Doxepin Hydrochloride

1 INDICATIONS AND USAGE Doxepin tablets are indicated for the treatment of insomnia characterized by difficulty with sleep maintenance. The clinical trials performed in support of efficacy were up to 3 months in duration. Doxepin tablets are indicated for the treatment of insomnia characterized by difficulties with sleep maintenance. ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION The dose of doxepin tablets should be individualized. Initial dose: 6 mg, once daily for adults ( 2.1 ) and 3 mg, once daily for the elderly. ( 2.1 , 2.2 ) Take within 30 minutes of bedtime. Total daily dose should not exceed 6 mg. ( 2.3 ) Should not be taken within 3 hours of a meal. ( 2.3 , 12.3 ) 2.1 Dosing in Adults The recommended dose of doxepin tablets for adults is 6 mg once daily. A 3 mg once daily dose may be appropriate for some patients, if clinically indicated. 2.2 Dosing in the Elderly The recommended starting dose of doxepin tablets in elderly patients (≥65 years old) is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated. 2.3 Administration Doxepin tablets should be taken within 30 minutes of bedtime. To minimize the potential for next day effects, doxepin tablets should not be taken within 3 hours of a meal [ see Clinical Pharmacology (12.3) ]. The total doxepin tablets dose should not exceed 6 mg per day.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of labeling: Abnormal thinking and behavioral changes [see Warnings and Precautions (5.2)] . Suicide risk and worsening of depression [ see Warnings and Precautions (5.3) ] . CNS Depressant effects [ see Warnings and Precautions (5.4) ] . The most common treatment-emergent adverse reactions, reported in ≥ 2% of patients treated with doxepin, and more commonly than in patients treated with placebo, were somnolence/sedation, nausea, and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 and or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The pre-marketing development program for doxepin tablets included doxepin HCl exposures in 1017 subjects (580 insomnia patients and 437 healthy subjects) from 12 studies conducted in the United States. 863 of these subjects (580 insomnia patients and 283 healthy subjects) participated in six randomized, placebo-controlled efficacy studies with doxepin doses of 1 mg, 3 mg, and 6 mg for up to 3-months in duration. Because clinical studies 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. However, data from the doxepin studies provide the physician with a basis for estimating the relative contributions of drug and non-drug factors to adverse reaction incidence rates in the populations studied. Associated with Discontinuation of Treatment The percentage of subjects discontinuing Phase 1, 2, and 3 trials for an adverse reaction was 0.6% in the placebo group compared to 0.4%, 1.0%, and 0.7% in the doxepin 1 mg, 3 mg, and 6 mg groups, respectively. No reaction that resulted in discontinuation occurred at a rate greater than 0.5%. Adverse Reactions Observed at an Incidence of ≥ 2% in Controlled Trials Table 1 shows the incidence of treatment-emergent adverse reactions from three long-term (28 to 85 days) placebo-controlled studies of doxepin in adult (N=221) and elderly (N=494) subjects with chronic insomnia. Reactions reported by Investigators were classified using a modified MedDRA dictionary of preferred terms for purposes of establishing incidence. The table includes only reactions that occurred in 2% or more of subjects who received doxepin 3 mg or 6 mg in which the incidence in subjects treated with doxepin was greater than the incidence in placebo-treated subjects. Table 1 Incidence (%) of Treatment-Emergent Adverse Reactions in Long-term Placebo-Controlled Clinical Trials System Organ Class Preferred Term* Placebo (N=278) Doxepin 3 mg (N=157) Doxepin 6 mg (N=203) Nervous System Disorders Somnolence/Sedation 4 6 9 Infections and Infestations Upper Respiratory Tract Infection/Nasopharyngitis 2 4 2 Gastroenteritis 0 2 0 Gastrointestinal Disorders Nausea 1 2 2 Vascular Disorders Hypertension 0 3 < 1 * Includes reactions that occurred at a rate of ≥2% in any doxepin-treated group and at a higher rate than placebo. The most common treatment-emergent adverse reaction in the placebo and each of the doxepin dose groups was somnolence/sedation. 