Silenor

SILENOR- doxepin hydrochloride tablet
Currax Pharmaceuticals LLC

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 .

2. DOSAGE AND ADMINISTRATION

The dose of SILENOR should be individualized.

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.

3. DOSAGE FORMS AND STRENGTHS

SILENOR is an immediate-release, oval-shaped, tablet for oral administration available in strengths of 3 mg and 6 mg. The tablets are blue (3 mg) or green (6 mg) and are debossed with 3 or 6, respectively, on one side and SP on the other. SILENOR tablets are not scored.

4. CONTRAINDICATIONS

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.

5. WARNINGS AND PRECAUTIONS

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 activities that may occur the day following ingestion.

When taken with SILENOR, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated [s ee Warnings and Precautions (5.2) and Drug Interactions (7.3, 7.4)]. Patients should not consume alcohol with SILENOR [s ee Warnings and Precautions (5.2) and Drug Interactions (7.3)]. Patients should be cautioned about potential additive effects of SILENOR used in combination with CNS depressants or sedating antihistamines [s ee Warnings and Precautions (5.2) and Drug Interactions (7.4)].

6. ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of labeling:

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 ClassPreferred Term * Placebo (N=278) SILENOR 3 mg (N=157) SILENOR 6 mg (N=203)
*
Includes reactions that occurred at a rate of ≥ 2% in any SILENOR-treated group and at a higher rate than placebo.
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.

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