Doxepin

1 INDICATIONS AND USAGE 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.

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 (greater than or equal to 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.

3 DOSAGE FORMS AND STRENGTHS Doxepin tablets is an immediate-release, oval-shaped, tablet for oral administration available in strengths of 3 mg and 6 mg. The 3 mg tablets are white to off white oval-shaped tablets, debossed with “DOET” on one side and “3” on the other side. The 6 mg tablets are white to off white oval-shaped tablets, debossed with “DOET” on one side and “6” on the other side. Doxepin tablets are not scored. 3 mg and 6 mg tablets. Tablets not scored. ( 3 )

4 CONTRAINDICATIONS Hypersensitivity to doxepin hydrochloride, inactive ingredients, or other dibenzoxepines. ( 4.1 ) Co-administration 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 HCl, any of its inactive ingredients, or other dibenzoxepines. 4.2. Co-administration 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.

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 greater than or equal to 2% of patients treated with doxepin tablets, 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 Ajanta Pharma USA Inc. at 1-855-664-7744 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 tablets 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 tablets 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 tablets 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 greater than or equal to 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 tablets 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 tablets 3 mg or 6 mg in which the incidence in subjects treated with doxepin tablets 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 tablets 3 mg (N=157) Doxepin tablets 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 greater than or equal to 2% in any doxepin tablets-treated group and at a higher rate than placebo. The most common treatment-emergent adverse reaction in the placebo and each of the doxepin tablets 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 tablets. In a one-night, double-blind study conducted in 565 healthy adult subjects …

7 DRUG INTERACTIONS MAO inhibitors: Doxepin tablets 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 tablets 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 tablets is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations. The ability of Doxepin tablets to induce CYP isozymes is not known. 7.2 Cimetidine Doxepin tablets 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 tablets [see Clinical Pharmacology (12.3) ] 7.3 Alcohol When taken with Doxepin tablets, 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 tablets, 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).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Third trimester use may increase the risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulties, hypotonia, tremor, irritability) in the neonate. ( 8.1 ) Lactation: Breastfeeding not recommended. ( 8.2 ) Pediatric Use: Safety and effectiveness have not been evaluated. ( 8.4 ) Geriatric Use: The recommended starting dose is 3 mg. Monitor prior to considering dose escalation. ( 2.2 , 8.5 ) Use in Patients with Comorbid Illness: Initiate treatment with 3 mg in patients with hepatic impairment or tendency to urinary retention. ( 8.6 , 4.3 ) 8.1 Pregnancy Risk Summary Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage (see Data) . There are risks of poor neonatal adaptation with exposure to tricyclic antidepressants (TCAs), including doxepin, during pregnancy (see Clinical Considerations) . In animal reproduction studies, oral administration of doxepin to rats and rabbits during the period of organogenesis caused adverse developmental effects at doses 65 and 23 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC, respectively. Oral administration of doxepin to pregnant rats during pregnancy and lactation resulted in decreased pup survival and a delay in pup growth at doses 60 times the MRHD based on AUC (see Data) . The estimated 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 Fetal/Neonatal adverse reactions Neonates exposed to TCAs, including doxepin, late in the third trimester 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, 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 tablets in the third trimester of pregnancy for poor neonatal adaptation syndrome. Data Human Data Published epidemiologic studies of pregnant women exposed to TCAs, including doxepin, 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. Animal Data When doxepin (30, 100, and 150 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, developmental toxicity (increased incidences of fetal structural abnormalities consisting of non-ossified bones in the skull and sternum and decreased fetal body weights) and maternal toxicity were noted at greater than or equal to100 mg/kg/day, which produced plasma exposures (AUCs) of doxepin and nordoxepin (the primary metabolite in humans) approximately 65 and 53 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for embryo-fetal developmental toxicity in rats (30 mg/kg/day) are approximately 6 and 5 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. When doxepin (10, 30, and 60 mg/kg/day) was administered orally to pregnant rabbits during the period of organogenesis, fetal body weights were reduced at the highest dose in the absence of maternal toxicity, which produced plasma AUCs of doxepin and nordoxepin approximately 23 and 56 times, respectively, the plasma …

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 .

