Doxepin: uses, appearance and warnings

Doxepin Hydrochloride capsules are indicated for the treatment of major depressive disorder (MDD) in adults. Doxepin Hydrochloride capsules are a tricyclic antidepressant (TCA) indicated for the treatment of major depressive disorder (MDD) in adults ( 1 ).

• 10 mg, yellow opaque cap, yellow opaque body, imprinted in black with 10 mg and MD 12 • 25 mg, yellow opaque cap, white opaque body, imprinted in black with 25 mg and MD 13 • 50 mg, Ivory opaque cap, Ivory opaque body, imprinted in black with 50 mg and MD 14 • 75 mg, Green opaque cap, Green opaque body, imprinted in black with 75 mg and MD 15 • 100 mg, Green opaque cap, White opaque body, imprinted in black with 100 mg and MD 16 • Capsules: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg ( 3 )

Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride capsules, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg or 100 mg of doxepin. The 10 mg capsule is a yellow opaque body imprinted with "10 mg" in black ink and yellow opaque cap imprinted with "MD12" in black ink filled with white to off white powder. They are available as follows: NDC 72205-088-91 bottles of 100 capsules NDC 72205-088-99 bottles of 1000 capsules The 25 mg capsule is a white opaque body imprinted with "25 mg" in black ink and yellow opaque cap imprinted with "MD13" in black ink filled with white to off white powder. They are available as follows: NDC 72205-089-91 bottles of 100 capsules NDC 72205-089-99 bottles of 1000 capsules The 50 mg capsule is a ivory opaque body imprinted with "50 mg" in black ink and ivory opaque cap imprinted with "MD14" in black ink filled with white to off white powder. They are available as follows: NDC 72205-090-91 bottles of 100 capsules NDC 72205-090-99 bottles of 1000 capsules The 75 mg capsule is a green opaque body imprinted with "75 mg" in black ink and green opaque cap imprinted with "MD15" in black ink filled with white to off white powder. They are available as follows: NDC 72205-091-91 bottles of 100 capsules NDC 72205-091-99 bottles of 1000 capsules The 100 mg capsule is a White opaque body imprinted with "100 mg" in black ink and green opaque cap imprinted with "MD16" in black ink filled with white to off white powder. They are available as follows: NDC 72205-092-91 bottles of 100 capsules NDC 72205-092-99 bottles of 1000 capsules Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Doxepin Hydrochloride is contraindicated in patients: • With hypersensitivity to doxepin (hypersensitivity reactions have included tongue edema and urticaria). The possibility of cross sensitivity with other dibenzoxepines should be kept in mind. • With glaucoma [see Warnings and Precautions (5.3) ]. • With current or past urinary retention [see Adverse Reactions (6.1) ]. • Taking MAOIs, or within 14 days of stopping MAOIs (including the MAOIs linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. • Hypersensitivity to doxepin ( 4 ) • Glaucoma ( 4 ) • Current or past urinary retention ( 4 ) • Taking MAOIs, or within 14 days of stopping MAOIs ( 4 )

• Suicidal Thoughts and Behaviors : Monitor for clinical worsening and suicide thoughts and behaviors. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride, in patients who are experiencing emergent suicidal thoughts or behaviors. ( 5.1 ) • Serotonin Syndrome : Risk increases with concomitant use of other serotonergic drugs. Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride and any concomitant serotonergic agents immediately and initiate supportive treatment if serotonin syndrome occurs. ( 5.2 , 7 ) • Angle-Closure Glaucoma : Avoid use of doxepin hydrochloride in patients with untreated anatomically narrow angles. ( 5.3 ) • Sedation and Driving Risks : Because doxepin hydrochloride can cause sedation, warn patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride. ( 5.4 ) • Activation of Mania or Hypomania : Prior to initiating antidepressant therapy, screen for bipolar disorder. doxepin hydrochloride is not approved for use in treating bipolar depression. ( 5.5 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 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. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients 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. 5.2 Serotonin Syndrome Tricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use 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 to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions (7)] . Serotonin syndrome symptoms may 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 gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an 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 is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI [see Dosage and Administration (2.4) and Drug Interactions (7.1) ] . Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride may trigger an angle closure glaucoma attack in a patient with anatomically narrow angles who does not have a patent iridectomy. …

The following clinically significant adverse reactions are described elsewhere in the labeling: • Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions ( 5.1 )] • Serotonin Syndrome [see Warnings and Precautions (5.2) ] • Angle-Closure Glaucoma [see Warnings and Precautions (5.3) ] • Sedation and Driving Risks [see Warnings and Precautions (5.4) ] • Activation of Mania or Hypomania [see Warnings and Precautions (5.5) ] • Risk of Seizures [see Warnings and Precautions (5.6) ] • Psychosis [see Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence ≥ 5%) are somnolence, dry mouth, dizziness, constipation and fatigue. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at1-800-FDA-1088 or www.fda.gov/medwatch. …

Table 2 describe the clinically significant drug interactions of doxepin hydrochloride with other drugs or classes. Table 2: Clinically Significant Drug Interactions with doxepin hydrochloride Monoamine Oxidase Inhibitors Prevention or Management Doxepin Hydrochloride is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue. The use of doxepin hydrochloride within14 days of discontinuation of an MAOI or the use of MAOI within 14 days of discontinuation of doxepin hydrochloride is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI is contraindicated . Clinical Effect(s) Concomitant use of doxepin hydrochloride and MAOIs increases the risk of serotonin syndrome [Warnings and Precautions (5.2) ] . …