RECENT MAJOR CHANGES

1 INDICATIONS AND USAGE

Doxepin hydrochloride capsules are indicated for the treatment of major depressive disorder (MDD) in adults.

2 DOSAGE AND ADMINISTRATION

2.1 Screen for Bipolar Disorder Prior to Starting Doxepin hydrochloride Capsules

Prior 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)]

2.2 Recommended Dosage

The recommended starting oral dosage for doxepin hydrochloride capsules is 25 mg three times daily or 75 mg once daily. The recommended drug 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.

2.3 Switching Patients to or from a Monoamine Oxidase Inhibitor

Wait 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), and Drug Interactions (7)].

Wait at least 14 days after discontinuation of doxepin hydrochloride capsules before initiating therapy with an MAOI [see Contraindications (4.4), Warnings and Precautions (5.2), and Drug Interactions (7)].

2.4 Dosage Modifications Intended to Reduce the Risk of Anticholinergic Effects

If anticholinergic effects (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 Inhibitors

Reduce the doxepin hydrochloride 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 Metabolizers

Reduce the doxepin hydrochloride dosage based on doxepin plasma concentrations in patients who are known CYP2D6 and CYP2C19 poor metabolizers [see Use in Specific Populations (8.7)].

2.7 Discontinuation of Doxepin Hydrochloride Capsules Treatment

When discontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued [see Adverse Reactions (6)].

3 DOSAGE FORMS AND STRENGTHS

Capsules:

● 10 mg capsule is light yellow to yellow opaque cap / light yellow to yellow opaque body, hard gelatin capsule, imprinted withon cap and "424" on body with black ink containing white to off white powder.

● 25 mg capsule is light yellow to yellow opaque cap / white to off white opaque body, hard gelatin capsule, imprinted withon cap and "425" on body with black ink containing white to off white powder.

● 50 mg capsule is light yellow to yellow opaque cap and light yellow to yellow opaque body, hard gelatin capsule, imprinted withon cap and "426" on body with black ink containing white to off white powder.

● 75 mg capsule is light green to green opaque cap and light green to green opaque body, hard gelatin capsule, imprinted withon cap and "427" on body with black ink containing white to off white powder.

● 100 mg capsule is light green to green opaque cap and white to off white opaque body, hard gelatin capsule, imprinted withon cap and "428" on body with black ink containing white to off white powder.

Active ingredients in the capsules include: 10 mg, 25, mg, 50 mg, 75 mg, and 100 mg of doxepin.

4 CONTRAINDICATIONS

Doxepin hydrochloride capsules are 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)].

5 WARNINGS AND PRECAUTIONS

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
18-24 years old	5 additional patients
	Decreases Compared to Placebo
25-64 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, and 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. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Doxepin hydrochloride capsules are contraindicated in patients with glaucoma. Avoid use of doxepin hydrochloride capsules in patients with untreated anatomically narrow angles.

5.4 Sedation and Driving Risks

Because doxepin hydrochloride can cause sedation, warn patients of the risk of sedation and caution patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride capsules. Also caution patients that their response to alcohol may be potentiated. Sedating drugs, including doxepin hydrochloride, may cause over sedation in geriatric patients.

5.5 Activation of Mania or Hypomania

In patients with 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 in treating bipolar depression.

5.6 Risk of Seizures

Caution should be used when doxepin hydrochloride is given to patients with a history of seizure disorder, because this drug may lower the seizure threshold. Patients with a history of seizures should be monitored during doxepin hydrochloride use to identify recurrence of seizures or increase in frequency of seizures.

5.7 Psychosis

In patients with schizophrenia, treatment with doxepin hydrochloride for MDD may activate psychosis. If this occurs, stop doxepin hydrochloride and consider alternative treatment options.

6 ADVERSE REACTIONS

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)] To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions (≥ 2% of doxepin hydrochloride -treated patients) in 1,635 doxepin hydrochloride -treated patients with MDD in clinical trials included somnolence (17%), dry mouth (15%), dizziness (6%), constipation (5%), fatigue (5%), blurred vision (3%), tachycardia (3%), hypotension (3%), insomnia (2%), tremor (2%), nausea (2%), hyperhidrosis (2%), and increased weight (2%).

Other Adverse Reactions Observed in Clinical Trials

Other adverse reactions that occurred at an incidence of < 2% in patients treated with doxepin hydrochloride in clinical trials were:

.