11 DESCRIPTION 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

10 OVERDOSAGE Doxepin is routinely administered for indications other than insomnia at doses 10-to 50-fold higher than the highest recommended dose of doxepin tablets. The signs and symptoms associated with doxepin use at doses several-fold higher than the maximum recommended dose (Excessive dose) of doxepin tablets for the treatment of insomnia are described [see Overdosage ( 10.1 )] , as are signs and symptoms associated with higher multiples of the maximum recommended dose (Critical overdose) [see Overdosage ( 10.2 )]. 10.1. Signs and Symptoms of Excessive Doses The following adverse effects have been associated with use of doxepin at doses higher than 6 mg. Anticholinergic Effects : constipation and urinary retention. Central Nervous System : disorientation, hallucinations, numbness, paresthesias, extrapyramidal symptoms, seizures, tardive dyskinesia. Cardiovascular: hypotension. Gastrointestinal: aphthous stomatitis, indigestion. Endocrine: raised 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. Other : tinnitus, weight gain, sweating, flushing, jaundice, alopecia, exacerbation of asthma, and hyperpyrexia (in association with chlorpromazine). 10.2. Signs and Symptoms of Critical Overdose Manifestations of doxepin critical overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Electrocardiogram changes, particularly in QRS axis or width, are clinically significant indicators of tricyclic compound toxicity. Other signs of overdose may include, but are not limited to: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia. 10.3. Recommended Management As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. In addition, the possibility of a multiple drug ingestion should be considered. If an overdose is suspected, an ECG should be obtained and cardiac monitoring should be initiated immediately. The patient’s airway should be protected, an intravenous line should be established, and gastric decontamination should be initiated. 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 overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by administration of 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 greater than or equal to 0.10 seconds may be the best indication of the severity of an overdose. Serum alkalinization, using intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55 for patients with dysrhythmias and/or QRS widening. 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 greater than 7.60 or a pCO2 less than 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hype …

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Doxepin tablets, 3 mg are light blue color round shaped, uncoated biconvex tablets having mottled surface and debossed with '393' on one side and plain on the other, and are supplied as: NDC-72578-181-06 in bottle of 30 tablets with child-resistant closure NDC-72578-181-16 in bottle of 90 tablets with child-resistant closure NDC-72578-181-01 in bottle of 100 tablets NDC-72578-181-05 in bottle of 500 tablets NDC-72578-181-10 in bottle of 1,000 tablets NDC-72578-181-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Doxepin tablets, 6 mg are light green color round shaped, uncoated biconvex tablets having mottled surface and debossed with '394' on one side and plain on the other, and are supplied as: NDC-72578-182-06 in bottle of 30 tablets with child-resistant closure NDC-72578-182-16 in bottle of 90 tablets with child-resistant closure NDC-72578-182-01 in bottle of 100 tablets NDC-72578-182-05 in bottle of 500 tablets NDC-72578-182-10 in bottle of 1,000 tablets NDC-72578-182-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets 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.

16.1 How Supplied Doxepin tablets, 3 mg are light blue color round shaped, uncoated biconvex tablets having mottled surface and debossed with '393' on one side and plain on the other, and are supplied as: NDC-72578-181-06 in bottle of 30 tablets with child-resistant closure NDC-72578-181-16 in bottle of 90 tablets with child-resistant closure NDC-72578-181-01 in bottle of 100 tablets NDC-72578-181-05 in bottle of 500 tablets NDC-72578-181-10 in bottle of 1,000 tablets NDC-72578-181-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Doxepin tablets, 6 mg are light green color round shaped, uncoated biconvex tablets having mottled surface and debossed with '394' on one side and plain on the other, and are supplied as: NDC-72578-182-06 in bottle of 30 tablets with child-resistant closure NDC-72578-182-16 in bottle of 90 tablets with child-resistant closure NDC-72578-182-01 in bottle of 100 tablets NDC-72578-182-05 in bottle of 500 tablets NDC-72578-182-10 in bottle of 1,000 tablets NDC-72578-182-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets