Doxepin

For depression, the capsule label recommends starting at 25 mg three times a day or 75 mg once a day, aiming for 75 to 150 mg a day, with a maximum of 100 mg three times a day. It notes that the mechanism in depression is not well understood [1]. Silenor is used at far lower doses: 6 mg once a day for adults, 3 mg for some patients and as the starting dose for people 65 and older, and never more than 6 mg a day [2].

Most of each dose, 55% to 87%, is metabolized on its first pass through the liver, forming the active metabolite nordoxepin (N-desmethyldoxepin) [1]. The Silenor label names CYP2C19 and CYP2D6 as the main enzymes, with smaller roles for CYP1A2 and CYP2C9, and gives half-lives of about 15 hours for doxepin and 31 hours for nordoxepin [2]. CPIC notes that doxepin's first-pass metabolism, at about 70% on average, is higher than the roughly 50% typical of tricyclics [3].

Doxepin is a mixture of two isomers, E and Z, and the two genes act on them differently. In a study of healthy volunteers given a single 75 mg dose, clearance of E-doxepin was 406, 247 and 127 L/h in CYP2D6 normal, intermediate and poor metabolizers, and normal metabolizers had about half the bioavailability of poor metabolizers, a sign of how much CYP2D6 removes on the first pass. CYP2C19 mattered mainly for Z-doxepin, whose clearance was 73 L/h in CYP2C19 poor metabolizers against 191 L/h in normal metabolizers. Exposure to the active metabolite, desmethyldoxepin, was about four times higher in CYP2D6 poor metabolizers (median AUC 5.28 against 1.28). The authors concluded that CYP2D6 poor metabolizers might be at higher risk of side effects at common doses [4].

The amitriptyline page explains how the two genes are scored and why tricyclics are read as a pair. In CPIC's frequency tables, about 6.5% of people of European ancestry are CYP2D6 poor metabolizers [5], and CYP2C19 poor metabolizers are about 2.4% of people of European ancestry and 13% of people of East Asian ancestry [6].

Doxepin's FDA label goes further than most tricyclic labels. The capsule label says the recommended dose in CYP2D6 and CYP2C19 poor metabolizers is lower than in normal metabolizers and tells prescribers to reduce the dose based on doxepin blood levels; it gives the same instruction for people taking strong CYP2D6 inhibitors [1]. FDA's Table of Pharmacogenetic Associations lists doxepin with both genes in its first section, for associations where the data support therapeutic management recommendations; the other tricyclics on this site appear only in its section on drug levels. For doxepin, FDA summarizes that poor metabolizers have higher levels and a higher risk of side effects, and may need dose reductions [7]. The Silenor label itself has no genotype-specific dosing [2].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) considers it reasonable to extend its amitriptyline recommendations to doxepin, with fewer supporting data [3]. Both genes are CPIC level B: genetic information could be used to change prescribing, because alternative therapy or dosing is extremely likely to be as effective and safe as non-genetic dosing [8]. CPIC's tables are written for antidepressant doses and do not address the 3 mg and 6 mg doses used for insomnia [3].

When both genes have a result, a Gene2Rx report shows one combined CPIC recommendation. The advice in each cell matches the amitriptyline table, but CPIC rates every doxepin recommendation optional except a normal result for both genes [3][9]. CYP2D6 groups follow the activity score: poor 0, intermediate 0.25 to 1, normal 1.25 to 2.25, ultrarapid above 2.25 [10].

If only one gene has a result, the single-gene advice matches the rows in which the other gene is normal.

The Dutch Pharmacogenetics Working Group (DPWG) gives specific numbers in its 2026 tricyclic guideline: 40% of the normal doxepin dose for CYP2D6 poor metabolizers, 80% for intermediate metabolizers and twice the normal dose for ultrarapid metabolizers [12]. Gene2Rx reports use the CPIC recommendations.

Bring the report to your prescriber or pharmacist, and say which form of doxepin you take, because the dose differs more than tenfold between the products. CPIC considers genotype-guided dosing most useful when a tricyclic is started [3]. Do not start, stop or change doxepin because of a genetic result without talking to your prescriber.

Medicines that change the picture

Drugs that block CYP2D6 or CYP2C19 can raise doxepin levels in people with normal genes, which is called phenoconversion. FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors, and fluconazole, fluoxetine, fluvoxamine and ticlopidine as strong CYP2C19 inhibitors [13]. The capsule label calls for monitoring doxepin levels with strong CYP2D6 inhibitors and with cimetidine, and for possibly raising the dose with carbamazepine, which lowers doxepin exposure [1]. Cimetidine doubles Silenor exposure, so the Silenor label caps the dose at 3 mg when the two are combined [2].

Other factors

Sedating drugs, doxepin included, may cause confusion and oversedation in older adults, who usually start on lower doses [1]. Alcohol and other sedatives add to doxepin's sedation, and the capsule label advises avoiding alcohol [1].

Consumer arrays from 23andMe, AncestryDNA and MyHeritage are not clinical-grade tests, and their raw data is labeled as not for medical use. They read fixed positions and can miss rare variants. Array processing uses imputation to infer some variants that were not measured directly, but a variant at a position the data does not cover cannot be seen, so a normal result means none of the assessed variants was found among the positions your data covers. "Indeterminate" means the alleles found could not be assigned a function.

The label's own instruction for poor metabolizers relies on doxepin blood levels, which measure actual exposure whatever the cause. A clinical CYP2D6 and CYP2C19 test can be worth asking about when the answer will drive a decision.

I take Silenor for sleep. Does my result matter?

The Silenor label has no genotype-specific dosing, and CPIC's tables are written for antidepressant doses [2][3]. The same enzymes clear the drug at any dose, so a poor metabolizer result is still worth mentioning to your prescriber.

Is doxepin cream affected?

The guidance on this page is for doxepin taken by mouth. The CPIC guideline and the labels cited here do not cover the cream.

1. Doxepin hydrochloride capsules (Mylan): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, CYP2D6 and CYP2C19 poor metabolizer dosing and interactions.
2. Silenor (doxepin) tablets (Currax): prescribing information. DailyMed, US National Library of Medicine. Low-dose doxepin for insomnia: dosing, metabolism and the cimetidine interaction.
3. Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther (2017). CPIC recommendations, tricyclic metabolism, dose scope and evidence summary.
4. Kirchheiner J et al. Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics (2002). Doxepin clearance by CYP2D6 and CYP2C19 genotype.
5. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
6. CPIC. CYP2C19 frequency table (spreadsheet). Phenotype frequencies by biogeographic group.
7. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
8. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
9. CPIC guideline for CYP2D6, CYP2C19 and tricyclic antidepressants (ClinPGx guideline page). Current recommendation tables, including updates since publication.
10. Caudle KE et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci (2020). The CYP2D6 activity score ranges used since 2019.
11. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
12. Kleine Schaars K et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and CYP2C19 and tricyclic antidepressants. Eur J Hum Genet (2026). The Dutch tricyclic recommendations.
13. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP2C19 inhibitors and inducers.