Desvenlafaxine (Page 9 of 12)

11 DESCRIPTION

Desvenlafaxine extended-release tablets are extended-release tablets for oral administration that contain desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder.

Desvenlafaxine succinate is designated 1-[(1RS)-2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol hydrogen butanedioate monohydrate and has the molecular formula of C16 H25 NO2 (free base) and C16 H25 NO2 •C4 H6 O4 •H2 O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below.

Desvenlafaxine Structural Formula
(click image for full-size original)

Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21.

Desvenlafaxine extended-release tablets are formulated as extended-release tablets for once-a-day oral administration.

Each tablet contains 76 mg or 152 mg of desvenlafaxine succinate equivalent to 50 mg or 100 mg of desvenlafaxine, respectively.

Inactive ingredients consist of hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, red iron oxide, silicon dioxide, titanium dioxide and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of the antidepressant action of desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

12.2 Pharmacodynamics

Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1 -histaminergic, or α1 -adrenergic receptors in vitro. Desvenlafaxine also lacked monoamine oxidase (MAO) inhibitory activity.

ECG Changes

Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval.

12.3 Pharmacokinetics

The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional in a dose range of 50 mg per day to 600 mg per day. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4 to 5 days. At steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.

Absorption and Distribution

The absolute oral bioavailability of desvenlafaxine extended-release tablets after oral administration is about 80%.

A food-effect study involving administration of desvenlafaxine extended-release tablets to healthy subjects under fasting and fed conditions (high-fat meal, 800 to 1000 calories) indicated that desvenlafaxine Cmax was increased about 16% in the fed state, while the AUCs were similar. This difference is not expected to be clinically significant; therefore, desvenlafaxine extended-release tablets can be taken without regard to meals [see Dosage and Administration (2.1)].

The plasma protein binding of desvenlafaxine is low (30%) and is independent of drug concentration. The desvenlafaxine volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.

Metabolism and Elimination

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after administration of 100 mg, the pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine.

Drug Interaction Studies

Inhibitors of CYP3A4 (Ketoconazole)

CYP3A4 is a minor pathway for the metabolism of desvenlafaxine. In a clinical study, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve (AUC) of desvenlafaxine (400 mg single dose) by about 43% and Cmax by about 8%. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher concentrations of desvenlafaxine.

Inhibitors of Other CYP Enzymes

Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of desvenlafaxine.

Drugs Metabolized by CYP2D6 (e.g., Desipramine, Dextromethorphan, Metoprolol, Atomoxetine)

In vitro studies showed minimal inhibitory effect of desvenlafaxine on CYP2D6. Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. When desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the Cmax and AUC of desipramine increased approximately 25% and 17%, respectively. When 400 mg (8 times the recommended 50 mg dose) was administered, the Cmax and AUC of desipramine increased approximately 50% and 90%, respectively. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 can result in higher concentrations of that drug [see Drug Interactions (7.5)].

Drugs Metabolized by CYP3A4 (Midazolam)

In vitro , desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. In a clinical study, desvenlafaxine 400 mg daily (8 times the recommended 50 mg dose) was co-administered with a single 4 mg dose of midazolam (a CYP3A4 substrate). The AUC and Cmax of midazolam decreased by approximately 31% and 16%, respectively. Concomitant use of desvenlafaxine with a drug metabolized by CYP3A4 can result in lower exposures to that drug.

Drugs Metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19

In vitro , desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes.

In vitro , desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of desvenlafaxine are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter, and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter.

Special Populations

Age

In a study of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in Cmax and a 55% increase in AUC in subjects older than 75 years of age (n = 17), compared with subjects 18 to 45 years of age (n = 16). Subjects 65 to 75 years of age (n = 15) had no change in Cmax , but an approximately 32% increase in AUC, compared to subjects 18 to 45 years of age [see Dosage and Administration (2.2)].

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