinicians have stated that clear evidence supporting greater efficacy of doxylamine and pyridoxine in fixed combination compared with pyridoxine alone for the management of nausea and vomiting of pregnancy is lacking and have suggested that pyridoxine alone be used as the preferred first-line drug therapy.113,114 In addition, the clinical importance of the greater statistical efficacy of doxylamine in fixed combination with pyridoxine in comparison with placebo in the pivotal clinical trial108 (with a greater mean decrease in the 15-point PUQE scale of 0.9 compared with placebo) has been questioned by some clinicians.113 Based on a systematic review, another group of experts concluded that high-quality evidence to support the use of any drugs, including doxylamine and pyridoxine in fixed combination, for the treatment of nausea and vomiting of pregnancy currently is lacking.119 However, other clinicians have suggested that the temporal association of a twofold increase in rates of hospitalization for hyperemesis gravidarum in the US following the removal of a fixed combination of doxylamine and pyridoxine that was previously commercially available may be indicative of the clinical importance of the fixed combination.115,116

The safety and efficacy of doxylamine in fixed combination with pyridoxine have not been studied in women with hyperemesis gravidarum.105,106

Allergic Rhinitis

Doxylamine succinate is also used in combination with antitussives and decongestants for the temporary relief of cold and cough symptoms.

Administration

Doxylamine succinate is administered orally.102,105,106

The fixed combination of doxylamine/pyridoxine delayed-release Diclegis^® and extended-release Bonjesta^® tablets should be taken on an empty stomach with a glass of water; the tablets should be swallowed whole and should not be crushed, chewed, or split.105,106

Dosage

Insomnia

As a nighttime sleep aid, the usual dosage of doxylamine succinate for self-medication in adults and children 12 years of age or older is 25 mg taken 30 minutes before retiring or as directed by a clinician.102 Because chronic insomnia may be indicative of a serious underlying physical, emotional, or psychological condition requiring professional medical attention, patients should be advised to consult a clinician if insomnia persists continuously for longer than 2 weeks.102

Nausea and Vomiting of Pregnancy

Doxylamine/Pyridoxine Fixed-combination Therapy

When used as doxylamine/pyridoxine delayed-release tablets (Diclegis^®) for the management of nausea and vomiting of pregnancy that has not responded to conservative management, the recommended initial dosage is doxylamine succinate 20 mg in fixed combination with pyridoxine hydrochloride 20 mg (2 tablets) at bedtime.105 If symptoms the next day are adequately controlled, this dosage should be continued daily at bedtime.105 However, if symptoms persist into the afternoon of the second day, a morning dosage of doxylamine succinate 10 mg in fixed combination with pyridoxine hydrochloride 10 mg (1 tablet) should be added on day 3.105 If symptoms are adequately controlled, this daily dosage regimen (1 tablet in the morning and 2 tablets at bedtime) should be continued.105 If symptoms persist, an additional dose of doxylamine succinate 10 mg in fixed combination with pyridoxine hydrochloride 10 mg (1 tablet) should be added midafternoon on day 4, for a maximum total daily dosage of 4 tablets (1 in the morning, 1 midafternoon, and 2 at bedtime).105

When used as doxylamine/pyridoxine extended-release tablets (Bonjesta^®) for the treatment of nausea and vomiting of pregnancy that has not responded to conservative management, the recommended initial dosage is doxylamine succinate 20 mg in fixed combination with pyridoxine hydrochloride 20 mg (1 tablet) at bedtime.106 If symptoms the next day are adequately controlled, this dosage should be continued daily at bedtime.106 However, if symptoms persist into the second day, a morning dosage of doxylamine succinate 20 mg in fixed combination with pyridoxine hydrochloride 20 mg (1 tablet) should be added for a maximum daily dosage of 2 tablets (1 in the morning and 1 at bedtime).106

Fixed-combination therapy with doxylamine and pyridoxine should be taken regularly, not on an as-needed basis.105,106 The need for continued therapy should be reassessed as the patient's pregnancy progresses.105,106

Allergic Rhinitis

As an antihistamine, the usual dosage of doxylamine succinate for self-medication in adults and children 12 years of age or older is 7.5-12.5 mg every 4-6 hours, not to exceed 75 mg in 24 hours. Alternatively, under the direction of a clinician, these adults and children may receive dosages up to 25 mg every 4-6 hours, or 2 mg/kg or 60 mg/m² daily in divided doses, not to exceed 150 mg daily. For self-medication in children 6 to younger than 12 years of age, the usual antihistaminic dosage is 3.75-6.25 mg every 4-6 hours, not to exceed 37.5 mg in 24 hours. Alternatively, under the direction of a clinician, these children may receive dosages up to 12.5 mg every 4-6 hours, or 2 mg/kg or 60 mg/m² daily in divided doses, not to exceed 75 mg daily. Under the direction of a clinician, children 2 to younger than 6 years of age may receive an antihistaminic dosage of 1.9-3.125 mg every 4-6 hours, not to exceed 18.75 mg in 24 hours. (See Cautions: Pediatric Precautions.)

