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WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increase the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)] . Doxepin hydrochloride capsules are not approved for use in pediatric patients [see Use in Specific Populations (8.4)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thoughts and behaviors in pediatric and young adults taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors (5.1) • Doxepin hydrochloride capsules are not approved for use in pediatric patients (8.4)

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Prior to initiating treatment with doxepin hydrochloride capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania. (2.1) Recommended starting oral dosage is 25 mg three times daily or 75 mg once daily. (2.2) 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) Maximum recommended dosage is 100 mg three times daily. (2.2) Wait at least 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI) before initiating therapy with doxepin hydrochloride capsules. (2.3) 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, 2.5, 2.6). When discontinuing doxepin hydrochloride capsules, gradually reduce the dosage until discontinued. (2.7) 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 with on 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 with on 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 with on 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 with on 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 with on 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. Capsules:10 mg, 25 mg, 50 mg, 75 mg, and 100 mg, (3) Image Image Image Image Image

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)]. Hypersensitivity to doxepin (4) Glaucoma (4) Current or past urinary retention (4) Taking MAOIs, or within 14 days of stopping MAOIs (4)

5 WARNINGS AND PRECAUTIONS 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 18-24 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.

ging 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.

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.

<table ID="ID163" width="602" styleCode="Noautorules"><col width="301"/><col width="301"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"> <content styleCode="bold"> Age Range</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Increases Compared to Placebo</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> &lt; 18 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14 additional patients </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 18-24 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 additional patients </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Decreases Compared to Placebo</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 25-64 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 fewer patient </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"><content styleCode="underline">&gt;</content> 65 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 fewer patients </td></tr></tbody></table>

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. Most common adverse reactions (incidence ≥ 5%) are somnolence, dry mouth, dizziness, constipation and fatigue. 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.

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)] .

ent 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. Serotonergic Drugs : 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. (5.2, 7) Strong CYP2D6 Inhibitors : Concomitant use of TCAs with drugs that can inhibit CYP2D6 may require lower dosages for the TCA or the other drug, and monitor TCA plasma levels. (7) Carbamazepine : Monitor doxepin plasma concentrations and increase doxepin hydrochloride dosage in patients taking carbamazepine. (7) Cimetidine : Monitor doxepin plasma concentrations and consider reducing the doxepin hydrochloride dosage in patients taking cimetidine. (7) Alcohol : Avoid concomitant use. (7) CNS Depressants : Dosage reduction may be needed based on clinical response and tolerability. (7) Tolazamide : Monitor glucose levels and reduce the doxepin hydrochloride dosage as appropriate. (7)

<table ID="ID303" width="660" styleCode="Noautorules"><col width="212"/><col width="448"/><tbody><tr><td colspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Monoamine Oxidase Inhibitors </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 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<content styleCode="italics">. </content> Starting doxepin hydrochloride in a patient who is being treated with an MAOI is contraindicated<content styleCode="italics">. </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of doxepin hydrochloride and MAOIs increases the risk of serotonin syndrome <content styleCode="italics">[Warnings and Precautions (5.2)]</content> . </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Other Serotonergic Drugs (Besides MAOIs) </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 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 <content styleCode="italics">[see Warnings and Precautions (5.2)]. </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Mechanism and Clinical </content> <content styleCode="italics">Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of doxepin hydrochloride with other serotonergic drugs increases the risk of serotonin syndrome <content styleCode="italics">[see Warnings and Precautions (5.2)]. </content> </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Strong CYP2D6 Inhibitors </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Monitor doxepin plasma concentrations and reduce the doxepin hydrochloride dosage or the strong CYP2D6 inhibitor as appropriate <content styleCode="italics">[see Dosage and Administration (2.5)].

ntent styleCode="italics">Prevention or Management </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Monitor doxepin plasma concentrations and reduce the doxepin hydrochloride dosage or the strong CYP2D6 inhibitor as appropriate <content styleCode="italics">[see Dosage and Administration (2.5)]. </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Mechanism and Clinical </content> <content styleCode="italics">Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase the exposures of doxepin <content styleCode="italics">[see Clinical </content> <content styleCode="italics">Pharmacology (12.3)] </content> which may increase the risk of doxepin hydrochloride related adverse reactions <content styleCode="italics">[see Warnings and Precautions (5) and Adverse Reactions (6)]. </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Examples </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong CYP2D6 Inhibitors. </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Carbamazepine </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Monitor doxepin plasma concentrations and consider increasing the doxepin hydrochloride dosage in patients taking carbamazepine. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Mechanism and Clinical </content> <content styleCode="italics">Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of carbamazepine with doxepin hydrochloride decreases the exposure of doxepin <content styleCode="italics">[see Clinical Pharmacology (12.3)] </content> which could lead to reduced treatment effect. </td></tr><tr><td valign="top" styleCode=" Lrule Botrule" align="left"><content styleCode="bold"> Cimetidine </content> </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Monitor doxepin plasma concentrations and consider reducing the doxepin hydrochloride dosage in patients taking cimetidine. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Mechanism and Clinical </content> <content styleCode="italics">Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of doxepin hydrochloride with cimetidine may increase the exposures of doxepin <content styleCode="italics">[see Clinical Pharmacology (12.3)] </content> which may increase the risk of doxepin hydrochloride -related anticholinergic effects (e.g., dry mouth, blurred vision, constipation) <content styleCode="italics">[see Adverse Reactions (6.1)]. </content> </td></tr><tr><td valign="top" styleCode=" Lrule Botrule" align="left"><content styleCode="bold"> Alcohol </content> </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management <content styleCode="bold"> </content></content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Avoid concomitant use with alcohol.

/td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management <content styleCode="bold"> </content></content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Avoid concomitant use with alcohol. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Mechanism and Clinical </content> <content styleCode="italics">Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Doxepin hydrochloride may potentiate the sedative effects of alcohol <content styleCode="italics">[see Warnings and Precautions (5.4)]</content> . </td></tr><tr><td valign="top" styleCode=" Lrule Botrule" align="left"><content styleCode="bold"> CNS Depressants </content> </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management <content styleCode="bold"> </content></content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Dosage reduction of doxepin hydrochloride and/or the CNS depressant may be needed based on clinical response and tolerability. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Mechanism and Clinical </content> <content styleCode="italics">Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> When concomitantly administered with doxepin hydrochloride, the sedative effects of CNS depressant may be potentiated <content styleCode="italics">[see Warnings and Precautions (5.4)]</content> . </td></tr><tr><td valign="top" styleCode=" Lrule Botrule" align="left"><content styleCode="bold"> Tolazamide </content> </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Prevention or Management <content styleCode="bold"> </content></content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Monitor glucose levels and reduce the doxepin hydrochloride dosage as appropriate. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Effect(s) </content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Doxepin hydrochloride may cause severe hypoglycemia when concomitantly used with tolazamide. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 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) Lactation : Breastfeeding not recommended. (8.2) Geriatric Use : May cause confusion and oversedation. (8.5) CYP2C19 and CYP2D6 Poor Metabolizers : Increased risk of doxepin hydrochloride -associated adverse reactions. (8.7) 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.

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 C 19 H 21 NO•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 (6 H )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 pic

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 bottles of 100 capsules, with child-resistant closure The 25 mg capsule is light yellow to yellow opaque cap/white to off white opaque body, hard gelatin capsule, imprinted with on cap and "425" on body with black ink containing white to off white powder. They are available as follows: NDC 72603-391-01 bottles of 100 capsules, with child-resistant closure The 50 mg capsule is light yellow to yellow opaque cap and light yellow to yellow opaque body, hard gelatin capsule, imprinted with on cap and "426"" on body with black ink containing white to off white powder. They are available as follows: NDC 72603-392-01 bottles of 100 capsules, with child-resistant closure The 75 mg capsule is light green to green opaque cap and light green to green opaque body, hard gelatin capsule, imprinted with on cap and "427" on body with black ink containing white to off white powder. They are available as follows: NDC 72603-393-01 bottles of 100 capsules, with child-resistant closure The 100 mg capsule is light green to green opaque cap and white to off white opaque body, hard gelatin capsule, imprinted with on cap and "428" on body with black ink containing white to off white powder. They are available as follows: NDC 72603-394-01 bottles of 100 capsules, with child-resistant closure Store at 20° to 25°C (68° to 77°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. Image Image Image Image Image

