Doxepin Hydrochloride Prescribing Information
In pooled analyses of placebo-controlled trials of antidepressant drugs including tricyclic antidepressants and other antidepressant classes that included approximately 77,000 adult patients and 4,500 pediatric patients (doxepin hydrochloride is not approved for use in pediatric patients), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.
Age Range | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated |
Increases Compared to Placebo | |
| < 18 years old | 14 additional patients |
| 18 to 24 years old | 5 additional patients |
Decreases Compared to Placebo | |
| 25 to 64 years old | 1 fewer patient |
| ≥ 65 years old | 6 fewer patients |
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all doxepin hydrochloride-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of doxepin hydrochloride therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the health care provider. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride, in patients who are experiencing emergent suicidal thoughts or behaviors.
The safety and effectiveness of doxepin hydrochloride in pediatric patients have not been established.
Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients
Dosage and Administration (If anticholinergiceffects (e.g., dry mouth, blurred vision, constipation) develop, reduce the doxepin hydrochloride capsules dosage [see Adverse Reactions (6.1)]. Reducethe doxepin hydrochloride capsules dosage based on doxepin plasma concentrations when used concomitantly with strong CYP2D6 inhibitors [see Drug Interactions (7)]. Reducethe doxepin hydrochloride capsules dosage based on doxepin plasma concentrations in patients who are known CYP2D6 and CYP2C19 poormetabolizers [see Use in Specific Populations (8.7)]. Whendiscontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued [see Adverse Reactions (6)] . | 7/2025 |
Warnings and Precautions (Tricyclic antidepressants,including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitantuse of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans,tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended totreat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions (7)] .Serotonin syndrome symptomsmay include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia,labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinalsigns and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotoninsyndrome. The concomitantuse of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatmentwith an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated withan MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it isnecessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloridecapsules, discontinue doxepin hydrochloride capsules before initiating treatment with the MAOI [see Dosage and Administration (2.4) and Drug Interactions (7)] .Monitorall patients taking doxepin hydrochloride capsules for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitantserotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use ofdoxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk forserotonin syndrome and monitor for symptoms. In patientswith bipolar disorder, treating MDD with doxepin hydrochloride may precipitate a mixed/manic episode. Prior to initiating treatment with doxepin hydrochloride capsules,screen patients for any personal or family history of bipolar disorder, mania, or hypomania. Doxepin hydrochloride is not approved for use intreating bipolar depression. | 7/2025 |
Doxepin hydrochloride capsules are indicated for the treatment of major depressive disorder (MDD) in adults.
- Prior to initiating treatment with doxepin hydrochloride capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania. ()
2.1 Screen for Bipolar Disorder Prior to Starting Doxepin Hydrochloride CapsulesPrior to initiating treatment with doxepin hydrochloride capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
[see Warnings and Precautions (5.5)]. - Recommended starting oral dosage is 25 mg three times daily or 75 mg once daily. ()
2.2 Recommended DosageThe recommended starting oral dosage for doxepin hydrochloride capsule is 25 mg three times daily or 75 mg once daily. The recommended target total oral dosage range for doxepin hydrochloride capsule is between 75 mg/day and 150 mg/day (may be given once daily or in divided doses). The maximum recommended oral dosage for doxepin hydrochloride capsule is 100 mg three times daily.
- Recommended target total dosage range is between 75 mg/day and 150 mg/day (may be given once daily or in divided doses). ()
2.2 Recommended DosageThe recommended starting oral dosage for doxepin hydrochloride capsule is 25 mg three times daily or 75 mg once daily. The recommended target total oral dosage range for doxepin hydrochloride capsule is between 75 mg/day and 150 mg/day (may be given once daily or in divided doses). The maximum recommended oral dosage for doxepin hydrochloride capsule is 100 mg three times daily.
- Maximum recommended dosage is 100 mg three times daily. ()
2.2 Recommended DosageThe recommended starting oral dosage for doxepin hydrochloride capsule is 25 mg three times daily or 75 mg once daily. The recommended target total oral dosage range for doxepin hydrochloride capsule is between 75 mg/day and 150 mg/day (may be given once daily or in divided doses). The maximum recommended oral dosage for doxepin hydrochloride capsule is 100 mg three times daily.
- Wait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with doxepin hydrochloride capsules. ()
2.3 Switching Patients to or from a Monoamine Oxidase InhibitorWait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with doxepin hydrochloride capsules
[see Contraindications (4), Warnings and Precautions (5.2),andDrug Interactions (7)].Wait at least 14 days after discontinuation of doxepin hydrochloride capsules before initiating therapy with an MAOI
[see Contraindications (4), Warnings and Precautions (5.2),andDrug Interactions (7)]. - See the Full Prescribing Information for dosage modifications intended to reduce the risk of anticholinergic effects, for strong CYP2D6 inhibitors, and in known CYP2D6 and CYP2C19 poor metabolizers. (,
2.4 Dosage Modifications Intended to Reduce the Risk of Anticholinergic EffectsIf anticholinergiceffects (e.g., dry mouth, blurred vision, constipation) develop, reduce the doxepin hydrochloride capsules dosage[see Adverse Reactions (6.1)].,2.5 Dosage Modifications for Strong CYP2D6 InhibitorsReducethe doxepin hydrochloride capsules dosage based on doxepin plasma concentrations when used concomitantly with strong CYP2D6 inhibitors[see Drug Interactions (7)].)2.6 Dosage Modifications in Known CYP2D6 and CYP2C19 Poor MetabolizersReducethe doxepin hydrochloride capsules dosage based on doxepin plasma concentrations in patients who are known CYP2D6 and CYP2C19 poormetabolizers[see Use in Specific Populations (8.7)]. - When discontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued. ()
2.7 Discontinuation of Doxepin Hydrochloride Capsules TreatmentWhendiscontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued[see Adverse Reactions (6)].