Doxylamine shares the toxic potentials of other antihistamines, and the usual precautions of antihistamine therapy should be observed. (See Cautions in the Antihistamines General Statement 4:00.)

Precautions and Contraindications

Contraindications

Doxylamine succinate is contraindicated in patients with known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation.105,106

Doxylamine in fixed combination with pyridoxine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.105,106

Use of Fixed Combinations

When doxylamine is used in fixed combination with pyridoxine, the usual cautions, precautions, and contraindications associated with pyridoxine must be considered in addition to those associated with doxylamine.105,106

Pediatric Precautions

Like other antihistamines, doxylamine should not be used in premature or full-term neonates. (See Cautions: CNS Effects and Pediatric Precautions, in the Antihistamines General Statement 4:00.) Safety and efficacy of doxylamine as a nighttime sleep aid in children younger than 12 years of age have not been established.102 In addition, children may be more prone than adults to paradoxically experience CNS stimulation rather than sedation when antihistamines are used as nighttime sleep aids. Because doxylamine may cause marked drowsiness that may be potentiated by other CNS depressants (e.g., sedatives, tranquilizers), the antihistamine should be used in children receiving one of these drugs only under the direction of a physician. As an antihistamine, doxylamine should be used in children 2 to younger than 6 years of age only under the direction of a physician; use of the drug in children younger than 2 years of age is not recommended.

Safety and efficacy of doxylamine succinate in fixed combination with pyridoxine hydrochloride in children younger than 18 years of age have not been established.105,106

Overdosage of doxylamine has been reported in children.105,106 Manifestations have included coma, generalized tonic-clonic (grand mal) seizures, cardiorespiratory arrest, and death.105,106 The manufacturer states that children appear to be at high risk for cardiorespiratory arrest secondary to doxylamine overdosage.105,106

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving preparations containing antihistamines (including doxylamine), cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the FDA) for the symptomatic treatment of cold and cough have not been established. Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in the Antihistamines General Statement 4:00.

Pregnancy and Lactation

Pregnancy

Doxylamine succinate in fixed combination with pyridoxine hydrochloride is intended for use in the management of nausea and vomiting of pregnancy.105,106,108,110

Numerous epidemiologic studies (including cohort studies, case-control studies, and meta-analyses) have been performed to investigate possible teratogenic effects of doxylamine in fixed combination with pyridoxine in pregnant women.105,106,111,112 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 in fixed combination, with or without dicyclomine hydrochloride (a drug included in a combination product that was previously commercially available for nausea and vomiting of pregnancy).105,106,111 Another meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no clinically important associations between fetal abnormalities and first trimester exposure to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.105,106,112 A reanalysis of data from another meta-analysis supporting the safety of doxylamine during pregnancy found that the strength of the data had been overstated, both in terms of the numbers of patients exposed to doxylamine succinate and the reported odds ratio, which suggested a potential protective effect of antihistamines with regard to fetal malformations.117,118 However, the reanalysis did not find evidence of an increased risk of fetal malformations associated with doxylamine use.118

Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine; however, after evaluating extensive data and information concerning the possible teratogenicity of the drug, FDA concluded that it is unlikely that doxylamine is teratogenic. FDA recognized, however, that despite the large number of pregnancies evaluated to date the possibility that doxylamine may be weakly teratogenic cannot be excluded. Doxylamine was commercially available in the US for the treatment of nausea and vomiting associated with pregnancy in combination with dicyclomine and pyridoxine until 1976, and then in combination with only pyridoxine until 1983 when the manufacturer voluntarily discontinued manufacturing and distributing the combination. FDA stated that the removal of products containing doxylamine and pyridoxine that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness.109 Most epidemiologic studies (case-control and cohort) in which fixed combinations of doxylamine and pyridoxine with or without dicyclomine were used during pregnancy indicate that an association between use of these combinations and adverse fetal effects does not appear to exist.111,112 In a few studies, a weak association between use of the fixed combinations during pregnancy and specific fetal abnormalities (e.g., pyloric stenosis, cardiac defects, oral clefts) was reported, but a causal relationship with the drugs was not established and these findings have not been confirmed by many other studies. Women considering self-medication with doxylamine during pregnancy should consult a health professional for advice regarding the relative risks and benefits of such therapy.101,102

