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Doxepin Pharmacodynamics: Indication or Adverse Effect?

Doxepin is a tricyclic antidepressant first approved for the treatment of depression in 1969 by the FDA. Tricyclic antidepressants are famous for their anticholinergic adverse effects including sedation and have been replaced by better-tolerated medications as first-line agents for depression. Doxepin pharmacodynamics helps determine what indications it may be beneficial for. Doxepin specifically, has a unique pharmacodynamic profile that makes it possible to selectively enhance sedation while avoiding other anticholinergic effects. In vitro studies show a much higher affinity of doxepin for receptors of sedation (histamine H1) than receptors associated with other “adverse effects” such as acetylcholine, norepinephrine, and serotonin. What this means is that at low doses, doxepin can quite selectively cause sedation and therefore be used as a treatment for insomnia.

Effectiveness

The starting dose of doxepin in depression is typically 75mg daily with a max daily dose of 300mg. Doses of 25-50mg have been shown to be effective for sleep with few adverse effects compared to placebo. Based on 6 placebo-controlled trials investigating doxepin doses of 1-6mg in adults with transient or chronic insomnia, the FDA approved Silenor (doxepin 3, 6mg tablets) in 2010 for the treatment of insomnia in people with difficulty staying asleep. A REMS program was subsequently removed in 2011 as safety and efficacy were evaluated. Silenor is an immediate release doxepin formulation that is given 30 minutes prior to sleep, without food at a starting dose of 6mg in adults and 3mg in ages 65+. The max dose is 6mg daily. Clinical trials consistently showed benefit in both subjective and objective scores of sleep quality with 10-50 minutes of increased sleep time with doxepin compared to control. Adverse effects were mild and did not vary with respect to placebo.

Affordability

Silenor is often not covered by insurance. If covered, Silenor requires prior authorization, step-therapy, or is in tier 3 of most plans. With a wholesale acquisition cost of ~$500/month, this medication is not affordable for most. Generic Silenor is now available, though the cost of it is not much cheaper at ~400/month. Alternatively, generic doxepin 10mg capsules and doxepin 6mg/0.6mL oral solution are ~$10 and ~$5/month, respectively. Doxepin doses of greater than 6mg are listed on the American Geriatrics Society Beers Criteria for potentially inappropriate medications in the elderly, however at doses 10-30 times lower than common antidepressant doses it is unlikely that risk outweighs the cost-savings benefits of these formulations. Importantly, doxepin doses of greater than 6mg are off-label use for the treatment of insomnia.

The doxepin pharmacodynamics allow it to be a potential option for insomnia.  At low dosages, this is an option in the elderly when other options such as Z-drugs, benzodiazepines, and antipsychotics are listed on Beers Criteria at all effective doses. Dose escalation of doxepin should likely be avoided in the elderly due to the probable occurrence of anticholinergic activity. Cost is a serious barrier (Slienor) and thus I have only seen this medication used a few times. Most commonly, I have seen the cheaper product used when the patient suffers from itching and insomnia at night. Have you seen this medication (brand or generic) used for insomnia in your practice? Comment below!

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The article was written by Evan Odean in collaboration with Eric Christianson, PharmD, BCGP, BCPS.

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Sources:

Weber Juliane M, Siddiqui Asif A, Wagstaff Antona J, et al. Low-Dose Doxepin In the Treatment of Insomnia. CNS Drugs 2010; 24(8): 713-720.

Product Information: Silenor, doxepin hydrochloride tablet. [package insert]. Currax Pharmaceuticals LLC, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1bec1223-5239-4eb6-a9e8 62444106d2c0. Accessed 20 February, 2021.

Doxepin Hydrochloride. Micromedex Solutions. Micromedex Solutions [online]. Updated 1 February, 2021. IBM. Accessed 10 February, 2021.

U.S. Food & Drug Administration. Druga@FDA: FDA-Approved Drugs. Silenor. Silver Spring, MD. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=02 036. Accessed 10 February, 2021.

Written By Eric Christianson

February 21, 2021

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