6.2 Studies Pertinent to Safety Concerns for Sleep-promoting Drugs Residual Pharmacological Effect in Insomnia Trials Five randomized, placebo-controlled studies in adults and the elderly assessed next-day psychomotor function within 1 hour of awakening utilizing the digit-symbol substitution test (DSST), symbol copying test (SCT), and visual analog scale (VAS) for sleepiness, following night time administration of doxepin. In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, doxepin 6 mg showed modest negative changes in SCT and VAS. In a 35-day, double-blind, placebo-controlled, parallel group study of doxepin 3 and 6 mg in 221 adults with chronic insomnia, small decreases in the DSST and SCT occurred in the 6 mg group. In a 3-month, double-blind, placebo-controlled, parallel group study in 240 elderly subjects with chronic insomnia, doxepin 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS. 6.3 Other Reactions Observed During the Pre-marketing Evaluation of Doxepin Doxepin was administered to 1017 subjects in clinical trials in the United States. Treatment-emergent adverse reactions recorded by clinical investigators were standardized using a modified MedDRA dictionary of preferred terms. The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions reported by subjects treated with doxepin. Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 subjects; Infrequent adverse reactions are those that occurred in fewer than 1/100 subjects and more than 1/1000 subjects. Rare adverse reactions are those that occurred in fewer than 1/1000 subjects. Adverse reactions that are listed in Table 1 are not included in the following listing of frequent, infrequent, and rare AEs. Blood and Lymphatic System Disorders : Infrequent: anemia; Rare: thrombocythemia. Cardiac Disorders : Rare: atrioventricular block, palpitations, tachycardia, ventricular extrasystoles. Ear and Labyrinth Disorders : Rare: ear pain, hypoacusis, motion sickness, tinnitus, tympanic membrane perforation. Eye Disorders : Infrequent: eye redness, vision blurred; Rare: blepharospasm, diplopia, eye pain, lacrimation decreased. Gastrointestinal Disorders : Infrequent: abdominal pain, dry mouth, gastroesophageal reflux disease, vomiting; Rare: dyspepsia, constipation, gingival recession, haematochezia, lip blister. General Disorders and Administration Site Conditions : Infrequent: asthenia, chest pain, fatigue; Rare: chills, gait abnormal, edema peripheral. Hepatobiliary Disorders : Rare: hyperbilirubinemia. Immune System Disorders : Rare: hypersensitivity. Infections and Infestations : Infrequent: bronchitis, fungal infection, laryngitis, sinusitis, tooth infection, urinary tract infection, viral infection; Rare: cellulitis staphylococcal, eye infection, folliculitis, gastroenteritis viral, herpes zoster, infective tenosynovitis, influenza, lower respiratory tract infection, onychomycosis, pharyngitis, pneumonia. Injury, Poisoning and Procedural Complications : Infrequent: back injury, fall, joint sprain; Rare: bone fracture, skin laceration. Investigations : Infrequent: blood glucose increased; Rare: alanine aminotransferase increased, blood pressure decreased, blood pressure increased, electrocardiogram ST-T segment abnormal, electrocardiogram QRS complex abnormal, heart rate decreased, neutrophil count decreased, QRS axis abnormal, transaminases increased. Metabolism and Nutrition Disorders : Infrequent: anorexia, decreased appetite, hyperkalemia, hypermagnesemia, increased appetite; Rare: hypokalemia. Musculoskeletal and Connective Tissue Disorders : Infrequent: arthralgia, back pain, myalgia, neck pain, pain in extremity; Rare: joint range of motion decreased, muscle cramp, sensation of heaviness. Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) : Rare: lung adenocarcinoma stage I, malignant melanoma. Nervous System Disorders : Frequent: dizziness; Infrequent: dysgeusia, lethargy, parasthesia, syncope; Rare: ageusia, ataxia, cerebrovascular accident, disturbance in attention, migraine, sleep paralysis, syncope vasovagal, tremor. Psychiatric Disorders : Infrequent: abnormal dreams, adjustment disorder, anxiety, depression; Rare: confusional state, elevated mood, insomnia, libido decreased, nightmare. Reproductive System and Breast Disorders : Rare: breast cyst, dysmenorrhea. Renal and Urinary Disorders : Rare: dysuria, enuresis, hemoglobinuria, nocturia. Respiratory, Thoracic and Mediastinal Disorders : Infrequent: nasal congestion, pharyngolaryngeal pain, sinus congestion, wheezing; Rare: cough, crackles lung, nasopharyngeal disorder, rhinorrhea, dyspnea. Skin and Subcutaneous Tissue Disorders: Infrequent: skin irritation; Rare: cold sweat, dermatitis, erythema, hyperhidrosis, pruritis, rash, rosacea. Surgical and Medical Procedures: Rare: arthrodesis. Vascular Disorders : Infrequent: pallor; Rare: blood pressure inadequately controlled, hematoma, hot flush. In addition, the reactions below have been reported for other tricyclics and may be idiosyncratic (not related to dose). Allergic : photosensitization, skin rash. Hematologic : agranulocytosis, eosinophilia, leukopenia, purpura, thrombocytopenia.