Most reproduction studies in various animal species using doxylamine and pyridoxine alone or in fixed combination have not revealed evidence of harm to the fetus. Studies in rats and mice using doxylamine succinate dosages up to 125 times the maximum human dosage did not reveal evidence of observable congenital abnormalities, but wavy ribs and diaphragmatic hernias occurred in rats at dosages 125-375 times the maximum human dosa an overall increase in fetal wastage, varying from zero to threefold, occurred in most rodents receiving dosages 125 or more times greater than the maximum human dosage. Once daily administration of doxylamine succinate and pyridoxine hydrochloride in pregnant rats during organogenesis (gestational day 6-15) resulted in increased fetal resorptions, decreased fetal body weight, and increased skeletal variations with reduced ossification at dosages 60-100 times the highest clinical dosage based on body surface area.105 In a study in pregnant cynomolgus monkeys receiving doxylamine succinate and pyridoxine hydrochloride once daily during organogenesis (gestational day 22-50) at dosages up to 3.2 times the highest proposed clinical dosage based on body surface area, there were no observed malformations and no evidence of embryo, fetal, or maternal toxicity.105 In another study in pregnant cynomolgus and rhesus monkeys and baboons receiving doxylamine succinate and pyridoxine hydrochloride at dosages 0.5-20 times higher than the clinical dosage based on body surface area, ventricular septal defects were observed in preterm (gestational day 100) fetuses; no relationship between dosage and incidence of ventricular septal defects was observed, and no ventricular septal defects were observed in infant monkeys at term.105 In addition, no ventricular septal defects were observed at gestational day 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.105 In a small study in monkeys receiving a fixed combination of doxylamine succinate and pyridoxine hydrochloride throughout fetal organogenesis at dosages 10-20 times the maximum human dosage, intraventricular septal defects were present in 4 of 7 fetuses delivered on day 100 of gestation (full-term gestation is about 160 days), while 2 fetuses aborted on the 46th and 56th day of gestation appeared to be developing normally and 3 other fetuses allowed to develop to term were normal. The importance of septal defects in these monkeys is not known, since an opening in the septum is usually present early during fetal development in monkeys. In other studies in monkeys receiving the fixed combination for shorter periods of time, there was no evidence of fetal toxicity.

Lactation

Doxylamine succinate is expected to be distributed into human milk, because of its low molecular weight.103,105,106 Adverse effects (e.g., excitement, irritability, and sedation) have been reported in infants presumably exposed to doxylamine through human milk.105,106 Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of doxylamine.105,106 Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman. The manufacturer of doxylamine/pyridoxine in fixed combination states that this preparation should not be used in nursing women.105,106

Pharmacokinetics

Following oral administration of a single 25-mg dose of doxylamine succinate in healthy adults, mean peak plasma concentrations of about 100 ng/mL occur within 2-3 hours after administration. Doxylamine is absorbed from the GI tract, principally in the jejunum.105 Sedative effects occur approximately 30 minutes after oral administration.102 The drug has an elimination half-life of about 10 hours in healthy adults.

Following oral administration of a single dose (2 tablets; each tablet containing doxylamine succinate 10 mg in fixed combination with pyridoxine hydrochloride 10 mg) as delayed-release tablets in healthy, nonpregnant women, mean peak plasma concentrations of doxylamine occurred within about 7.2 hours after administration.105 Following oral administration of a single dose of doxylamine succinate 20 mg in fixed combination with pyridoxine hydrochloride 20 mg as extended-release tablets in healthy, premenopausal women in the fasting state, mean peak plasma concentrations of doxylamine occurred within about 4.5 hours after administration.106 A delay in doxylamine absorption has been reported when the fixed combination of doxylamine and pyridoxine (as delayed- or extended-release tablets) is administered with food; however, the extent of doxylamine absorption was not affected.105,106 (See Dosage and Administration: Administration.)

In a single-dose, crossover trial in healthy, premenopausal women, one extended-release tablet containing doxylamine succinate 20 mg and pyridoxine hydrochloride 20 mg was bioequivalent to two delayed-release tablets (each tablet containing doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg per tablet).106 In a multiple-dose, crossover trial in healthy, premenopausal women, one extended-release tablet containing doxylamine succinate 20 mg and pyridoxine hydrochloride 20 mg given twice daily for 11 days was bioequivalent to the delayed-release tablets containing doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg per tablet given as 1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime.106

Doxylamine is metabolized in the liver by N -dealkylation mainly to N -desmethyldoxylamine and N,N -didesmethyldoxylamine.105,106 These metabolites of doxylamine are mainly excreted by the kidneys.105,106 When administered as the fixed combination containing doxylamine and pyridoxine in healthy fasting premenopausal women, the terminal elimination half-life of doxylamine is approximately 11.9 or 12.5 hours for the extended-release or delayed-release formulation, respectively.105,106 Accumulation of doxylamine has been observed following multiple-dose administration of the delayed-release tablets; however, time to reach peak concentration was not affected by multiple doses.105

Chemistry and Stability

Chemistry

Doxylamine is an ethanolamine-derivative antihistamine. Doxylamine succinate occurs as a white or creamy white powder with a characteristic odor and has solubilities of approximately 1 g/mL in water and 0.5 g/mL in alcohol at 25°C. The drug has pK_a values of 5.8 and 9.3. A 1% aqueous solution of doxylamine succinate has a pH of 4.8-5.2.

Stability

Doxylamine succinate tablets should be stored at a temperature of 20-25°C.102

Doxylamine succinate/pyridoxine hydrochloride delayed-release and extended-release tablets should be stored in tightly closed containers at 20-25°C (may be exposed to 15-30°C).105,106 The tablets should be protected from moisture, and the desiccant canister should not be removed from the bottle.105,106

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of doxylamine, see the Antihistamines General Statement 4:00.

Please see the general statement for a list of references.