17 PATIENT COUNSELING INFORMATION Advise patients to read FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during doxepin hydrochloride treatment and when the dosage is increased or decreased, and instruct them to report suicidal thinking and behavior to their health care provider [see Warnings and Precautions (5.1)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome particularly with the concomitant use of doxepin hydrochloride and other serotonergic drugs (e.g., other TCAs, SSRIs, SNRIs, triptans, opioids), lithium, tryptophan, buspirone, and St. John's Wort and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2), Drug Interactions (7)]. Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome. Angle-Closure Glaucoma Advise patients that taking doxepin hydrochloride can cause pupillary dilation, which in susceptible individuals, can trigger angle closure glaucoma. 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 [see Warnings and Precautions (5.3)]. Effects on Driving and Operating Heavy Machinery Inform patients that doxepin hydrochloride can cause sedation and caution them against driving a car or operating dangerous machinery while taking doxepin hydrochloride [see Warnings and Precautions (5.4)]. Activation of Mania or Hypomania Advise patients to observe for signs of mania/hypomania activation and instruct them to report such symptoms to the healthcare provider. Drug Interactions Inform patients that the use of doxepin hydrochloride and certain other drugs increases the risk of doxepin hydrochloride -associated adverse reactions or alternatively lower doxepin hydrochloride effectiveness. Instruct patients to inform their healthcare provider about all the drugs that they are taking before taking doxepin hydrochloride. Alcohol Use Advise patients to avoid the use of alcohol while taking doxepin hydrochloride [see Drug Interactions (7.5)]. Pregnancy Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to doxepin hydrochloride during pregnancy. Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during doxepin hydrochloride treatment. Advise pregnant women that doxepin hydrochloride use late in pregnancy may increase the risk for neonatal complications requiring prolonged hospitalization, respiratory support, or tube feeding [see Use in Specific Populations (8.1)]. Lactation Advise patients that breastfeeding is not recommended during doxepin hydrochloride treatment [see Use in Specific Populations (8.2)]. Manufactured for: Northstar Rx LLC Memphis TN 38141. Toll-Free: 1-800-206-7821 Manufactured by: Mankind Pharma Limited Paonta Sahib, Sirmaur Himachal Pradesh 173025, India. Issued August 2025, V-02

SPL MEDGUIDE MEDICATION GUIDE DOXEPIN HYDROCHLORIDE capsules for oral use What is the most important information I should know about doxepin hydrochloride capsules? Doxepin hydrochloride capsules can cause serious side effects, including: Increased risk of suicidal thoughts and actions. Doxepin hydrochloride capsules and other antidepressant medicines may increase the risk of suicidal thoughts and actions in people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Doxepin hydrochloride capsules are not for use in children. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. • Call your health care provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions. Keep all follow-up visits with your health care provider as scheduled. Call your health care provider between visits as needed, especially if you have concerns about symptoms. Call your health care provider or get emergency help right away if you or a family member have any of the following symptoms, especially if they are new, worse, or worry you: suicide attempts thoughts about suicide or dying acting aggressive, being angry, or violent acting on dangerous impulses new or worse depression new or worse anxiety panic attacks feeling very agitated or restless new or worse irritability trouble sleeping an extreme increase in activity or talking (mania) other unusual changes in behavior or mood See "What are the possible side effects of doxepin hydrochloride capsules?" for more information about side effects. What is doxepin hydrochloride capsules ? Doxepin hydrochloride capsules are a prescription medicine used to treat adults with a certain type of depression called major depressive disorder (MDD). It is not known if doxepin hydrochloride capsules are safe and effective for use in children. Do not take doxepin hydrochloride capsules if you: Are allergic to doxepin, or any of the ingredients in doxepin hydrochloride capsules. See the end of this Medication Guide for a complete list of ingredients in doxepin hydrochloride capsules have glaucoma have or have had trouble urinating are taking, or have stopped taking within the last 14 days, a medicine called a Monoamine Oxidase Inhibitor (MAOI), including the antibiotic linezolid or intravenous methylene blue o Ask your health care provider or pharmacist if you are not sure if you are taking an MAOI, including the antibiotic linezolid or intravenous methylene blue o Do not start taking an MAOI for at least 14 days after you stop treatment with doxepin hydrochloride capsules Before taking doxepin hydrochloride capsules , tell your health care provider about all your medical conditions, including if you: have, or have a family history of bipolar disorder, mania, or hypomania have or had depression, suicidal thoughts or behavior have kidney or liver problems have or had seizures or convulsions are pregnant or plan to become pregnant. Taking doxepin hydrochloride capsules during your third trimester of pregnancy may harm your unborn baby.

mily history of bipolar disorder, mania, or hypomania have or had depression, suicidal thoughts or behavior have kidney or liver problems have or had seizures or convulsions are pregnant or plan to become pregnant. Taking doxepin hydrochloride capsules during your third trimester of pregnancy may harm your unborn baby. Tell your health care provider if you become pregnant or think you may be pregnant during treatment with doxepin hydrochloride capsules o Babies born to mothers who take certain medicines, including doxepin hydrochloride capsules, during the third trimester of pregnancy may have symptoms of sedation, such as breathing problems, sluggishness, low muscle tone, feeding problems, and withdrawal symptoms. Talk to your health care provider about the risks to your unborn or newborn baby if you take doxepin hydrochloride capsules during pregnancy o There is a pregnancy registry for women who are exposed to doxepin hydrochloride capsules during pregnancy. The purpose of this registry is to collect information about the health of women exposed to doxepin hydrochloride and their babies. If you become pregnant during treatment with doxepin hydrochloride, talk to your health care provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ are breastfeeding or plan to breastfeed. Doxepin hydrochloride can pass into your breast milk and harm your baby. Do not breastfeed during treatment with doxepin hydrochloride capsules. Talk to your health care provider about the best way to feed your baby during treatment with doxepin hydrochloride capsules Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Doxepin Hydrochloride and other medicines may affect each other causing possible serious side effects. Doxepin hydrochloride capsules may affect the way other medicines work and other medicines may affect the way doxepin hydrochloride capsules works. Especially tell your health care provider if you take: medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) medicines to treat migraine headaches known as triptans other tricyclic antidepressants tetracyclic antidepressants opioids lithium tryptophan buspirone St. John's Wort carbamazepine cimetidine tolazamide medicines that can cause drowsiness Ask your health care provider if you are not sure if you are taking any of these medicines. Your health care provider can tell you if it is safe to take doxepin hydrochloride capsules with your other medicines. Do not start or stop any other medicines during treatment with doxepin hydrochloride without first talking to your healthcare provider. Know the medicines you take. Keep a list of them to show to your healthcare providers when you start to take a new medicine. How should I take doxepin hydrochloride capsules ? Take doxepin hydrochloride capsules exactly as your health care provider tells you to take it. Do not change your dose or stop taking doxepin hydrochloride capsules without first talking to your healthcare provider. Your health care provider may need to change the dose of doxepin hydrochloride capsules until it is the right dose for you. If you miss a dose of doxepin hydrochloride capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, do not take the missed dose and take your next dose at the regular time. Do not take two doses of doxepin hydrochloride capsules at the same time.

til it is the right dose for you. If you miss a dose of doxepin hydrochloride capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, do not take the missed dose and take your next dose at the regular time. Do not take two doses of doxepin hydrochloride capsules at the same time. If you take too much doxepin hydrochloride capsules, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should I avoid while taking doxepin hydrochloride capsules ? Do not drive a car or another motor vehicle, operate heavy machinery, or do dangerous activities while taking doxepin hydrochloride capsules. Doxepin hydrochloride capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. Do not drink alcohol during treatment with doxepin hydrochloride capsules. Drinking alcohol during treatment with doxepin hydrochloride capsules can increase your risk of having serious side effects. What are the possible side effects of doxepin hydrochloride capsules ? Doxepin hydrochloride capsules can cause serious side effects, including: See "What is the most important information I should know about doxepin hydrochloride capsules ?" Serotonin syndrome. Taking doxepin hydrochloride capsules can cause a potentially life-threatening problem called serotonin syndrome. The risk of developing serotonin syndrome is increased when doxepin hydrochloride capsules are taken with certain other medicines. See " Do not take doxepin hydrochloride capsules if you :" Stop taking doxepin hydrochloride capsules and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome agitation seeing or hearing things that are not real (hallucinations) confusion coma fast heartbeat changes in blood pressure dizziness sweating flushing high body temperature (hyperthermia) shaking (tremors), stiff muscles, or muscle twitching loss of coordination seizures nausea, vomiting, diarrhea Eye problems (angle-closure glaucoma). Doxepin hydrochloride capsules may cause a type of eye problem called angle-closure glaucoma in people with certain eye problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Manic episodes. Manic episodes may happen in people with bipolar disorder who take doxepin hydrochloride capsules. Symptoms may include: o greatly increased energy o severe trouble sleeping o racing thoughts o reckless behavior o unusually grand ideas o excessive happiness or irritability o talking more or faster than usual Seizures (convulsions) The most common side effects of doxepin hydrochloride capsules include: feeling overly sleepy • constipation dry mouth • tiredness dizziness These are not all the possible side effects of doxepin hydrochloride capsules. Call your health care provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088 How should I store doxepin hydrochloride capsules ? Store doxepin hydrochloride capsules at controlled room temperature between 20°C to 25°C (68°F to 77°F). Keep doxepin hydrochloride capsules and all medicines out of the reach of children. General Information about the safe and effective use of doxepin hydrochloride capsules . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take doxepin hydrochloride capsules for a condition for which it was not prescribed.

