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Doxylamine Succinate

Class: First Generation Antihistamines
ATC Class: R06AA09
VA Class: AH102
CAS Number: 562-10-7
Brands: Bonjesta (combination), Diclegis (combination), Good Sense Sleep Aid, Unisom

Medically reviewed on Sep 24, 2018

Introduction

First generation antihistamine; an ethanolamine derivative.103 105 106 a b

Uses for Doxylamine Succinate

Insomnia

Self-medication for short-term management of insomnia,a particularly in individuals who have difficulty falling asleep.102

Safety and efficacy not fully established; however, FDA states that, pending further accumulation of data, doxylamine-containing nighttime sleep aids approved for this use may continue to be marketed in the US.

Nausea and Vomiting of Pregnancy

Used in fixed combination with pyridoxine for treatment of nausea and vomiting of pregnancy in women not responding to conservative management.105 106 110

Not studied in patients with hyperemesis gravidarum.105 106

Allergic Rhinitis

Temporary relief of rhinorrhea, sneezing, lacrimation, itching eyes, or oronasopharyngeal itching associated with allergic rhinitis (e.g., hay fever) or other upper respiratory allergies.101

Doxylamine Succinate Dosage and Administration

Administration

Oral Administration

Administer orally as tablets.102 105 106 a

Delayed-release and extended-release tablets: Administer on an empty stomach with a glass of water.105 106 Swallow whole; do not chew, crush, or split.105 106

Dosage

Available as doxylamine succinate; dosage expressed in terms of the salt.102

Also available as fixed-combination tablets containing doxylamine succinate and pyridoxine hydrochloride.105 106

Individualize dosage according to patient’s response and tolerance.b

Pediatric Patients

Insomnia
Oral

Self-medication in children ≥12 years of age: 25 mg 30 minutes before retiring or as directed by a clinician.102

Allergic Rhinitis

Children 2 to <6 years of age: 1.9–3.125 mg every 4–6 hours, not to exceed 18.75 mg in 24 hours.

Children 6 to <12 years of age: For self-medication, 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, 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.

Children ≥12 years of age: For self-medication, 7.5–12.5 mg every 4–6 hours, not to exceed 75 mg in 24 hours. Alternatively, under the direction of a clinician, 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.

Adults

Insomnia
Oral

Self-medication: 25 mg 30 minutes before retiring or as directed by a clinician.102

Nausea and Vomiting of Pregnancy
Oral

Doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg delayed-release tablets (Diclegis): Initially, 2 tablets at bedtime.105 If symptoms the next day are adequately controlled, continue this dosage daily at bedtime.105 If symptoms persist into the afternoon of day 2, add 1 tablet in the morning on day 3.105 If symptoms are adequately controlled, continue this daily dosage regimen (1 tablet in the morning and 2 tablets at bedtime).105 If symptoms persist, add 1 tablet midafternoon on day 4.105

Doxylamine succinate 20 mg/pyridoxine hydrochloride 20 mg extended-release tablets (Bonjesta): Initially, 1 tablet at bedtime.106 If symptoms the next day are adequately controlled, continue this dosage daily at bedtime.106 If symptoms persist, add 1 tablet in the morning to the regimen.106

Delayed- or extended-release tablets: Take on schedule, not on an as-needed basis.105 106 Reassess need for continued therapy as pregnancy progresses.105 106

Allergic Rhinitis
Oral

Self-medication: 7.5–12.5 mg every 4–6 hours, not to exceed 75 mg in 24 hours. Alternatively, under the direction of a clinician, 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.

Prescribing Limits

Pediatric Patients

Insomnia
Oral

Self-medication in children ≥12 years of age: Maximum 2 weeks.102

Allergic Rhinitis
Oral

Children 2 to <6 years of age: Maximum 18.75 mg in 24 hours.

Children 6 to <12 years of age: For self-medication, maximum 37.5 mg in 24 hours. Under the direction of a clinician, maximum 75 mg daily.

Children ≥12 years of age: For self-medication, maximum 75 mg in 24 hours. Under the direction of a clinician, maximum 150 mg daily.

Adults

Insomnia
Oral

Self-medication: Maximum 2 weeks.102

Allergic Rhinitis
Oral

For self-medication, maximum 75 mg in 24 hours. Under the direction of a clinician, maximum 150 mg daily.

