Source: FDA, National Drug Code (US) Revision Year: 2023
The mechanism of action of doxepin in sleep maintenance is unclear; however, doxepin’s effect could be mediated through antagonism of the H1 receptor.
Doxepin has high binding affinity to the H1 receptor (Ki<1 nM).
In a thorough QTc prolongation clinical study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg.
The median time to peak concentrations (Tmax) of doxepin occurred at 3.5 hours postdose after oral administration of a 6 mg dose to fasted healthy subjects. Peak plasma concentrations (Cmax) of SILENOR increased in approximately a dose-proportional manner for 3 mg and 6 mg doses. The AUC was increased by 41% and Cmax by 15% when 6 mg SILENOR was administered with a high fat meal. Additionally, compared to the fasted state, Tmax was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended that SILENOR not be taken within 3 hours of a meal [see Dosage and Administration (2.3)].
SILENOR is widely distributed throughout the body tissues. The mean apparent volume of distribution following a single 6 mg oral dose of SILENOR to healthy subjects was 11,930 liters. SILENOR is approximately 80% bound to plasma proteins.
Following oral administration, SILENOR is extensively metabolized by oxidation and demethylation. The primary metabolite is N-desmethyldoxepin (nordoxepin).
The primary metabolite undergoes further biotransformation to glucuronide conjugates.
In vitro studies have shown that CYP2C19 and CYP2D6 are the major enzymes involved in doxepin metabolism, and that CYP1A2 and CYP2C9 are involved to a lesser extent.
Doxepin appears not to have inhibitory effects on human CYP enzymes at therapeutic concentrations. The potential of doxepin to induce metabolizing enzymes is not known. Doxepin is not a Pgp substrate.
Doxepin is excreted in the urine mainly in the form of glucuronide conjugates.
Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. The apparent terminal half-life (t½) of doxepin was 15.3 hours and for nordoxepin was 31 hours.
Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of these CYP isozymes may increase the exposure of doxepin.
The effect of cimetidine, a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4, on SILENOR plasma concentrations was evaluated in healthy subjects. When cimetidine 300 mg BID was co-administered with a single dose of SILENOR 6 mg, there was approximately a 2-fold increase in SILENOR Cmax and AUC compared to SILENOR given alone. A maximum dose of doxepin in adults and elderly should be 3 mg, when doxepin is co-administered with cimetidine.
The effect of sertraline HCl, a selective serotonin reuptake inhibitor, on doxepin plasma concentrations was evaluated in a daytime study conducted with 24 healthy subjects. Following co-administration of doxepin 6 mg with sertraline 50 mg (at steady-state), the doxepin mean AUC and Cmax estimates were approximately 21% and 32% higher, respectively, than those obtained following administration of doxepin alone. Psychomotor function as measured by the digit symbol substitution test and symbol copy test performance was decreased more at 2-4 hours post dosing for the combination of sertraline and doxepin as compared to doxepin alone, but subjective measures of alertness were comparable for the two treatments.
The effects of renal impairment on doxepin pharmacokinetics have not been studied. Because only small amounts of doxepin and nordoxepin are eliminated in the urine, renal impairment would not be expected to result in significantly altered doxepin concentrations.
The effects of SILENOR in patients with hepatic impairment have not been studied. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic impairment may display higher doxepin concentrations than healthy individuals.
Poor metabolizers of CYP2C19 and CYP2D6 may have higher doxepin plasma levels than normal subjects.
No evidence of carcinogenic potential was observed when doxepin was administered orally to hemizygous Tg.rasH2 mice for 26 weeks at doses of 25, 50, 75, and 100 mg/kg/day.
Doxepin was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.
When doxepin (10, 30, and 100 mg/kg/day) was orally administered to male and female rats prior to, during and after mating, adverse effects on fertility (increased copulatory interval and decreased corpora lutea, implantation, viable embryos and litter size) and sperm parameters (increased percentages of abnormal sperm and decreased sperm motility) were observed. The plasma exposures (AUC) for doxepin and nordoxepin at the no-effect dose for adverse effects on reproductive performance and fertility in rats (10 mg/kg/day) are less than those in humans at the maximum recommended human dose of 6 mg/day.
The efficacy of SILENOR for improving sleep maintenance was supported by six randomized, double-blind studies up to 3 months in duration that included 1,423 subjects, 18 to 93 years of age, with chronic (N=858) or transient (N=565) insomnia. SILENOR was evaluated at doses of 1 mg, 3 mg, and 6 mg relative to placebo in inpatient (sleep laboratory) and outpatient settings.
The primary efficacy measures for assessment of sleep maintenance were the objective and subjective time spent awake after sleep onset (respectively, objective Wake After Sleep Onset [WASO] and subjective WASO).
Subjects in studies of chronic insomnia were required to have at least a 3-month history of insomnia.
A randomized, double-blind, parallel-group study was conducted in adults (N=221) with chronic insomnia.
SILENOR 3 mg and 6 mg was compared to placebo out to 30 days.
SILENOR 3 mg and 6 mg were superior to placebo on objective WASO. SILENOR 3 mg was superior to placebo on subjective WASO at night 1 only. SILENOR 6 mg was superior to placebo on subjective WASO at night 1, and nominally superior at some later time points out to Day 30.
Elderly subjects with chronic insomnia were assessed in two parallel-group studies.
The first randomized, double-blind study assessed SILENOR 1 mg and 3 mg relative to placebo for 3 months in inpatient and outpatient settings in elderly subjects (N=240) with chronic insomnia. SILENOR 3 mg was superior to placebo on objective WASO.
The second randomized, double-blind study assessed SILENOR 6 mg relative to placebo for 4 weeks in an outpatient setting in elderly subjects (N=254) with chronic insomnia. On subjective WASO, SILENOR 6 mg was superior to placebo.
Healthy adult subjects (N=565) experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a randomized, double-blind, parallel-group, single-dose study of SILENOR 6 mg relative to placebo. SILENOR 6 mg was superior to placebo on objective WASO and subjective WASO.
Potential withdrawal effects were assessed in a 35-day double blind study of adults with chronic insomnia who were randomized to placebo, SILENOR 3 mg, or SILENOR 6 mg. There was no indication of a withdrawal syndrome after discontinuation of SILENOR treatment (3 mg or 6 mg), as measured by the Tyrer’s Symptom Checklist. Discontinuation-period emergent nausea and vomiting occurred in 5% of subjects treated with 6 mg SILENOR, versus 0% in 3 mg and placebo subjects.
Rebound insomnia, defined as a worsening in WASO compared with baseline following discontinuation of treatment, was assessed in a double-blind, 35-day study in adults with chronic insomnia. SILENOR 3 mg and 6 mg showed no evidence of rebound insomnia.
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