all medicines out of the reach of children. General Information about the safe and effective use of doxepin hydrochloride capsules . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take doxepin hydrochloride capsules for a condition for which it was not prescribed. Do not give doxepin hydrochloride capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about doxepin hydrochloride capsules that is written for health professionals. What are the ingredients in doxepin hydrochloride capsules? Active ingredient: doxepin hydrochloride Inactive Ingredients for doxepin hydrochloride 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. For optional information about doxepin hydrochloride call Northstar Rx LLC at 1-800-206-7821 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: August 2025, V-02 Code No.: HP/Drugs/N-MNB/17/194

<table ID="ID241" width="732" styleCode="Noautorules"><col width="354"/><col width="83"/><col width="11"/><col width="651"/><tbody><tr><td colspan="4" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"> <content styleCode="bold"> MEDICATION GUIDE</content> <content styleCode="bold"> DOXEPIN HYDROCHLORIDE </content> <content styleCode="bold"> capsules </content> <content styleCode="bold"> for oral use </content> </td></tr><tr><td colspan="4" valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"> What is the most important information I should know about doxepin hydrochloride capsules? </content> <content styleCode="bold"> Doxepin hydrochloride capsules can cause serious side effects, including:</content> Increased risk of suicidal thoughts and actions. Doxepin hydrochloride capsules and other antidepressant medicines may increase the risk of suicidal thoughts and actions in people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Doxepin hydrochloride capsules are not for use in children. <content styleCode="bold"> How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? </content> &#x2022; Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. &#x2022; Call your health care provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions. Keep all follow-up visits with your health care provider as scheduled. Call your health care provider between visits as needed, especially if you have concerns about symptoms.

are provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions. Keep all follow-up visits with your health care provider as scheduled. Call your health care provider between visits as needed, especially if you have concerns about symptoms. <content styleCode="bold"> Call your health care provider or get emergency help right away if you or a family member have any of the following symptoms, especially if they are new, worse, or worry you:</content> </td></tr><tr><td valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>suicide attempts</item></list></td><td colspan="3" valign="top" styleCode=" Rrule" align="left"><list listType="unordered" styleCode="circle"><item>thoughts about suicide or </item></list> dying </td></tr><tr><td valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>acting aggressive, being angry, or violent</item></list></td><td colspan="3" valign="top" styleCode=" Rrule" align="left"><list listType="unordered" styleCode="circle"><item>acting on dangerous</item></list> impulses </td></tr><tr><td valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>new or worse depression</item></list></td><td colspan="3" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>new or worse anxiety</item></list></td></tr><tr><td valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>panic attacks</item></list></td><td colspan="3" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>feeling very agitated or restless</item></list></td></tr><tr><td valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>new or worse irritability</item></list></td><td colspan="3" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>trouble sleeping</item></list></td></tr><tr><td valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>an extreme increase in activity or talking (mania)</item></list></td><td colspan="3" valign="top" styleCode=" Rrule" align="left"><list listType="unordered" styleCode="circle"><item>other unusual changes in </item></list> behavior or mood </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"> See <content styleCode="bold"> &quot;What are the possible side effects of doxepin hydrochloride capsules?&quot;</content> for more information about side effects. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What is </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ? </content> Doxepin hydrochloride capsules are a prescription medicine used to treat adults with a certain type of depression called major depressive disorder (MDD). It is not known if doxepin hydrochloride capsules are safe and effective for use in children. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Do not take </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> if you: </content> Are allergic to doxepin, or any of the ingredients in doxepin hydrochloride capsules.

td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Do not take </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> if you: </content> Are allergic to doxepin, or any of the ingredients in doxepin hydrochloride capsules. See the end of this Medication Guide for a complete list of ingredients in doxepin hydrochloride capsules have glaucoma have or have had trouble urinating are taking, or have stopped taking within the last 14 days, a medicine called a Monoamine Oxidase Inhibitor (MAOI), including the antibiotic linezolid or intravenous methylene blue o Ask your health care provider or pharmacist if you are not sure if you are taking an MAOI, including the antibiotic linezolid or intravenous methylene blue o <content styleCode="bold"> Do not start taking an MAOI for at least 14 days after you stop treatment with </content><content styleCode="bold"> doxepin hydrochloride </content> <content styleCode="bold"> capsules</content> </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Before taking </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> , tell your health care provider about all your medical conditions, including if you: </content> have, or have a family history of bipolar disorder, mania, or hypomania have or had depression, suicidal thoughts or behavior have kidney or liver problems have or had seizures or convulsions are pregnant or plan to become pregnant. Taking doxepin hydrochloride capsules during your third trimester of pregnancy may harm your unborn baby. Tell your health care provider if you become pregnant or think you may be pregnant during treatment with doxepin hydrochloride capsules o Babies born to mothers who take certain medicines, including doxepin hydrochloride capsules, during the third trimester of pregnancy may have symptoms of sedation, such as breathing problems, sluggishness, low muscle tone, feeding problems, and withdrawal symptoms. Talk to your health care provider about the risks to your unborn or newborn baby if you take doxepin hydrochloride capsules during pregnancy o There is a pregnancy registry for women who are exposed to doxepin hydrochloride capsules during pregnancy. The purpose of this registry is to collect information about the health of women exposed to doxepin hydrochloride and their babies. If you become pregnant during treatment with doxepin hydrochloride, talk to your health care provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ are breastfeeding or plan to breastfeed. Doxepin hydrochloride can pass into your breast milk and harm your baby. Do not breastfeed during treatment with doxepin hydrochloride capsules. Talk to your health care provider about the best way to feed your baby during treatment with doxepin hydrochloride capsules <content styleCode="bold"> </content> <content styleCode="bold"> Tell your healthcare provider about all the medicines you take, </content> including prescription and over-the-counter medicines, vitamins, and herbal supplements. <content styleCode="bold"> </content> Doxepin Hydrochloride and other medicines may affect each other causing possible serious side effects. Doxepin hydrochloride capsules may affect the way other medicines work and other medicines may affect the way doxepin hydrochloride capsules works.

tamins, and herbal supplements. <content styleCode="bold"> </content> Doxepin Hydrochloride and other medicines may affect each other causing possible serious side effects. Doxepin hydrochloride capsules may affect the way other medicines work and other medicines may affect the way doxepin hydrochloride capsules works. <content styleCode="bold"> Especially tell your health care provider if you take: </content><content styleCode="bold"> </content> medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) medicines to treat migraine headaches known as triptans other tricyclic antidepressants tetracyclic antidepressants opioids lithium tryptophan buspirone St. John&apos;s Wort carbamazepine cimetidine tolazamide medicines that can cause drowsiness Ask your health care provider if you are not sure if you are taking any of these medicines. Your health care provider can tell you if it is safe to take doxepin hydrochloride capsules with your other medicines. Do not start or stop any other medicines during treatment with <content styleCode="bold"> doxepin hydrochloride</content> without first talking to your healthcare provider. Know the medicines you take. Keep a list of them to show to your healthcare providers when you start to take a new medicine. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> How should I take </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ? </content> Take doxepin hydrochloride capsules exactly as your health care provider tells you to take it. Do not change your dose or stop taking doxepin hydrochloride capsules without first talking to your healthcare provider. Your health care provider may need to change the dose of doxepin hydrochloride capsules until it is the right dose for you. If you miss a dose of doxepin hydrochloride capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, do not take the missed dose and take your next dose at the regular time. Do not take two doses of doxepin hydrochloride capsules at the same time. If you take too much doxepin hydrochloride capsules, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What should I avoid while taking </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ? </content> Do not drive a car or another motor vehicle, operate heavy machinery, or do dangerous activities while taking doxepin hydrochloride capsules. Doxepin hydrochloride capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. Do not drink alcohol during treatment with doxepin hydrochloride capsules. Drinking alcohol during treatment with doxepin hydrochloride capsules can increase your risk of having serious side effects. </td></tr><tr><td colspan="4" valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"> What are the possible side effects of </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ?

