Doxepin (Sinequan)

Primer

Doxepin (Trade name: Sinequan, Silenor) is a tricyclic antidepressant.

Dosing

  • Half-life: 3.5 hours
  • The time to peak concentration (Tmax) of doxepin at 6 mg is about 3.5 hours after oral administration in fasting individuals
    • The Tmax is delayed by approximately an additional 3 hours if doxepin is taken with a high-fat meal.
    • Thus, it is recommended that doxepin be taken without food, to minimize the risk of next day sedation, given it is possible for the Tmax to be as long as 6 hours after taking it.[1]

Indications

  • Insomnia (middle insomnia, doses of 3 to 6 mg qHS in Canada)[2]
  • Best used for the short-term treatment of maintenance (middle) insomnia, not initial insomnia

Mechanism

  • Doxepin is highly histaminergic and often used as a reference standard in drug comparison studies when looking at histaminergic activity.
    • Doxepin is the most potent antihistamine of the tricyclic antidepressants, with 4x the potency of amitriptyline and 800x the potency of diphenhydramine at the H1 receptor.[3]
  • At ultra-low dose ranges between 3 to 6 mg, there is very little muscarinic antagonism and highly selective H1 receptor antagonism
    • Thus, at these dose ranges, there are little to no anticholinergic effect[4]
    • Above 25 mg per day, doxepin’s selectivity for H1 receptors is lost and additional receptors (e.g., muscarinic, noradrenergic) are involved, increase the risk for anticholinergic activity.[5]

References

1) Atkin T, Comai S, Gobbi G. Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery. Pharmacol Rev. 2018 Apr;70(2):197-245. doi: 10.1124/pr.117.014381. PMID: 29487083.
2) Roth, T., Rogowski, R., Hull, S., Schwartz, H., Koshorek, G., Corser, B., ... & Lankford, A. (2007). Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep, 30(11), 1555-1561.
3) Atkin T, Comai S, Gobbi G. Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery. Pharmacol Rev. 2018 Apr;70(2):197-245. doi: 10.1124/pr.117.014381. PMID: 29487083.
4) Rojas-Fernandez, C. H., & Chen, Y. (2014). Use of ultra-low-dose (≤ 6 mg) doxepin for treatment of insomnia in older people. Canadian Pharmacists Journal/Revue des Pharmaciens du Canada, 147(5), 281-289.
5) Roth, T., Rogowski, R., Hull, S., Schwartz, H., Koshorek, G., Corser, B., ... & Lankford, A. (2007). Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep, 30(11), 1555-1561.