Silenor

1. INDICATIONS AND USAGE SILENOR is 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 . SILENOR (doxepin) tablets are indicated for the treatment of insomnia characterized by difficulties with sleep maintenance. ( 1 , 14 )

2. DOSAGE AND ADMINISTRATION The dose of SILENOR 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 SILENOR 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 SILENOR 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 SILENOR should be taken within 30 minutes of bedtime. To minimize the potential for next day effects, SILENOR should not be taken within 3 hours of a meal [ see Clinical Pharmacology (12.3) ] . The total SILENOR dose should not exceed 6 mg per day.

5. WARNINGS AND PRECAUTIONS Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use. ( 5.1 ) Abnormal thinking, behavioral changes, complex behaviors: May include "Sleep-driving" and hallucinations. Immediately evaluate any new onset behavioral changes. ( 5.2 ) Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount feasible to avoid intentional overdose. ( 5.3 ) CNS-depressant effects: Use can impair alertness and motor coordination. Avoid engaging in hazardous activities such as operating a motor vehicle or heavy machinery after taking drug. (5.4) Do not use with alcohol. ( 5.4 , 7.3 ) Potential additive effects when used in combination with CNS depressants or sedating antihistamines. Dose reduction may be needed. ( 5.4 , 7.4 ) Patients with severe sleep apnea: SILENOR is ordinarily not recommended for use in this population. ( 8.7 ) 5.1. Need to Evaluate for Comorbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with hypnotic drugs. 5.2. Abnormal Thinking and Behavioral Changes Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as "sleep-driving" may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of SILENOR should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably. 5.3. Suicide Risk and Worsening of Depression In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics. Doxepin, the active ingredient in SILENOR, is an antidepressant at doses 10- to 100-fold higher than in SILENOR. 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. Risk from the lower dose of doxepin in SILENOR can not be excluded. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. 5.4. CNS Depressant Effects After taking SILENOR, patients should confine their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking SILENOR, and should be cautioned about potential impairment in the performance of such activit…

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 SILENOR is 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 SILENOR 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 SILENOR is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.

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

8.1. 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 SILENOR 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 ≥100 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 AUCs at the MRHD. The plasma exposures at the no-effect dose for developmental effects (30 mg/kg/day) are approximately 8 and 25 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. Oral administration of doxepin (10, 30, and 100 mg/kg/day) to rats throughout pregnancy and lactation resulted in decreased pup survival and transient growth delay at the highest dose, which produced plasma AUCs of doxepin and nordoxepin approximately 60 and 39 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for adverse effects on pre- and postnatal development in rats (30 mg/kg/day) are approximately …

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 SILENOR, 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 Currax Pharmaceuticals LLC at 1-800-793-2145 and or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1. Clinical Trials Experience The pre-marketing development program for SILENOR 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 SILENOR 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 SILENOR 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 SILENOR 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 SILENOR 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 SILENOR 3 mg or 6 mg in which the incidence in subjects treated with SILENOR 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 Includes reactions that occurred at a rate of ≥ 2% in any SILENOR-treated group and at a higher rate than placebo. Placebo (N=278) SILENOR 3 mg (N=157) SILENOR 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 SILENOR 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 SILENOR. In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, SILENOR 6 mg showed modest negative changes in SCT and VAS. In a 35-day, double-blind, placebo-controlled, parallel group study of SILENOR…