Nausea and Vomiting of Pregnancy
Oral

Doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg delayed-release tablets (Diclegis): Maximum 4 tablets daily (i.e., 1 tablet in the morning, 1 tablet midafternoon, 2 tablets at bedtime).105

Doxylamine succinate 20 mg/pyridoxine hydrochloride 20 mg extended-release tablets (Bonjesta): Maximum 2 tablets daily (i.e., 1 tablet in the morning, 1 tablet at bedtime).106

Cautions for Doxylamine Succinate

Contraindications

Known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation.105 106

Doxylamine/pyridoxine fixed-combination therapy: Concomitant use of MAO inhibitors.105 106 (See Specific Drugs and Laboratory Tests under Interactions.)

Warnings/Precautions

Warnings

Use of Fixed Combinations

When used in fixed combination with pyridoxine, consider usual cautions, precautions, and contraindications associated with pyridoxine in addition to those associated with doxylamine.105 106

Concomitant Diseases

Because of possible anticholinergic effects (e.g., dryness of mouth, nose, and throat; dysuria; urinary retention),b patients with glaucoma, respiratory conditions (e.g., emphysema, chronic bronchitis), or difficulty urinating due to prostatic hypertrophy should consult a clinician before initiating therapy with doxylamine.101 102

Use with caution, if at all, in patients with asthma, increased IOP, angle-closure glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, or bladder neck obstruction.105 106 b

Use not recommended, unless under the direction of a clinician, in patients who have a breathing problem (e.g., emphysema, chronic bronchitis). Use generally not recommended in asthmatics who previously experienced a serious antihistamine-induced adverse bronchopulmonary effect.

CNS Effects

Risk of marked drowsiness.101 105 106 Caution when driving a motor vehicle or operating machinery.101 105 106 (See CNS Depressants under Interactions and also see Advice to Patients.)

Possible excitability (especially in children).101 b (See Pediatric Use under Cautions.)

General Precautions

Duration of Therapy

When used for insomnia, discontinue therapy and consult a clinician if insomnia persists for >2 weeks.102

Specific Populations

Pregnancy

Category A.103 105

Doxylamine/pyridoxine in fixed combination intended for use in the management of nausea and vomiting of pregnancy.105 106 108 110 No increased risk of congenital malformations associated with the drugs reported in epidemiologic studies of pregnant women.105 106 111 112

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

Lactation

Expected to be distributed into milk.103 105 106 Discontinue nursing or the drug. Do not use doxylamine/pyridoxine fixed-combination therapy in nursing women.105 106

Excitement, irritability, and sedation reported in infants presumably exposed to doxylamine through human milk;105 106 infants with respiratory syndromes (e.g., apnea) may be particularly at risk.105 106

Pediatric Use

Use not recommended in premature or full-term neonates.

Possible paradoxical excitement (e.g., restlessness, insomnia, tremors, euphoria, nervousness, delirium, palpitation, seizures).101 b

Safety and efficacy of doxylamine as a nighttime sleep aid in children <12 years of age not established.102 Consider risk of possible CNS stimulation when used as nighttime sleep aids.

Use as an antihistamine only under the direction of a clinician in children 2 to <6 years of age; use in children <2 years of age not recommended.

Safety and efficacy of doxylamine/pyridoxine in fixed combination in children <18 years of age not established.105 106

Risk of overdosage of doxylamine in children; manifestations include coma, generalized tonic-clonic (grand mal) seizures, cardiorespiratory arrest (children at high risk), death.105 106

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established. Therefore, FDA recommended not to use such preparations in children <2 years of age; safety and efficacy in older children under evaluation. 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 <4 years of age. FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns. Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.

Geriatric Use

Possible increased risk of dizziness, sedation, and hypotension.b

Common Adverse Effects

Drowsiness.101 105 106

Interactions for Doxylamine Succinate

Specific Drugs and Laboratory Tests

Drug or Laboratory Test

Interaction

Comments

CNS depressants (e.g., alcohol, hypnotics, sedatives, tranquilizers)

Possible additive CNS depression101 b

Avoid alcohol and other CNS depressants101 102 104 105 106

MAO inhibitors

MAO inhibitors prolong and intensify adverse CNS effects (i.e., anticholinergic effects) of antihistamines105 106 b

Concomitant use contraindicated105 106

Test, antigen or histamine

Inhalation-challenge testing with histamine or antigen: Possible suppression of test response

Antigen skin testing: Possible suppression of wheal and flare reactions

Doxylamine Succinate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations occur within 2–3 hours after oral administration.

