Introduction
Doxylamine succinate is a first-generation ethanolamine antihistamine with sedative properties. Originally developed in the 1940s, it remains widely used today primarily for its sedative effects in over-the-counter sleep aids and its antiemetic properties in combination products for nausea and vomiting during pregnancy. Doxylamine is classified as an H1 receptor antagonist and is structurally related to other ethanolamine-class antihistamines.
Mechanism of Action
Doxylamine exerts its therapeutic effects through competitive antagonism of histamine H1 receptors in the central nervous system. Its sedative properties result from its ability to cross the blood-brain barrier and block central H1 receptors. The antiemetic effects are mediated through action on the chemoreceptor trigger zone in the area postrema of the medulla oblongata. As a first-generation antihistamine, doxylamine also possesses anticholinergic, antiemetic, and local anesthetic properties.
Indications
- FDA-approved for the treatment of short-term insomnia
- FDA-approved in combination with pyridoxine for the treatment of nausea and vomiting during pregnancy
- Off-label uses include:
- Allergic rhinitis and urticaria - Motion sickness prevention - Adjunct therapy for parkinsonian symptoms
Dosage and Administration
Adults (Insomnia): 25 mg orally 30 minutes before bedtime Pregnancy-related nausea/vomiting: 10 mg doxylamine/10 mg pyridoxine combination tablet (Diclegis®/Diclectin®) - specific dosing regimen per product labeling Special Populations:- Geriatric: Consider lower starting dose due to increased sensitivity
- Hepatic impairment: Use with caution; consider dose reduction
- Renal impairment: Use with caution
- Pediatrics: Safety and efficacy not established for children under 12 years
Pharmacokinetics
Absorption: Rapidly absorbed from GI tract; peak plasma concentrations reached within 2-3 hours Distribution: Widely distributed throughout body tissues; crosses blood-brain barrier and placenta Metabolism: Extensively metabolized in the liver via cytochrome P450 system Elimination: Half-life approximately 10-12 hours; excreted primarily in urine as metabolites Protein binding: Approximately 75-80%Contraindications
- Hypersensitivity to doxylamine or other ethanolamine-class antihistamines
- Concomitant use with monoamine oxidase inhibitors (MAOIs)
- Narrow-angle glaucoma
- Urinary retention
- Severe hepatic impairment
- Neonates and premature infants
Warnings and Precautions
- CNS Depression: May impair mental and physical abilities; caution when operating machinery
- Anticholinergic Effects: May cause dry mouth, blurred vision, urinary retention
- Sleep Behaviors: Complex sleep behaviors including sleep-walking, sleep-driving reported
- Pregnancy: Category A in combination with pyridoxine for nausea/vomiting; Category B when used alone
- Geriatric Patients: Increased risk of falls, confusion, and anticholinergic effects
- Asthma/COPD: May thicken secretions and impair expectoration
Drug Interactions
- CNS Depressants: Enhanced sedation with alcohol, benzodiazepines, opioids
- MAOIs: Contraindicated due to risk of hypertensive crisis
- Anticholinergics: Additive anticholinergic effects with tricyclic antidepressants, antipsychotics
- Hepatic Enzyme Inhibitors: May increase doxylamine concentrations (e.g., cimetidine, ketoconazole)
- Hepatic Enzyme Inducers: May decrease doxylamine efficacy (e.g., rifampin, carbamazepine)
Adverse Effects
Common (>10%):- Drowsiness/sedation
- Dry mouth
- Dizziness
- Headache
- Gastrointestinal disturbances
- Blurred vision
- Urinary retention
- Paradoxical excitation (especially in children)
- Anaphylaxis
- Blood dyscrasias
- Hepatotoxicity
- Cardiac arrhythmias
Monitoring Parameters
- Efficacy of intended indication (sleep quality, nausea control)
- Signs of excessive sedation or CNS depression
- Anticholinergic side effects (dry mouth, urinary retention, constipation)
- Mental status changes in elderly patients
- Fall risk assessment in vulnerable populations
- Liver function tests with long-term use
Patient Education
- Take medication 30 minutes before bedtime for sleep indication
- Avoid alcohol and other CNS depressants during therapy
- Be cautious when driving or operating machinery until effects are known
- Rise slowly from sitting/lying position to prevent dizziness
- Report any unusual behaviors during sleep (sleep-walking, sleep-driving)
- Use sugar-free formulations if diabetic due to potential for dry mouth
- Do not crush or chew extended-release formulations
- Store at room temperature away from moisture and heat
References
1. Pharmaceutical Press. Martindale: The Complete Drug Reference. 38th ed. London: Pharmaceutical Press; 2014. 2. Drugs.com. Doxylamine Monograph. Updated 2023. 3. FDA prescribing information for Diclegis® (doxylamine succinate and pyridoxine hydrochloride). 4. TGA approved Product Information for Restavit® (doxylamine succinate). 5. Matok I, Clark S, Caroillon L, et al. Study of the safety of doxylamine in pregnancy. J Allergy Clin Immunol. 2012;129(3):S1-S10. 6. American Academy of Sleep Medicine. Clinical guidelines for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504. 7. Lexicomp Online. Doxylamine monograph. Wolters Kluwer Clinical Drug Information, Inc. 2023.