12.3 Pharmacokinetics Absorption The median time to peak concentrations (T max ) of doxepin occurred at 3.5 hours postdose after oral administration of a 6 mg dose to fasted healthy subjects. Peak plasma concentrations (C max ) of doxepin increased in approximately a dose-proportional manner for 3 mg and 6 mg doses. The AUC was increased by 41% and C max by 15% when 6 mg doxepin was administered with a high fat meal. Additionally, compared to the fasted state, T max was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended that doxepin not be taken within 3 hours of a meal [ see Dosage and Administration (2.3)]. Distribution Doxepin is widely distributed throughout the body tissues. The mean apparent volume of distribution following a single 6 mg oral dose of doxepin to healthy subjects was 11,930 liters. Doxepin is approximately 80% bound to plasma proteins. Metabolism Following oral administration, doxepin is extensively metabolized by oxidation and demethylation.The primary metabolite is N-desmethyldoxepin (nordoxepin). The primary metabolite undergoes further biotransformation to glucuronide conjugates. In vitro studies have shown that CYP2C19 and CYP2D6 are the major enzymes involved in doxepin metabolism, and that CYP1A2 and CYP2C9 are involved to a lesser extent. Doxepin appears not to have inhibitory effects on human CYP enzymes at therapeutic concentrations. The potential of doxepin to induce metabolizing enzymes is not known. Doxepin is not a Pgp substrate. Excretion Doxepin is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. The apparent terminal half-life (t ½) of doxepin was 15.3 hours and for nordoxepin was 31 hours. Drug Interactions Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of these CYP isozymes may increase the exposure of doxepin. Cimetidine The effect of cimetidine, a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4, on doxepin plasma concentrations was evaluated in healthy subjects. When cimetidine 300 mg BID was co-administered with a single dose of doxepin 6 mg, there was approximately a 2­ fold increase in doxepin C max and AUC compared to doxepin given alone. A maximum dose of doxepin in adults and elderly should be 3 mg, when doxepin is co-administered with cimetidine. Sertraline The effect of sertraline HCl, a selective serotonin reuptake inhibitor, on doxepin plasma concentrations was evaluated in a daytime study conducted with 24 healthy subjects. Following co-administration of doxepin 6 mg with sertraline 50 mg (at steady-state), the doxepin mean AUC and C max estimates were approximately 21% and 32% higher, respectively, than those obtained following administration of doxepin alone. Psychomotor function as measured by the digit symbol substitution test and symbol copy test performance was decreased more at 2-4 hours post dosing for the combination of sertraline and doxepin as compared to doxepin alone, but subjective measures of alertness were comparable for the two treatments. Special Populations Renal Impairment The effects of renal impairment on doxepin pharmacokinetics have not been studied. Because only small amounts of doxepin and nordoxepin are eliminated in the urine, renal impairment would not be expected to result in significantly altered doxepin concentrations. Hepatic Impairment The effects of doxepin in patients with hepatic impairment have not been studied. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Poor Metabolizers of CYPs Poor metabolizers of CYP2C19 and CYP2D6 may have higher doxepin plasma levels than normal subjects.