Absorbed from the GI tract, mainly in the jejunum.105

Doxylamine/pyridoxine delayed-release tablets in fixed combination: Peak plasma concentrations of doxylamine occur about 7.2 hours after oral administration.105

Doxylamine/pyridoxine extended-release tablets in fixed combination: Peak plasma concentrations of doxylamine occur about 4.5 hours after oral administration.106

One doxylamine succinate 20 mg/pyridoxine hydrochloride 20 mg extended-release tablet was bioequivalent to 2 doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg delayed-release tablets.106

One doxylamine succinate 20 mg/pyridoxine hydrochloride 20 mg extended-release tablet given twice daily for 11 days was bioequivalent to 4 doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg delayed-release tablets daily given as 1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime.106

Doxylamine/pyridoxine delayed-release tablets in fixed combination: Accumulation of doxylamine observed following multiple-dose administration; time to reach peak concentration not affected by multiple doses.105

Onset

Sedative effects occur approximately 30 minutes after oral administration.102

Effect of Food

Delayed- or extended-release tablets (doxylamine/pyridoxine in fixed combination): Administration of food may delay absorption and onset of action; extent of doxylamine absorption not affected.105 106 (See Administration under Dosage and Administration.)

Distribution

Distribution likely into human milk because of drug's low molecular weight.103 105 106

Elimination

Metabolism

Metabolized in the liver by N-dealkylation to N-desmethyldoxylamine and N,N-didesmethyldoxylamine.105 106

Half-life

Approximately 10 hours.

Delayed-release tablets (doxylamine/pyridoxine in fixed combination): Approximately 12.5 hours.105

Extended-release tablets (doxylamine/pyridoxine in fixed combination): Approximately 11.9 hours.106

Excretion

Principal metabolites, N-desmethyldoxylamine and N,N-didesmethyldoxylamine, excreted mainly by the kidneys.105 106

Stability

Storage

Oral

Tablets

Doxylamine tablets: 20–25°C.102 a

Doxylamine/pyridoxine delayed-release and extended-release tablets: 20–25°C (may be exposed to 20–25°C); protect from moisture.105 106 Keep bottle tightly closed; do not remove desiccant canister from bottle.105 106

Actions

  • Blocks H1-receptor sites and prevents the action of histamine on the cell.b

  • Suppresses flare and pruritus that accompany the endogenous release of histamine.b

  • Exhibits some activities common to anticholinergics, ganglionic and adrenergic blocking agents, local anesthetics, and antispasmodics.b

  • Antihistamines do not block the stimulating effect of histamine on gastric acid secretion, which is mediated by the H2-receptors of the parietal cells.b

Advice to Patients

  • Risk of marked drowsiness; avoid alcohol and use caution when driving or operating machinery.101 102 104 105 106 Importance of advising women receiving doxylamine/pyridoxine in fixed combination to not engage in such activities until clinician consulted.105 106

  • When used for insomnia, consult a clinician if sleeplessness persists continuously for >2 weeks.102

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.101 102 Importance of patients already receiving another CNS depressant (e.g., sedatives, tranquilizers) not undertaking self-medication without first consulting a clinician.101 102 Importance of advising women receiving doxylamine/pyridoxine in fixed combination to avoid taking the drug concomitantly with alcohol or other CNS depressants.105 106

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed;101 102 advise women considering self-medication with doxylamine during pregnancy to consult a clinician regarding the relative risks and benefits of such therapy.102

  • Importance of informing patients of other important precautionary information.101 102 105 106 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Doxylamine Succinate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg*

Doxylamine Succinate Tablets

Good Sense Sleep Aid Tablets

Perrigo

Unisom SleepTabs (scored)

Chattem

Doxylamine Succinate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, delayed-release, film-coated

10 mg with Pyridoxine Hydrochloride 10 mg

Diclegis

Duchesnay

Tablets, extended-release, film-coated

20 mg with Pyridoxine Hydrochloride 20 mg

Bonjesta

Duchesnay

Doxylamine succinate is also commercially available in combination with antitussives and decongestants.

AHFS DI Essentials™. © Copyright 2018, Selected Revisions September 24, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

101. Zyber Pharmaceuticals, Inc. Aldex AN (doxylamine succinate) oral suspension prescribing information. Gonzales, LA; undated.

