Doxepin

12.1 Mechanism of Action The mechanism of action of doxepin in sleep maintenance is unclear; however, doxepin’s effect could be mediated through antagonism of the H1 receptor.

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; Infre

7 DRUG INTERACTIONS 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).