ride capsules can increase your risk of having serious side effects. </td></tr><tr><td colspan="4" valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"> What are the possible side effects of </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ? </content> <content styleCode="bold"> Doxepin hydrochloride</content><content styleCode="bold"> capsules</content><content styleCode="bold"> can cause serious side effects, including: </content> See <content styleCode="bold"> &quot;What is the most important information I should know about </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ?&quot; </content> <content styleCode="bold"> Serotonin syndrome. </content> Taking doxepin hydrochloride capsules can cause a potentially life-threatening problem called serotonin syndrome. The risk of developing serotonin syndrome is increased when doxepin hydrochloride capsules are taken with certain other medicines. See &quot;<content styleCode="bold"> Do not take </content><content styleCode="bold"> doxepin hydrochloride</content><content styleCode="bold"> capsules if you</content> :&quot; Stop taking <content styleCode="bold"> doxepin hydrochloride</content><content styleCode="bold"> capsules</content> and <content styleCode="bold"> call your healthcare provider or go to the nearest hospital emergency room right away </content> if you have any of the following signs and symptoms of serotonin syndrome </td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>agitation</item></list></td><td colspan="2" valign="top" styleCode=" Rrule" align="left"><list listType="unordered" styleCode="circle"><item>seeing or hearing things that are not real (hallucinations)</item></list> </td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>confusion</item></list></td><td colspan="2" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>coma</item></list></td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>fast heartbeat</item></list></td><td colspan="2" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>changes in blood pressure</item></list></td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>dizziness</item></list></td><td colspan="2" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>sweating</item></list></td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>flushing</item></list></td><td colspan="2" valign="top" styleCode=" Rrule"><list listType="unordered" styleCode="circle"><item>high body temperature (hyperthermia)</item></list></td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule"><list listType="unordered" styleCode="circle"><item>shaking (tremors), stiff muscles, or muscle twitching</item></list></td><td colspan="2" valign="top" styleCode=" Rrule" align="left"><list listType="unordered" styleCode="circle"><item>loss of coordination</item></list> </td></tr><tr><td colspan="2" valign="top" styleCode=" Lrule Botrule"><list listType="unordered" styleCode="circle"><item>seizures</item></list></td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="left"><list listType="unordered" styleCode="circle"><item>nausea, vomiting, diarrhea</item></list> </td></tr><tr><td colspan="4" valign="top" styleCode=" Lrule Rrule" align="left"> <content styleCode="bold"> Eye problems (angle-closure glaucoma).

/list></td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="left"><list listType="unordered" styleCode="circle"><item>nausea, vomiting, diarrhea</item></list> </td></tr><tr><td colspan="4" valign="top" styleCode=" Lrule Rrule" align="left"> <content styleCode="bold"> Eye problems (angle-closure glaucoma). </content> Doxepin hydrochloride capsules may cause a type of eye problem called angle-closure glaucoma in people with certain eye problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. <content styleCode="bold"> Manic episodes. </content> Manic episodes may happen in people with bipolar disorder who take doxepin hydrochloride capsules. Symptoms may include: </td></tr><tr><td colspan="3" valign="top" styleCode=" Lrule" align="left"> o greatly increased energy </td><td valign="top" styleCode=" Rrule" align="left"> o severe trouble sleeping </td></tr><tr><td colspan="3" valign="top" styleCode=" Lrule" align="left"> o racing thoughts </td><td valign="top" styleCode=" Rrule" align="left"> o reckless behavior </td></tr><tr><td colspan="3" valign="top" styleCode=" Lrule" align="left"> o unusually grand ideas </td><td valign="top" styleCode=" Rrule" align="left"> o excessive happiness or irritability </td></tr><tr><td colspan="3" valign="top" styleCode=" Lrule" align="left"> o talking more or faster than usual </td><td valign="top" styleCode=" Rrule" align="left"> </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="bold"> Seizures (convulsions) </content> <content styleCode="bold"> The most common side effects of </content><content styleCode="bold"> doxepin hydrochloride</content><content styleCode="bold"> capsules include: </content> feeling overly sleepy &#x2022; constipation dry mouth &#x2022; tiredness dizziness These are not all the possible side effects of doxepin hydrochloride capsules. Call your health care provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> How should I store </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> ? </content> Store doxepin hydrochloride capsules at controlled room temperature between 20&#xB0;C to 25&#xB0;C (68&#xB0;F to 77&#xB0;F). Keep doxepin hydrochloride capsules and all medicines out of the reach of children. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> General Information about the safe and effective use of </content><content styleCode="bold"> doxepin hydrochloride capsules</content><content styleCode="bold"> . </content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take doxepin hydrochloride capsules for a condition for which it was not prescribed. Do not give doxepin hydrochloride capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about doxepin hydrochloride capsules that is written for health professionals. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What are the ingredients in </content><content styleCode="bold"> doxepin hydrochloride</content><content styleCode="bold"> capsules?

doxepin hydrochloride capsules that is written for health professionals. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What are the ingredients in </content><content styleCode="bold"> doxepin hydrochloride</content><content styleCode="bold"> capsules? </content> <content styleCode="italics">Active ingredient: </content> doxepin hydrochloride <content styleCode="italics">Inactive Ingredients for </content><content styleCode="bold"><content styleCode="italics">doxepin hydrochloride</content></content> colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch (maize), and sodium lauryl sulfate. The empty gelatin capsule shells contain D&amp;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&amp;C Yellow 6, the 75 mg and 100 mg empty gelatin capsule shells contain FD&amp;C Green 3 and the 10 mg empty gelatin capsule shells contain FD&amp;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. For optional information about doxepin hydrochloride call Northstar Rx LLC at 1-800-206-7821<content styleCode="bold"> </content> </td></tr></tbody></table>

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of doxepin hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin hydrochloride is not approved for use in pediatric patients (see Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use).

DESCRIPTION Doxepin hydrochloride, USP is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C 19 H 21 NO•HCl having a molecular weight of 316. It is a white or almost white crystalline powder. It is freely soluble in water, in alcohol and in methylene chloride. Doxepin HCl 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. Doxepin Hydrochloride Inactive Ingredients : Microcrystalline cellulose, sodium lauryl sulfate, pregelatinized starch, colloidal silicon dioxide and magnesium stearate. The capsule shell contains titanium dioxide, iron oxide yellow, gelatin, sodium lauryl sulfate. Additionally, 75 mg and 100 mg capsule shell also contains FD&C Blue 1. The capsule shells are printed with edible black ink containing shellac, iron oxide black and potassium hydroxide. FDA approved dissolution method differs from the USP dissolution method.

CLINICAL PHARMACOLOGY The mechanism of action of doxepin hydrochloride is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin HCl does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses, norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, doxepin hydrochloride can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these compounds has been reported. Doxepin hydrochloride is virtually devoid of euphoria as a side effect. Characteristic of this type of compound, doxepin hydrochloride has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.

INDICATIONS AND USAGE Doxepin hydrochloride capsules are recommended for the treatment of: Psychoneurotic patients with depression and/or anxiety. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. The target symptoms of psychoneurosis that respond particularly well to doxepin hydrochloride capsules include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. Clinical experience has shown that doxepin hydrochloride capsule is safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin hydrochloride capsule is not recommended for use in children under 12 years of age.

CONTRAINDICATIONS Doxepin hydrochloride capsules are contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind. Doxepin hydrochloride capsules are contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.

WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

ll patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers Such monitoring should include daily observation by families and caregivers. Prescriptions for doxepin hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that doxepin hydrochloride are not approved for use in treating bipolar depression. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Usage in Geriatrics: The use of doxepin hydrochloride on a once-a-day dosage regimen in geriatric patients should be adjusted carefully based on the patient’s condition (see PRECAUTIONS; Geriatric Use ). Usage in Pregnancy: Reproduction studies have been performed in rats, rabbits, monkeys and dogs and there was no evidence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride .

dence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride . Usage in Children: The use of doxepin hydrochloride in children under 12 years of age is not recommended because safe conditions for its use have not been established.

