Doxepine Hcl 50 mg · Hard-gelatin capsules

The mechanism of action of the doxepin hydrochloride in the treatment of MDD in adult patients is not well understood.

Absorption — In healthy volunteers, a single oral doxepin hydrochloride dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between 2 and 4 hours (mean 2.9 hours) after doxepin hydrochloride administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between 2 and 10 hours after doxepin hydrochloride administration.

Distribution — The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%.

Elimination — In healthy volunteers, the plasma elimination half-life of doxepin ranged from 8 to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg.

Metabolism — After oral doxepin hydrochloride administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation.

Excretion — Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form.

Specific Populations — Patients with Hepatic Impairment: Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have a greater systemic doxepin exposure than those with normal liver function [see Use in Specific Populations(8.6)].

Patients with Renal Impairment: The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function.

Drug Interaction Studies — Carbamazepine: After concomitant use of doxepin hydrochloride and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin hydrochloride alone [see Drug Interactions (7)].

Strong CYP2D6 Inhibitors: CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase doxepin exposure [see Drug Interactions (7)].

Cimetidine: Cimetidine is a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with a single 6 mg dose of another oral doxepin product, there was approximately a 2-fold increase in doxepin Cmax and AUC compared to doxepin without cimetidine [see Drug Interactions (7)].

CYP2D6 Substrates: Concomitant use of doxepin hydrochloride and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.