What is doxylamine?

Doxylamine: An H1-Receptor Antagonist with Multiple Clinical Applications

Doxylamine is a first-generation H1-receptor antagonist with antihistamine, anticholinergic, and sedative properties that is FDA-approved for treating insomnia and nausea/vomiting of pregnancy. 1, 2

Pharmacology and Mechanism of Action

• Doxylamine functions as a histamine H1-receptor antagonist that blocks most of the pharmacologic effects of histamine mediated at H1 receptors 3
• Available as doxylamine succinate in 25 mg tablets for over-the-counter sleep aid use 1
• Also available in combination with pyridoxine (vitamin B6) in 10 mg/10 mg and 20 mg/20 mg formulations for treatment of nausea and vomiting of pregnancy 3
• Has a linear and dose-dependent pharmacokinetic profile across therapeutic doses (12.5-25 mg) 4

Clinical Applications

1. Treatment of Insomnia

• Marketed as an over-the-counter nighttime sleep aid (25 mg dose) 1, 5
• Particularly effective for maintenance insomnia (sleep disturbances in the last third of the night) 5
• Sedative effects are due to its central nervous system depressant properties 3, 5

2. Management of Nausea and Vomiting of Pregnancy (NVP)

• FDA-approved in combination with pyridoxine (Diclegis®) for NVP 6, 2
• Recommended by the American College of Obstetricians and Gynecologists (ACOG) as a first-line pharmacologic therapy for persistent NVP refractory to non-pharmacologic interventions 3
• Has FDA Pregnancy Category A status, indicating substantial safety data during pregnancy 2
• Early intervention with doxylamine-pyridoxine may help prevent progression to hyperemesis gravidarum 3

Dosing Considerations

• For insomnia: 25 mg taken orally at bedtime 1
• For NVP: Available in combination with pyridoxine in 10 mg/10 mg or 20 mg/20 mg formulations 3
• Dose proportionality has been demonstrated across the therapeutic range, allowing for predictable increases in systemic exposure 4

Safety Profile and Adverse Effects

• As a first-generation antihistamine, doxylamine can cause significant sedation and drowsiness 3
• Other common adverse effects include:
  • Anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation) 3
  • Dizziness and impaired coordination 3, 4
  • Potential for next-day impairment in cognitive and motor performance 3
• Safety concerns to be aware of:
  • Concomitant use with other CNS depressants (including alcohol) can enhance sedative effects 3
  • Potential for abuse and dependence has been reported in case studies 7
  • First-generation antihistamines like doxylamine have been associated with increased risk of automobile accidents and impaired performance 3

Special Considerations

• Doxylamine-pyridoxine combination has been extensively studied in pregnancy and is considered safe for use in pregnant women 6, 2
• In the treatment algorithm for NVP, doxylamine (with pyridoxine) is positioned as a first-line pharmacologic therapy after non-pharmacologic approaches have failed 3
• For treating insomnia, doxylamine should be used for short-term management only due to potential for tolerance and dependence 5, 7
• Caution is advised in older adults who may be more sensitive to anticholinergic effects 3

Clinical Pearls

• Doxylamine is the only FDA-approved antihistamine specifically indicated for NVP (in combination with pyridoxine) 2
• The sedative effects may persist beyond the intended sleep period, potentially affecting next-day functioning 3
• When used for NVP, early intervention is key to prevent progression to more severe forms of pregnancy-related nausea and vomiting 3
• Despite being available over-the-counter, patients should be counseled about potential for dependence with prolonged use 7