<table cellspacing="0" cellpadding="0" border="0" width="598.5"><colgroup><col width="42.4666666666667%"/><col width="57.5333333333333%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">Table 1 </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Age Range </content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"> </td><td styleCode="Rrule" align="center" valign="top">Increases Compared to Placebo </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">&lt;18 </td><td styleCode="Rrule" align="center" valign="top">14 additional cases </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">18 to 24 </td><td styleCode="Rrule" align="center" valign="top">5 additional cases </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="center" valign="top">Decreases Compared to Placebo </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">25 to 64 </td><td styleCode="Rrule" align="center" valign="top">1 fewer case </td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="top">&#x2265;65 </td><td styleCode="Rrule" align="center" valign="top">6 fewer cases </td></tr></tbody></table>

PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride . Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-today basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking doxepin hydrochloride capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. 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. Pediatric Use- Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS; Clinical Worsening and Suicide Risk ). Anyone considering the use of doxepin hydrochloride in a child or adolescent must balance the potential risks with the clinical need. Drug Interactions Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.

10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine.

ere dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin hydrochloride overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day). Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely (see PRECAUTIONS; Geriatric Use ). Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen. Geriatric Use A determination has not been made whether controlled clinical studies of doxepin hydrochloride included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin hydrochloride has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely (see WARNINGS ).

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride . Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-today basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking doxepin hydrochloride capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. 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. Pediatric Use- Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS; Clinical Worsening and Suicide Risk ). Anyone considering the use of doxepin hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

Drug Interactions Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants.

t length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin hydrochloride overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day). Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely (see PRECAUTIONS; Geriatric Use ). Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen.

Geriatric Use A determination has not been made whether controlled clinical studies of doxepin hydrochloride included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin hydrochloride has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely (see WARNINGS ).

ADVERSE REACTIONS NOTE: Some of the adverse reactions noted below have not been specifically reported with doxepin hydrochloride use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing doxepin hydrochloride. Anticholinergic Effects: Dry mouth, blurred vision, constipation, and urinary retention have been reported. If they do not subside with continued therapy, or become severe, it may be necessary to reduce the dosage. Central Nervous System Effects: Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued. Other infrequently reported CNS side effects are confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor. Cardiovascular: Cardiovascular effects including hypotension, hypertension, and tachycardia have been reported occasionally. Allergic: Skin rash, edema, photosensitization, and pruritus have occasionally occurred. Hematologic: Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura. Gastrointestinal: Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and aphthous stomatitis have been reported (see Anticholinergic Effects). Endocrine: Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels, and syndrome of inappropriate antidiuretic hormone secretion have been reported with tricyclic administration. Other: Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects. Withdrawal Symptoms: The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged doxepin hydrochloride administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms. To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day. In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day. In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25 to 50 mg/day. The total daily dosage of doxepin hydrochloride capsules may be given on a divided or once-a-day dosage schedule. If the once-a-day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment. Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks.

OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Deaths have been reported involving overdoses of doxepin. General Recommendations General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is strongly advised. If signs of toxicity occur at any time during this period, extended monitoring is recommended. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular A maximal limb-lead QRS duration of ≥0.1 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.6 or a pCO 2 <20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).

been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

HOW SUPPLIED Doxepin hydrochloride capsules USP, 25 mg are ivory opaque cap/white opaque body size ‘3’ hard gelatin capsule shell axially imprinted with ‘A 341’ on cap in black ink and filled with white to off white granular powder. NDC: 71335-2557-1: 30 Capsules in a BOTTLE NDC: 71335-2557-2: 60 Capsules in a BOTTLE NDC: 71335-2557-3: 28 Capsules in a BOTTLE NDC: 71335-2557-4: 18 Capsules in a BOTTLE NDC: 71335-2557-5: 90 Capsules in a BOTTLE Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • an extreme increase in activity and talking (mania) other unusual changes in behavior or mood • attempts to commit suicide • new or worse depression • new or worse anxiety • Visual problems • feeling very agitated or restless • eye pain • panic attacks • changes in vision • trouble sleeping (insomnia) • swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines.

discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. For more information call Alembic Pharmaceuticals Limited at 1-866-210-9797. Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-9797. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA Revised: 09/2021 Dispense with Medication Guide available at: http://www.alembicusa.com/medicationguide.aspx

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; thoughts about suicide or dying </td><td styleCode="Rrule" valign="middle"> &#x2022; an extreme increase in activity and talking (mania) other unusual changes in behavior or mood </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; attempts to commit suicide</td><td styleCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; new or worse depression</td><td styleCode="Rrule" valign="middle"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; new or worse anxiety</td><td styleCode="Rrule" valign="middle"> &#x2022; Visual problems</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; feeling very agitated or restless</td><td styleCode="Rrule" valign="middle"> &#x2022; eye pain</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; panic attacks</td><td styleCode="Rrule" valign="middle"> &#x2022; changes in vision</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; trouble sleeping (insomnia)</td><td styleCode="Rrule" rowspan="4" valign="middle"> &#x2022; swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; new or worse irritability</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> &#x2022; acting aggressive, being angry, or violent</td></tr><tr><td styleCode="Lrule Rrule" valign="middle"> &#x2022; acting on dangerous impulses</td></tr></tbody></table>

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of doxepin hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin hydrochloride is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use.)

DESCRIPTION Doxepin hydrochloride is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C 19 H 21 NO • HCl having a molecular weight of 315.84. It is a white or almost white, crystalline powder freely soluble in water, in ethanol and in dichloromethane. Soluble in chloroform and in methanol. It may be represented by the following structural formula: Chemically, 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. Each 10 mg, 25 mg, 50 mg, 75 mg and 100 mg doxepin hydrochloride capsules, USP for oral administration contains doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg and 100 mg of doxepin, respectively and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, pregelatinized starch 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 10 mg, 25 mg and 50 mg empty gelatin capsule shells contain FD&C Yellow No. 6 and the 75 mg and 100 mg empty gelatin capsule shells contain FD&C Green No. 3. The imprinting ink contains black iron oxide, propylene glycol, potassium hydroxide and shellac. FDA approved dissolution method differs from the USP dissolution method. stru

CLINICAL PHARMACOLOGY The mechanism of action of doxepin hydrochloride is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin hydrochloride does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, doxepin hydrochloride can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these compounds has been reported. Doxepin hydrochlorideis virtually devoid of euphoria as a side effect. Characteristic of this type of compound, doxepin hydrochloride has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.

INDICATIONS AND USAGE Doxepin Hydrochloride Capsules, USP are recommended for the treatment of: Psychoneurotic patients with depression and/or anxiety. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. The target symptoms of psychoneurosis that respond particularly well to doxepin hydrochloride capsules include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. Clinical experience has shown that doxepin hydrochloride capsules are safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin hydrochloride capsules are not recommended for use in children under 12 years of age.

WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for doxepin hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that doxepin hydrochloride is not approved for use in treating bipolar depression. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Geriatric Use The use of doxepin hydrochloride on a once a day dosage regimen in geriatric patients should be adjusted carefully based on the patient's condition (see PRECAUTIONS: Geriatric Use). Pregnancy Reproduction studies have been performed in rats, rabbits, monkeys and dogs and there was no evidence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride.

idence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride. Pediatric Use The use of doxepin hydrochloride in children under 12 years of age is not recommended because safe conditions for its use have not been established.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><col width="15%"/><col width="84%"/><tbody><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Age Range</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Drug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="left" styleCode="Rrule" valign="top">Increases Compared to Placebo </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">&lt; 18 </td><td align="left" styleCode="Rrule" valign="top">14 additional cases </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">18 to 24 </td><td align="left" styleCode="Rrule" valign="top">5 additional cases </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="left" styleCode="Rrule" valign="top">Decreases Compared to Placebo </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">25 to 64 </td><td align="left" styleCode="Rrule" valign="top">1 fewer case </td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="top">&#x2265; 65 </td><td align="left" styleCode="Rrule" valign="top">6 fewer cases </td></tr></tbody></table>

PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions" is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Clinical Worsening and Suicide Risk Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day to day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking doxepin hydrochloride capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. 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. DRUG INTERACTIONS Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

(TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Doxepin hydrochloride is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin hydrochloride when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin hydrochloride has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects.

s already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin hydrochloride overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin hydrochloride (75 mg/day). Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely (see PRECAUTIONS: Geriatric Use). Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen. Pediateric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone considering the use of doxepin hydrochloride in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use A determination has not been made whether controlled clinical studies of doxepin hydrochloride included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin hydrochloride has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely. (See WARNINGS.)

Information for Patients Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions" is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

DRUG INTERACTIONS Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Doxepin hydrochloride is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin hydrochloride when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin hydrochloride has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved.

O inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin hydrochloride overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin hydrochloride (75 mg/day). Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely (see PRECAUTIONS: Geriatric Use). Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen.

Pediateric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone considering the use of doxepin hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use A determination has not been made whether controlled clinical studies of doxepin hydrochloride included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin hydrochloride has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride and observed closely. (See WARNINGS.)

ADVERSE REACTIONS NOTE: Some of the adverse reactions noted below have not been specifically reported with doxepin hydrochloride use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing doxepin hydrochloride. Anticholinergic Effects: Dry mouth, blurred vision, constipation and urinary retention have been reported. If they do not subside with continued therapy or become severe, it may be necessary to reduce the dosage. Central Nervous System Effects: Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued. Other infrequently reported CNS side effects are confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia and tremor. Cardiovascular: Cardiovascular effects including hypotension, hypertension and tachycardia have been reported occasionally. Allergic: Skin rash, edema, photosensitization and pruritus have occasionally occurred. Hematologic: Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia and purpura. Gastrointestinal: Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia and aphthous stomatitis have been reported. (See Anticholinergic Effects.) Endocrine: Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels and syndrome of inappropriate antidiuretic hormone secretion have been reported with tricyclic administration. Other: Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects. Withdrawal Symptoms The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged doxepin hydrochloride administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms. To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Deaths have been reported involving overdoses of doxepin hydrochloride. General Recommendations General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is strongly advised. If signs of toxicity occur at any time during this period, extended monitoring is recommended. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular A maximal limb lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO 2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration.

ty in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Psychiatric Follow-up Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

DOSAGE AND ADMINISTRATION For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day. In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day. In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25 to 50 mg/day. The total daily dosage of doxepin hydrochloride capsules may be given on a divided or once a day dosage schedule. If the once a day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment. Antianxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks.

HOW SUPPLIED Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP equivalent to 100 mg of doxepin. 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: 70518-4179-00 PACKAGING: 30 in 1 BLISTER PACK 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. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Medication Guide Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with your or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying new or worse irritability attempts to commit suicide acting aggressive, being angry, or violent new or worse depression acting on dangerous impulses new or worse anxiety an extreme increase in activity and talking (mania) feeling very agitated or restless other unusual changes in behavior or mood panic attacks Visual problems: eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. trouble sleeping (insomnia) Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088. What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines.

discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of doxepin hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin hydrochloride is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use).

DESCRIPTION Doxepin hydrochloride is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C 19 H 21 NO•HCl having a molecular weight of 315.84. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform. Its structural formula is: C 19 H 21 NO●HCl MW: 315.84 Chemically,Doxepin HCl 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(6 H )ylidene- N,N -dimethyl-hydrochloride. Each doxepin hydrochloride capsule is equivalent to 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg of doxepin for oral administration. Each capsule contains the following inactive ingredients: corn starch, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, gelatin, magnesium stearate, pharmaceutical glaze, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide and other ingredients. In addition, the 10 mg capsule contains FD&C Yellow #6; the 25 mg and 50 mg capsules contain FD&C Yellow #6 and propylene glycol; the 75 mg capsule contains FD&C Green #3 and propylene glycol, and the 100 mg capsule contains FD&C Green #3. This is the chemical structure

<table><col/><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>C ₁₉H ₂₁NO&#x25CF;HCl </paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"> <paragraph>MW: 315.84</paragraph></td></tr></tbody></table>

CLINICAL PHARMACOLOGY The mechanism of action of doxepin HCl is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin HCl does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, anti-serotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses, norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, doxepin HCl can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these compounds has been reported. Doxepin HCl is virtually devoid of euphoria as a side effect. Characteristic of this type of compound, doxepin HCl has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.

INDICATIONS AND USAGE Doxepin HCl is recommended for the treatment of: 1.Psychoneurotic patients with depression and/or anxiety. 2.Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). 3.Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). 4.Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. The target symptoms of psychoneurosis that respond particularly well to doxepin HCl include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. Clinical experience has shown that doxepin HCl is safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin HCl is not recommended for use in children under 12 years of age.

CONTRAINDICATIONS Doxepin HCl is contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind. Doxepin HCl is contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.

WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

ll patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for doxepin hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that doxepin hydrochloride is not approved for use in treating bipolar depression. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Doxepin Hydrochloride Capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Geriatric Use The use of doxepin HCl on a once-a-day dosage regimen in geriatric patients should be adjusted carefully based on the patient’s condition (see PRECAUTIONS-Geriatric Use ). Pregnancy Reproduction studies have been performed in rats, rabbits, monkeys and dogs and there was no evidence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride.

idence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride. Pediatric Use The use of doxepin HCl in children under 12 years of age is not recommended because safe conditions for its use have not been established.

<table><caption>Table 1</caption><col width="14%"/><col width="86%"/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"> <paragraph>Age Range</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"> <paragraph>Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> </td><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>Increases Compared to Placebo</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>&lt; 18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>14 additional cases</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>18 to 24</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>5 additional cases</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> </td><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>Decreases Compared to Placebo</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>25 to 64</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>1 fewer case</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"> <paragraph>&#x2265; 65</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"> <paragraph>6 fewer cases</paragraph></td></tr></tbody></table>

PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride. Patients should be advised that taking Doxepin Hydrochloride Capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. 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. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Drug Interactions Drugs Metabolized by P450 2D6 : The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

(TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin HCl. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin HCl overdosage.

apy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin HCl overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day). Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin HCl and observed closely (see PRECAUTIONS-Geriatric Use ). Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer dosage regimen. Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS – Clinical Worsening and Suicide Risk ). Anyone considering the use of doxepin HCl in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use A determination has not been made whether controlled clinical studies of doxepin HCl included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin HCl has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin HCl and observed closely. (See WARNINGS. )

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride. Patients should be advised that taking Doxepin Hydrochloride Capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. 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. Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

Drug Interactions Drugs Metabolized by P450 2D6 : The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin HCl. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants.

t length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin HCl overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day). Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin HCl and observed closely (see PRECAUTIONS-Geriatric Use ). Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer dosage regimen. Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS – Clinical Worsening and Suicide Risk ). Anyone considering the use of doxepin HCl in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use A determination has not been made whether controlled clinical studies of doxepin HCl included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin HCl has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin HCl and observed closely. (See WARNINGS. )

ADVERSE REACTIONS NOTE: Some of the adverse reactions noted below have not been specifically reported with doxepin HCl use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing doxepin HCl. Anticholinergic Effects: Dry mouth, blurred vision, constipation, and urinary retention have been reported. If they do not subside with continued therapy, or become severe, it may be necessary to reduce the dosage. Central Nervous System Effects: Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued. Other infrequently reported CNS side effects are confusion, disorientation, hallucinations, numbness, paresthesia, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia and tremor. Cardiovascular: Cardiovascular effects including hypotension, hypertension, and tachycardia have been reported occasionally. Allergic: Skin rash, edema, photosensitization, and pruritus have occasionally occurred. Hematologic: Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura. Gastrointestinal: Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and aphthous stomatitis have been reported. ( See Anticholinergic Effects.) Endocrine: Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels and syndrome of inappropriate antidiuretic hormone secretion have been reported with tricyclic administration. Other: Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects. Withdrawal Symptoms: The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged doxepin HCl administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms.

OVERDOSAGE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations: Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Deaths have been reported involving overdoses of doxepin. General Recommendations: General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks and seizures is strongly advised. If signs of toxicity occur at any time during this period, extended monitoring is recommended. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Gastrointestinal Decontamination All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated. Cardiovascular A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO 2 < 20mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration.

y in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital and phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies and only in consultation with a poison control center. Psychiatric Follow-up Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate. Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

DOSAGE AND ADMINISTRATION For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day. In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day. In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25 to 50 mg/day. The total daily dosage of doxepin HCl may be given on a divided or once-a-day dosage schedule. If the once-a-day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment. Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks.

HOW SUPPLIED Doxepin HCl capsules USP, equivalent to 150 mg of doxepin are hard gelatin capsules with white opaque body and blue opaque cap, imprinted “Par 222” on both body and cap. They are supplied in NDC: 70518-0386-00 NDC: 70518-0386-01 PACKAGING: 30 in 1 BLISTER PACK PACKAGING: 30 in 1 BLISTER PACK Store at 20°to 25°C (68°-77°F) [see USP Controlled Room Temperature]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

Medication Guide Doxepin Hydrochloride (dok ˊsĕ-pin hī-drō-klōrˊīd) Capsules USP Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1.Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2.Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3.How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling very agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Visual problems: eye pain, changes in vision, swelling or redness in or around the eye What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Visual problems: Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes.

just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. For Medication Guide, please visit www.endo.com. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

DESCRIPTION Doxepin hydrochloride is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C 19 H 21 NO • HCl having a molecular weight of 315.84. It is a white or almost white, crystalline powder freely soluble in water, in ethanol and in dichloromethane. Soluble in chloroform and in methanol. It may be represented by the following structural formula: Chemically, 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. Each 10 mg, 25 mg, 50 mg, 75 mg and 100 mg doxepin hydrochloride capsules, USP for oral administration contains doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg and 100 mg of doxepin, respectively and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, pregelatinized starch 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 10 mg, 25 mg and 50 mg empty gelatin capsule shells contain FD&C Yellow No. 6 and the 75 mg and 100 mg empty gelatin capsule shells contain FD&C Green No. 3. The imprinting ink contains black iron oxide, propylene glycol, potassium hydroxide and shellac. FDA approved dissolution method differs from the USP dissolution method.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="15%"/><col width="84%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">Age Range</content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Drug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="left" valign="top">Increases Compared to Placebo </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">&lt; 18 </td><td styleCode="Rrule" align="left" valign="top">14 additional cases </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">18 to 24 </td><td styleCode="Rrule" align="left" valign="top">5 additional cases </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="left" valign="top">Decreases Compared to Placebo </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">25 to 64 </td><td styleCode="Rrule" align="left" valign="top">1 fewer case </td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="top">&#x2265; 65 </td><td styleCode="Rrule" align="left" valign="top">6 fewer cases </td></tr></tbody></table>

PRECAUTIONS Information for Patients Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions" is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride. Clinical Worsening and Suicide Risk Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day to day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking doxepin hydrochloride capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. 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. DRUG INTERACTIONS Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

Information for Patients Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with doxepin hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions" is available for doxepin hydrochloride. The prescriber or health professional should instruct patients, their families and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking doxepin hydrochloride.

HOW SUPPLIED Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP 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. NDC: 71335-2804-1: 60 CAPSULEs in a BOTTLE, PLASTIC NDC: 71335-2804-2: 30 CAPSULEs in a BOTTLE, PLASTIC NDC: 71335-2804-3: 90 CAPSULEs in a BOTTLE, PLASTIC NDC: 71335-2804-4: 120 CAPSULEs in a BOTTLE, PLASTIC 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. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 Issued on: June 2022

DESCRIPTION Doxepin hydrochloride cream, 5% is a topical cream. Each gram contains: 50 mg of doxepin hydrochloride, USP (equivalent to 44.3 mg of doxepin). Doxepin hydrochloride, USP is one of a class of agents known as dibenzoxepin tricyclic antidepressant compounds. It is an isomeric mixture of N,N-dimethyldibenz[ b,e ]oxepin-∆ 11(6H),γ -propylaminehydrochloride. Doxepin hydrochloride, USP has a molecular formula of C 19 H 21 NO•HCl and a molecular weight of 315.84. Doxepin hydrochloride cream, 5% is a white cream and contains the following inactive ingredients: sorbitol solution, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, white petrolatum, benzyl alcohol, titanium dioxide, and purified water. 1

CLINICAL PHARMACOLOGY Although doxepin hydrochloride does have H 1 and H 2 histamine receptor blocking actions, the exact mechanism by which doxepin exerts its antipruritic effect is unknown. Doxepin hydrochloride cream can produce drowsiness in significant numbers of patients, and this sedation may reduce awareness, including awareness of pruritic symptoms. In 19 pruritic eczema patients treated with doxepin hydrochloride cream, plasma doxepin concentrations ranged from non-detectable to 47 ng/mL from percutaneous absorption. Plasma levels from topical application of doxepin hydrochloride cream can result in CNS and other systemic side effects. Once absorbed into the systemic circulation, doxepin undergoes hepatic metabolism that results in conversion to pharmacologically-active desmethyldoxepin. Further glucuronidation results in urinary excretion of the parent drug and its metabolites. Desmethyldoxepin has a half-life that ranges from 28 to 52 hours and is not affected by multiple dosing. Plasma levels of both doxepin and desmethyldoxepin are highly variable and are poorly correlated with dosage. Wide distribution occurs in body tissues including lungs, heart, brain, and liver. Renal disease, genetic factors, age, and other medications affect the metabolism and subsequent elimination of doxepin (see PRECAUTIONS, Drug Interactions ).

INDICATIONS AND USAGE Doxepin hydrochloride cream, 5% is indicated for the short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus (see DOSAGE AND ADMINISTRATION ).

CONTRAINDICATIONS Because doxepin hydrochloride has an anticholinergic effect and because significant plasma levels of doxepin are detectable after topical doxepin hydrochloride cream application, the use of doxepin hydrochloride cream is contraindicated in patients with untreated narrow angle glaucoma or a tendency to urinary retention. Doxepin hydrochloride cream is contraindicated in individuals who have shown previous sensitivity to any of its components.

WARNINGS Drowsiness occurs in over 20% of patients treated with doxepin hydrochloride cream, especially in patients receiving treatment to greater than 10% of their body surface area. Patients should be warned about the possibility of sedation and cautioned against driving a motor vehicle or operating hazardous machinery while being treated with doxepin hydrochloride cream. The sedating effects of alcoholic beverages, antihistamines, and other CNS depressants may be potentiated when doxepin hydrochloride cream is used. If excessive drowsiness occurs it may be necessary to reduce the frequency of applications, the amount of cream applied, and/or the percentage of body surface area treated, or discontinue the drug. However, the efficacy with reduced frequency of applications has not been established. Keep this product away from the eyes.

PRECAUTIONS General Drowsiness Since drowsiness may occur with the use of doxepin hydrochloride cream, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while using this drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on doxepin hydrochloride cream (see PRECAUTIONS, Geriatric Use ). Use under occlusion Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with doxepin hydrochloride cream. Contact sensitization Use of doxepin hydrochloride cream can cause Type IV hypersensitivity reactions (contact sensitization) to doxepin. Drug Interactions Studies have not been performed examining drug interactions with doxepin hydrochloride cream. However, since plasma levels of doxepin following topical application of doxepin hydrochloride cream can reach levels obtained with oral doxepin hydrochloride therapy, the following drug interactions are possible following topical doxepin hydrochloride cream application: Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dosage regimen of a TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

lic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride cream. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. Alcohol Alcohol ingestion may exacerbate the potential sedative effects of doxepin hydrochloride cream. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of oral doxepin (75 mg/day). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and impairment of fertility studies have not been conducted with doxepin hydrochloride. Pregnancy Reproduction studies have been performed in which doxepin was orally administered to rats and rabbits at doses up to 0.6 and 1.2 times, respectively, the estimated exposure to doxepin that results from use of 16 grams of doxepin hydrochloride cream per day (four applications of four grams of cream per day; dose multiples reflect comparisons made following normalization of the data on the basis of body surface area estimates) and have revealed no evidence of harm to rat or rabbit fetuses due to doxepin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Doxepin is excreted in human milk after oral administration. It is possible that doxepin may also be excreted in human milk following topical application of doxepin hydrochloride cream. One case has been reported of apnea and drowsiness in a nursing infant whose mother was taking an oral dosage form of doxepin hydrochloride. Because of the potential for serious adverse reactions in nursing infants from doxepin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The use of doxepin hydrochloride cream in pediatric patients is not recommended. Safe conditions for use of doxepin hydrochloride cream in children have not been established. One case has been reported of a 2.5 year old child who developed somnolence, grand mal seizure, respiratory depression, ECG abnormalities, and coma after treatment with doxepin hydrochloride cream. A total of 27 grams had been applied over three days for eczema. He was treated with supportive care, activated charcoal, and systemic alkalization and recovered. Geriatric Use Clinical studies of doxepin hydrochloride cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

over three days for eczema. He was treated with supportive care, activated charcoal, and systemic alkalization and recovered. Geriatric Use Clinical studies of doxepin hydrochloride cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on doxepin hydrochloride cream (see WARNINGS ). An 80-year old male nursing home patient developed probable systemic anticholinergic toxicity which included urinary retention and delirium after doxepin hydrochloride cream had been applied to his arms, legs and back three times daily for two days.

General Drowsiness Since drowsiness may occur with the use of doxepin hydrochloride cream, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while using this drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on doxepin hydrochloride cream (see PRECAUTIONS, Geriatric Use ). Use under occlusion Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with doxepin hydrochloride cream. Contact sensitization Use of doxepin hydrochloride cream can cause Type IV hypersensitivity reactions (contact sensitization) to doxepin.

