DOXEPIN

Doxepin is available in 3 mg and 6 mg strength tablets for oral administration. Each tablet contains 3.39 mg or 6.78 mg doxepin hydrochloride, USP equivalent to 3 mg and 6 mg of doxepin, respectively. Chemically, doxepin hydrochloride, USP is an (E) and (Z) geometric, isomeric mixture of 1 propanamine, 3-dibenz[ b,e ]oxepin-11(6 H )ylidene- N,N -dimethyl-hydrochloride. It has the following structure: Doxepin hydrochloride, USP is a white or almost white crystalline powder, that is readily soluble in water, in alcohol and in methylene chloride. It has a molecular weight of 315.84 and molecular formula of C 19 H 21 NO•HCl. Each doxepin tablet contains the following inactive ingredients: FD&C Blue No.1 aluminium lake, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate and talc. In addition 6 mg tablet also contains D&C Yellow No. 10 aluminium lake. Structured formula for Doxepin

Doxepin tablets are indicated for the treatment of insomnia characterized by difficulties with sleep maintenance. ( 1 , 14 ) 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.

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) The dose of doxepin tablets should be individualized. 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.

Hypersensitivity to doxepin hydrochloride, inactive ingredients, or other dibenzoxepines. (4.1) Coadministration with Monoamine Oxidase Inhibitors (MAOIs): Do not administer if patient is taking MAOIs or has used MAOIs within the past two weeks. (4.2) Untreated narrow angle glaucoma or severe urinary retention. (4.3) 4.1 Hypersensitivity Doxepin tablets are contraindicated in individuals who have shown hypersensitivity to doxepin hydrochloride, any of its inactive ingredients, or other dibenzoxepines. 4.2 Coadministration with Monoamine Oxidase Inhibitors (MAOIs) Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Do not administer doxepin tablets if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment. 4.3 Glaucoma and Urinary Retention Doxepin tablets are contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.

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 Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 )]. 6.1 Clinical Trials Experience The premarketing development program for doxepin included doxepin hydrochloride 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%, 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 * Includes reactions that occurred at a rate of ≥ 2% in any doxepin-treated group and at a higher rate than placebo. 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 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 1,017 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 1/1,000 subjects. Rare adverse reactions are those that occurred in fewer than 1/1,000 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.

MAO inhibitors: Doxepin should not be administered in patients on MAOIs within the past two weeks. (4.2) Cimetidine: Increases exposure to doxepin. (7.2) Alcohol: Sedative effects may be increased with doxepin. (7.3, 5.4) CNS Depressants and Sedating Antihistamines: Sedative effects may be increased with doxepin. (7.4, 5.4) Tolazamide: A case of severe hypoglycemia has been reported. (7.5) 7.1 Cytochrome P450 Isozymes Doxepin is primarily metabolized by hepatic cytochrome P450 isozymes CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Inhibitors of these isozymes may increase the exposure of doxepin. Doxepin is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of doxepin to induce CYP isozymes is not known. 7.2 Cimetidine Doxepin exposure is doubled with concomitant administration of cimetidine, a nonspecific inhibitor of CYP isozymes. A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co-administered with doxepin [see Clinical Pharmacology ( 12.3 )] 7.3 Alcohol When taken with doxepin, the sedative effects of alcohol may be potentiated [see Warnings and Precautions ( 5.2 , 5.4 )] . 7.4 CNS Depressants and Sedating Antihistamines When taken with doxepin, the sedative effects of sedating antihistamines and CNS depressants may be potentiated [see Warnings and Precautions ( 5.2 , 5.4 )]. 7.5 Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 g/day) 11 days after the addition of oral doxepin (75 mg/day).

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature], protected from light. Dispense in a tight, light resistant container.