Ear and Labyrinth Disorders: Tinnitus. Gastrointestinal Disorders: Diarrhea, dyspepsia, vomiting. General Disorders and Administration Site Conditions: Asthenia, edema, chills. Metabolism and Nutrition Disorders: Decreased appetite. Nervous System Disorders: Ataxia, paresthesia, headache, extrapyramidal disorder. Psychiatric Disorders: Agitation, confusional state, libido decreased. Pulmonary Disorders: Asthma exacerbation. Renal and Urinary Disorders: Urinary retention. Reproductive System and Breast Disorders: Breast enlargement. Skin & Subcutaneous Tissue Disorders: Rash, pruritus. Vascular Disorders: Flushing.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of doxepin hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Agranulocytosis, leukopenia, thrombocytopenia, eosinophilia, purpura. Cardiac Disorders: Conduction disorder, arrhythmia. Endocrine Disorders: Inappropriate antidiuretic hormone secretion. Eye Disorders: Angle-closure glaucoma, mydriasis. Gastrointestinal Disorders: Aphthous stomatitis, abdominal pain upper. General Disorders and Administration Site Conditions: Facial edema, hyperpyrexia. Hepatobiliary Disorders: Jaundice. Investigations: Blood glucose increased. Nervous System Disorders: Hypoesthesia, dysgeusia, convulsion, tardive dyskinesia, serotonin syndrome. Psychiatric Disorders: Hallucination, disorientation. Reproductive System and Breast Disorders: Testicular swelling, gynecomastia, galactorrhea. Skin and Subcutaneous Tissue Disorders: Photosensitivity reaction, tongue edema, alopecia, urticaria. Vascular Disorders: Hypertension. Withdrawal syndrome occurred after stopping doxepin hydrochloride [see Drug Abuse and Dependence (9.3)].

The following adverse reaction has been reported with use with other tricyclic antidepressants: decreased blood glucose.

7 DRUG INTERACTIONS

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 within 14 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)] .
Other Serotonergic Drugs (Besides MAOIs)
Prevention or Management	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of doxepin hydrochloride and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Mechanism and Clinical Effect(s)	Concomitant use of doxepin hydrochloride with other serotonergic drugs increases the risk of serotonin syndrome [see Warnings and Precautions (5.2)].
Strong CYP2D6 Inhibitors
Prevention or Management	Monitor doxepin plasma concentrations and reduce the doxepin hydrochloride dosage or the strong CYP2D6 inhibitor as appropriate [see Dosage and Administration (2.5)].
Mechanism and Clinical Effect(s)	Concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase the exposures of doxepin [see Clinical Pharmacology (12.3)] which may increase the risk of doxepin hydrochloride related adverse reactions [see Warnings and Precautions (5) and Adverse Reactions (6)].
Examples	See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong CYP2D6 Inhibitors.
Carbamazepine
Prevention or Management	Monitor doxepin plasma concentrations and consider increasing the doxepin hydrochloride dosage in patients taking carbamazepine.
Mechanism and Clinical Effect(s)	Concomitant use of carbamazepine with doxepin hydrochloride decreases the exposure of doxepin [see Clinical Pharmacology (12.3)] which could lead to reduced treatment effect.
Cimetidine
Prevention or Management	Monitor doxepin plasma concentrations and consider reducing the doxepin hydrochloride dosage in patients taking cimetidine.
Mechanism and Clinical Effect(s)	Concomitant use of doxepin hydrochloride with cimetidine may increase the exposures of doxepin [see Clinical Pharmacology (12.3)] which may increase the risk of doxepin hydrochloride -related anticholinergic effects (e.g., dry mouth, blurred vision, constipation) [see Adverse Reactions (6.1)].
Alcohol
Prevention or Management	Avoid concomitant use with alcohol.
Mechanism and Clinical Effect(s)	Doxepin hydrochloride may potentiate the sedative effects of alcohol [see Warnings and Precautions (5.4)] .
CNS Depressants
Prevention or Management	Dosage reduction of doxepin hydrochloride and/or the CNS depressant may be needed based on clinical response and tolerability.
Mechanism and Clinical Effect(s)	When concomitantly administered with doxepin hydrochloride, the sedative effects of CNS depressant may be potentiated [see Warnings and Precautions (5.4)] .
Tolazamide
Prevention or Management	Monitor glucose levels and reduce the doxepin hydrochloride dosage as appropriate.
Clinical Effect(s)	Doxepin hydrochloride may cause severe hypoglycemia when concomitantly used with tolazamide.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There 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-research-programs/pregnancyregistry/antidepressants.

Risk Summary

Available 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 Considerations

Disease-associated Maternal and/or Embryofetal Risk

Women 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 Reactions Neonates 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.

Data

Human 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.

8.2 Lactation

Risk Summary

Data 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.

8.4 Pediatric Use

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 [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical 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.

8.6 Hepatic Impairment

The effect of hepatic impairment (HI) on the pharmacokinetics of doxepin has not been studied. Doxepin is primarily metabolized in the liver. Doxepin hydrochloride-treated patients with HI may have a greater systemic doxepin exposure than those with normal liver function. Consider obtaining doxepin concentrations in patients with HI and modifying the dosage as appropriate.

8.7 Use in Genomic Subgroups

The 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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Doxepin hydrochloride capsules contains doxepin, which is not a controlled substance.

9.2 Abuse

Doxepin hydrochloride capsules are not associated with abuse.

9.3 Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt cessation of doxepin hydrochloride capsules after prolonged administration can result in withdrawal symptoms, which is indicative of physical dependence.