Capsules:
- Doxepin hydrochloride capsules USP,10 mg:size “4” hard gelatin capsule with buff opaque cap and buff opaque body, imprinted “10” on cap with black ink and plain body filled with white to of white powder.
- Doxepin hydrochloride capsules USP,25 mg:size "3" hard gelatin capsule with ivory opaque cap and white opaque body, imprinted "25" on cap with black ink and plain body filled with white to off white powder.
- Doxepin hydrochloride capsules USP,50 mg:size "3" hard gelatin capsule with ivory opaque cap and ivory opaque body, imprinted "50" on cap with black ink and plain body filled with white to off white powder.
- Doxepin hydrochloride capsules USP,75 mg:size "2" hard gelatin capsule with brite lite green opaque cap and brite lite green opaque body, imprinted "75" on cap with black ink and plain body filled with white to off white powder.
- Doxepin hydrochloride capsules USP,100 mg:size "1" hard gelatin capsule with brite lite green opaque cap and white opaque body, imprinted "100" on cap with black ink and plain body filled with white to off white powder.
Active ingredients in the capsules include: 10 mg, 25, mg, 50 mg, 75 mg, and 100 mg of doxepin.
- Pregnancy: Neonates exposed to TCAs, including doxepin hydrochloride, late in the third trimester have developed poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability). Monitor neonates who were exposed to doxepin hydrochloride in the third trimester of pregnancy for poor neonatal adaptation syndrome. ()
8.1 PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including doxepin hydrochloride, during pregnancy. Health care providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants.
Risk SummaryAvailable data from published epidemiological studies and postmarketing reports have not established an increased risk for major birth defects or miscarriage with doxepin hydrochloride use
(see Data).There are risks(see Clinical Considerations):- To the mother associated with untreated depression in pregnancy.
- Poor neonate adaptation from exposure to tricyclic antidepressants (TCAs), including doxepin hydrochloride, during the third trimester of pregnancy.
Animal reproduction toxicity of doxepin has not been fully characterized.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical ConsiderationsDisease-associated Maternal and/or Embryofetal RiskWomen who discontinue antidepressants during pregnancy are more likely to experience a relapse of MDD than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of MDD who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated MDD when considering discontinuation of doxepin hydrochloride drugs during pregnancy and the postpartum period.
Fetal/Neonatal Adverse ReactionsNeonates previously exposed to TCAs, including doxepin hydrochloride, late in the third trimester during pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either direct toxic effects of TCAs or possibly a drug discontinuation syndrome. Monitor neonates who were exposed to doxepin hydrochloride in the third trimester of pregnancy for poor neonatal adaptation syndrome.
DataHuman Data:Published epidemiological studies of pregnant women exposed to TCAs, including doxepin hydrochloride, have not established an association with major birth defects, miscarriage, or adverse maternal outcomes. Methodological limitations of these observational studies include small sample size and lack of adequate controls. - Lactation: Breastfeeding not recommended. ()
8.2 LactationRisk SummaryData from published literature report the presence of doxepin and nordoxepin in human milk. There are reports of excessive sedation, respiratory depression, poor suckling and swallowing and hypotonia in breastfed infants exposed to doxepin at doses used to treat MDD. There are no data on the effects of doxepin on milk production.
Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during doxepin hydrochloride treatment.
- Geriatric Use: May cause confusion and oversedation. ()
8.5 Geriatric UseClinical studies of doxepin hydrochloride did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
Sedating drugs, including doxepin hydrochloride, may cause confusion and oversedation in geriatric patients. The recommended starting doxepin hydrochloride dosage in geriatric patients is generally lower than those of younger adult patients
. - CYP2C19 and CYP2D6 Poor Metabolizers: Increased risk of doxepin hydrochloride-associated adverse reactions. ()
8.7 Use in Genomic SubgroupsThe recommended doxepin hydrochloride dosage in CYP2C19 and CYP2D6 poor metabolizers is lower than the recommended dosage in CYP2C19 and CYP2D6 normal metabolizers
[see Dosage and Administration (2.6)].According to the literature, doxepin is primarily metabolized by CYP2D6 and/or CYP2C19; thus, the use of doxepin hydrochloride in CYP2D6 and/or CYP2C19 poor metabolizers will likely result in higher doxepin exposures and an increased risk of doxepin hydrochloride-associated adverse reactions.