102. Chattem. Unisom SleepTabs (doxylamine succinate) tablets product information. Chattanooga, TN. From Chattem website. Accessed 2017 Oct 24. http://www.unisom.com/our-products/unisom-sleeptabs/

103. Doxylamine. In: Briggs GG, Freeman RK, Towers CV, et al. Drugs in pregnancy and lactation. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017:454-7.

104. Chattem. Unisom SleepTabs (doxylamine succinate) common questions. Chattanooga, TN. Accessed 2017 Apr 19. http://www.unisom.com/common-questions.html

105. Duchesnay USA, Inc. Diclegis (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets prescribing information. Bryn Mawr PA; 2013 Apr.

106. Duchesnay USA, Inc. Bonjesta (doxylamine succinate and pyridoxine hydrochloride) extended-release tablets prescribing information. Bryn Mawr PA; 2016 Nov.

107. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 021876Orig1s000: Summary Review. From FDA website. Accessed 2017 Apr. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/021876Orig1s000SumR.pdf

108. Koren G, Clark S, Hankins GD et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol. 2010; 203:571.e1-7. http://www.ncbi.nlm.nih.gov/pubmed/20843504?dopt=AbstractPlus

109. US Department of Health and Human Services. Federal Register. Determination that Bendectin was not withdrawn from sale for reasons of safety or effectiveness. 1999; 64:43190-1.

110. . American College of Obstetricians and Gynecologists. Practice Bulletin No. 153: Nausea and vomiting of pregnancy. Obstet Gynecol. 2015; 126:e12-24. http://www.ncbi.nlm.nih.gov/pubmed/26287788?dopt=AbstractPlus

111. McKeigue PM, Lamm SH, Linn S et al. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology. 1994; 50:27-37. http://www.ncbi.nlm.nih.gov/pubmed/7974252?dopt=AbstractPlus

112. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharm. 1988; 22:813-24. http://www.ncbi.nlm.nih.gov/pubmed/3229352?dopt=AbstractPlus

113. Persaud N, Chin J, Walker M. Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy?. J Obstet Gynaecol Can. 2014; 36:343-348. http://www.ncbi.nlm.nih.gov/pubmed/24798673?dopt=AbstractPlus

114. Pimlott N, Kvern B, Woollard R. Motherisk and Canadian Family Physician. Can Fam Physician. 2017; 63:13-14. http://www.ncbi.nlm.nih.gov/pubmed/28115431?dopt=AbstractPlus

115. Kutcher JS, Engle A, Firth J et al. Bendectin and birth defects. II: Ecological analyses. Birth Defects Res A Clin Mol Teratol. 2003; 67:88-97. http://www.ncbi.nlm.nih.gov/pubmed/12769504?dopt=AbstractPlus

116. Koren G, Clark S, Hankins GD et al. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial. BMC Pregnancy Childbirth. 2015; 15:59. http://www.ncbi.nlm.nih.gov/pubmed/25884778?dopt=AbstractPlus

117. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol. 1997; 14:119-24. http://www.ncbi.nlm.nih.gov/pubmed/9259911?dopt=AbstractPlus

118. Chin JW, Gregor S, Persaud N. Re-analysis of safety data supporting doxylamine use for nausea and vomiting of pregnancy. Am J Perinatol. 2014; 31:701-10. http://www.ncbi.nlm.nih.gov/pubmed/24323370?dopt=AbstractPlus

119. Matthews A, Haas DM, O'Mathúna DP et al. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2015; :CD007575. http://www.ncbi.nlm.nih.gov/pubmed/26348534?dopt=AbstractPlus

500. Food and Drug Administration. Drugs for human use; unapproved and misbranded oral drugs labeled for prescription use and offered for relief of symptoms of cold, cough, or allergy, enforcement action dates. Notice. [Docket No. FDA-2011-N-0100] Fed Regist. 2011; 76:11794-8.

a. AHFS Drug Information 2018. McEvoy GK, ed. Doxylamine Succinate. Bethesda, MD: American Society of Health-System Pharmacists; 2018:. From AHFS Drug Information website. Accessed 2018 Mar 2. http://www.ahfsdruginformation.com

b. AHFS Drug Information 2018. McEvoy GK, ed. Antihistamines General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2018:1-8.

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