Drug Interactions Studies have not been performed examining drug interactions with doxepin hydrochloride cream. However, since plasma levels of doxepin following topical application of doxepin hydrochloride cream can reach levels obtained with oral doxepin hydrochloride therapy, the following drug interactions are possible following topical doxepin hydrochloride cream application: Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dosage regimen of a TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with doxepin hydrochloride cream. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine.

re dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. Alcohol Alcohol ingestion may exacerbate the potential sedative effects of doxepin hydrochloride cream. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of oral doxepin (75 mg/day).

Pregnancy Reproduction studies have been performed in which doxepin was orally administered to rats and rabbits at doses up to 0.6 and 1.2 times, respectively, the estimated exposure to doxepin that results from use of 16 grams of doxepin hydrochloride cream per day (four applications of four grams of cream per day; dose multiples reflect comparisons made following normalization of the data on the basis of body surface area estimates) and have revealed no evidence of harm to rat or rabbit fetuses due to doxepin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers Doxepin is excreted in human milk after oral administration. It is possible that doxepin may also be excreted in human milk following topical application of doxepin hydrochloride cream. One case has been reported of apnea and drowsiness in a nursing infant whose mother was taking an oral dosage form of doxepin hydrochloride. Because of the potential for serious adverse reactions in nursing infants from doxepin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The use of doxepin hydrochloride cream in pediatric patients is not recommended. Safe conditions for use of doxepin hydrochloride cream in children have not been established. One case has been reported of a 2.5 year old child who developed somnolence, grand mal seizure, respiratory depression, ECG abnormalities, and coma after treatment with doxepin hydrochloride cream. A total of 27 grams had been applied over three days for eczema. He was treated with supportive care, activated charcoal, and systemic alkalization and recovered.

Geriatric Use Clinical studies of doxepin hydrochloride cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on doxepin hydrochloride cream (see WARNINGS ). An 80-year old male nursing home patient developed probable systemic anticholinergic toxicity which included urinary retention and delirium after doxepin hydrochloride cream had been applied to his arms, legs and back three times daily for two days.

ADVERSE REACTIONS Controlled Clinical Trials Systemic Adverse Effects In controlled clinical trials of patients treated with doxepin hydrochloride cream, the most common systemic adverse event reported was drowsiness. Drowsiness occurred in 71 of 330 (22%) of patients treated with doxepin hydrochloride cream compared to 7 of 334 (2%) of patients treated with vehicle cream. Drowsiness resulted in the premature discontinuation of the drug in approximately 5% of patients treated with doxepin hydrochloride cream in controlled clinical trials. Local Site Adverse Effects In controlled clinical trials of patients treated with doxepin hydrochloride cream, the most common local site adverse event reported was burning and/or stinging at the site of application. These occurred in 76 of 330 (23%) of patients treated with doxepin hydrochloride cream compared to 54 of 334 (16%) of patients treated with vehicle cream. Most of these reactions were categorized as "mild"; however, approximately 25% of patients who reported burning and/or stinging reported the reaction as "severe". Four patients treated with doxepin hydrochloride cream withdrew from the study because of the burning and/or stinging. The table below presents the adverse events reported at an incidence of ≥1% in either doxepin hydrochloride cream or vehicle cream treatment groups during the trials: Adverse Event Doxepin Hydrochloride Cream N=330 Vehicle N=334 Burning/Stinging 76 (23.0%) 54 (16.2%) Drowsiness 71 (21.5%) 7 (2.1%) Dry Mouth 1 32 (9.7%) 4 (1.2%) Pruritus 2 13 (3.9%) 20 (6.0%) Fatigue/Tiredness 10 (3.0%) 5 (1.5%) Exacerbated Eczema 10 (3.0%) 8 (2.4%) Other Application Site Reaction 3 10 (3.0%) 16 (4.8%) Dizziness 4 7 (2.1%) 3 (0.9%) Mental Emotional Changes 6 (1.8%) 1 (0.3%) Taste Perversion 5 5 (1.5%) 1 (0.3%) Edema 4 (1.2%) 1 (0.3%) Headache 3 (0.9%) 14 (4.2%) 1 Includes reports of “dry lips”, “dry throat”, and “thirst” 2 Includes reports of “Pruritus Exacerbated” 3 Includes report of “increased irritation at application site” 4 Includes reports of “lightheadedness” and “dizziness/vertigo” 5 Includes reports of “bitter taste” and “metallic taste in mouth” Adverse events occurring in 0.5% to <1.0% of doxepin hydrochloride cream treated patients in the controlled clinical trials included: nervousness/anxiety, tongue numbness, fever, and nausea. To report SUSPECTED ADVERSE EVENTS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions. Postmarketing Experience Twenty-six cases of allergic contact dermatitis have been reported in patients using doxepin hydrochloride cream, twenty of which were documented by positive patch test to doxepin 5% cream.

<table width="800px" cellpadding="5"><col width="207.9pt"/><col width="124.25pt"/><col width="110.65pt"/><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Doxepin Hydrochloride Cream</content></paragraph><paragraph><content styleCode="bold">N=330</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Vehicle</content></paragraph><paragraph><content styleCode="bold">N=334</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Burning/Stinging</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>76 (23.0%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>54 (16.2%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Drowsiness</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>71 (21.5%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7 (2.1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry Mouth¹</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>32 (9.7%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1.2%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pruritus²</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13 (3.9%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>20 (6.0%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue/Tiredness</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 (3.0%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5 (1.5%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Exacerbated Eczema</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 (3.0%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>8 (2.4%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Other Application Site Reaction³</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>10 (3.0%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>16 (4.8%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness⁴</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7 (2.1%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (0.9%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Mental Emotional Changes</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6 (1.8%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (0.3%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Taste Perversion⁵</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5

ule"><paragraph>6 (1.8%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (0.3%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Taste Perversion⁵</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5 (1.5%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (0.3%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Edema</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1.2%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (0.3%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Headache</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (0.9%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>14 (4.2%)</paragraph></td></tr><tr><td colspan="3"><paragraph>¹ Includes reports of &#x201C;dry lips&#x201D;, &#x201C;dry throat&#x201D;, and &#x201C;thirst&#x201D;</paragraph></td></tr><tr><td colspan="3"><paragraph>² Includes reports of &#x201C;Pruritus Exacerbated&#x201D;</paragraph></td></tr><tr><td colspan="3"><paragraph>³ Includes report of &#x201C;increased irritation at application site&#x201D;</paragraph></td></tr><tr><td colspan="3"><paragraph>⁴ Includes reports of &#x201C;lightheadedness&#x201D; and &#x201C;dizziness/vertigo&#x201D;</paragraph></td></tr><tr><td colspan="3"><paragraph>⁵ Includes reports of &#x201C;bitter taste&#x201D; and &#x201C;metallic taste in mouth&#x201D;</paragraph></td></tr></tbody></table>

OVERDOSAGE Deaths may occur from overdosage with this class of drugs. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations Should overdosage with topical application of doxepin hydrochloride cream occur, the signs and symptoms may include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS . General Recommendations General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is strongly advised. If signs of toxicity occur at any time during this period, extended monitoring is recommended. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient. Cardiovascular A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO 2 <20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning. CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center. Pediatric Management The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

DOSAGE AND ADMINISTRATION A thin film of doxepin hydrochloride cream should be applied four times each day with at least a 3 to 4 hour interval between applications. There are no data to establish the safety and effectiveness of doxepin hydrochloride cream when used for greater than 8 days. Chronic use beyond eight days may result in higher systemic levels and should be avoided. Use of doxepin hydrochloride cream for longer than 8 days may result in an increased likelihood of contact sensitization. The risk for sedation may increase with greater body surface area application of doxepin hydrochloride cream (see WARNINGS ). Clinical experience has shown that drowsiness is significantly more common in patients applying doxepin hydrochloride cream to over 10% of body surface area; therefore, patients with greater than 10% of body surface area (see WARNINGS ) affected should be particularly cautioned concerning possible drowsiness and other systemic adverse effects of doxepin. If excessive drowsiness occurs, it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with doxepin hydrochloride cream.

HOW SUPPLIED Doxepin hydrochloride cream, 5% is a white cream and is available in a 45 g (NDC 0093-9609-95) tube. Store below 27°C (80°F). Manufactured By: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Iss. 6/2021

HOW SUPPLIED Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP equivalent to 75 mg of doxepin. 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: 70518-4222-00 PACKAGING: 30 in 1 BLISTER PACK 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. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762