10 OVERDOSAGE

Signs, Symptoms, and Complications of Doxepin Hydrochloride Overdose

Serious manifestations of tricyclic antidepressant (TCA) overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Deaths may occur from overdosage with TCAs, including doxepin hydrochloride. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of TCA toxicity. A maximal limb-lead QRS duration of ≥ 0.1 seconds may be the best indication of the TCA overdose severity.

Signs and symptoms of TCA toxicity develop rapidly after TCA overdose. Other signs of TCA overdose may include confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, or hyperpyrexia. There are reports of patients succumbing to fatal dysrhythmia late after TCA overdose.

Management of Overdose The following are recommendations for the management of a doxepin hydrochloride overdose. Contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

With a doxepin hydrochloride overdose, obtain an ECG and immediately initiate cardiac monitoring in the hospital. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS depression, respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is recommended. If signs of toxicity occur during this period, extended monitoring is recommended.

Monitoring of plasma doxepin levels should not guide doxepin hydrochloride overdose management.

Cardiovascular Toxicity Management: Intravenous sodium bicarbonate should be administered to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate to intravenous sodium bicarbonate therapy, hyperventilation may also be used. With concomitant use of hyperventilation and sodium bicarbonate therapy frequently monitor pH and pCO2. A pH > 7.6 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to intravenous sodium bicarbonate therapy/hyperventilation may respond to lidocaine therapy. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide) in the setting of TCA overdose. Hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in TCA overdose due to high tissue and protein binding of doxepin.

CNS Toxicity Management: In patients with TCA overdose who have CNS depression, early intubation is recommended because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, propofol). Avoid use of physostigmine to treat TCA overdose.

11 DESCRIPTION

Doxepin hydrochloride is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds.

The molecular formula of the compound is C₁₉H₂₁NO•HCl having a molecular weight of 315.84. It is a white to almost white crystalline powder freely soluble in water, in alcohol and methylene chloride.Doxepin hydrochloride is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of:

1-Propanamine, 3- dibenz[b,e]oxepin-11 (6H)ylidene-N,N-dimethyl-hydrochloride. The structural formula of doxepin is shown below.

Doxepin hydrochloride capsules are for oral administration.

Each 10 mg, 25 mg, 50 mg, 75 mg and 100 mg doxepin capsule for oral administration contains doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg and 100 mg of doxepin, respectively.

Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch (maize), and sodium lauryl sulfate.

The empty gelatin capsule shells contain D&C Yellow No. 10, gelatin, sodium lauryl sulfate and titanium dioxide. In addition, the 25 mg and 50 mg empty gelatin capsule shells contain FD&C Yellow 6, the 75 mg and 100 mg empty gelatin capsule shells contain FD&C Green 3 and the 10 mg empty gelatin capsule shells contain FD&C Red 3.

The imprinting ink contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution.

Meets USP Dissolution Test 4

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of the doxepin hydrochloride in the treatment of MDD in adult patients is not well understood.

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of doxepin have not been fully characterized.

12.3 Pharmacokinetics

Absorption

In healthy volunteers, a single oral doxepin hydrochloride dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between 2 and 4 hours (mean 2.9 hours) after doxepin hydrochloride administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between 2 and 10 hours after doxepin hydrochloride administration.

Distribution

The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%.

Elimination

In healthy volunteers, the plasma elimination half-life of doxepin ranged from 8 to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg.

Metabolism

After oral doxepin hydrochloride administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation.

Excretion

Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form.

Specific Populations

Patients with Hepatic Impairment: Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have a greater systemic doxepin exposure than those with normal liver function [see Use in Specific Populations (8.6)].

Patients with Renal Impairment: The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function.

Drug Interactions Studies

Carbamazepine: After concomitant use of doxepin hydrochloride and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin hydrochloride alone [see Drug Interactions (7)].

Strong CYP2D6 Inhibitors: CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase doxepin exposure [see Drug Interactions (7)].

Cimetidine: Cimetidine is a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with a single 6 mg dose of another oral doxepin product, there was approximately a 2-fold increase in doxepin Cmax and AUC compared to doxepin without cimetidine [see Drug Interactions (7)].

CYP2D6 Substrates: Concomitant use of doxepin hydrochloride and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of doxepin in animals has not been fully characterized.

Mutagenesis

The mutagenetic potential of doxepin in animals has not been fully characterized.

Impairment of Fertility Doxepin had no effect on female fertility in rats at oral doses up to 25 mg/kg/day (1.6x the human dose of 150 mg/day on a mg/m2 basis for a 60 kg human).

Insemination and conception were reduced in untreated female rats mated with male rats administered doxepin at 25 mg/kg/day for a period of ≥ 7 months.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg or 100 mg of doxepin.

The 10 mg capsule is light yellow to yellow opaque cap /light yellow to yellow opaque body, hard gelatin capsule, imprinted with on cap and "424" on body with black ink containing white to off white powder. They are available as follows:

NDC 72603-390-01