Desvenlafaxine: Package Insert and Label Information (Page 4 of 6)

8.5 Geriatric Use

Of the 4,158 patients in pre-marketing clinical studies with desvenlafaxine extended-release tablets, 6% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥ 65 years of age compared to patients <65 years of age treated with desvenlafaxine extended-release tablets [see Adverse Reactions (6.1 )]. For elderly patients, possible reduced renal clearance of desvenlafaxine extended-release tablets should be considered when determining dose [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)].

SSRIs and SNRIs, including desvenlafaxine extended-release tablets, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.9)].

8.6 Renal Impairment

Adjust the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr 15 to 50 mL/min, C-G), or end-stage renal disease (CLcr < 15 mL/min, C-G) [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)] .

8.7 Hepatic Impairment

Adjust the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) [see Dosage and Administration ( 2.3) and Clinical Pharmacology ( 12.3)] .

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Desvenlafaxine extended-release tablets are not a controlled substance.

10 OVERDOSAGE

10.1 Human Experience with Overdosage

There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine (desvenlafaxine extended-release tablets) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine extended-release tablets) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert.

In postmarketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine extended-release tablets) has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear.

10.2 Management of Overdosage

No specific antidotes for desvenlafaxine extended-release tablets are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.

11 DESCRIPTION

Desvenlafaxine extended-release tablets are an extended-release tablet for oral administration that contains 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 is designated RS -4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C 16 H 25 NO 2 (free base) and C 16 H 25 NO 2 •C 4 H 6 O 4 •H 2 O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below.

structure
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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 an extended-release tablet for once-a-day oral administration.

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.

Inactive ingredients for the 25 mg, 50 mg and 100 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate, polyethylene oxide and colloidal silicon dioxide and film coating, which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow and iron oxide red. The imprinting ink contains hypromellose, propylene glycol and iron oxide black.

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, H 1 -histaminergic, or α 1 -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 to 600 mg (1 to 12 times the recommended approved dosage) 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

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

Effect of Food

Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine C max about 16% and had no effect on AUC.

Distribution

Steady-state volume of distribution of desvenlafaxine is 3.4 L/kg. Plasma protein binding of desvenlafaxine is 30% and is independent of drug concentration.

Elimination

Metabolism

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype.

Excretion

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.

Specific Populations

No clinically significant differences in the exposures of desvenlafaxine were observed based on ethnicity (White, Black, Hispanic).

The effect of intrinsic patient factors on the pharmacokinetics of desvenlafaxine is presented in Figure 1.

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Drug Interaction Studies

Clinical Studies

Other Drugs on desvenlafaxine extended-release tablets

The effect of ketoconazole on the exposures of desvenlafaxine is summarized in Figure 2.

Figure 2. Effect of Other Drugs on Desvenlafaxine Pharmacokinetics

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Desvenlafaxine extended-release tablets on Other Drugs

The effects of desvenlafaxine extended-release tablets on the exposures of other drugs are summarized in Figure 3.

Figure 3. Effects of Desvenlafaxine Extended-Release Tablets on Pharmacokinetics of Other Drugs

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In Vitro Studies

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.

Desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, CYP2D6, or CYP3A4 isozymes. Desvenlafaxine does not induce CYP3A4 either.

Desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein (P-gp) transporter.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study.

Mice received desvenlafaxine succinate at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The AUC exposure at 300 mg/kg/day dose is estimated at 10 times the AUC exposure at an adult human dose of 100 mg per day.

Rats received desvenlafaxine succinate at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The AUC exposure at the highest dose is estimated at 11 (males) or 26 (females) times the AUC exposure at an adult human dose of 100 mg per day.

Mutagenesis

Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay.

Impairment of fertility

When desvenlafaxine succinate was administered orally to male and female rats, fertility was reduced at the high dose of 300 mg/kg/day, which is 10 (males) and 19 (females) times the AUC exposure at an adult human dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day, which is 3 (males) or 5 (females) times the AUC exposure at an adult human dose of 100 mg per day. These studies did not address reversibility of the effect on fertility. The relevance of these findings to humans is not known.

14 CLINICAL STUDIES

Major Depressive Disorder

The efficacy of desvenlafaxine extended-release tablets as a treatment for depression was established in four 8-week, randomized, double-blind, placebo-controlled, fixed-dose studies (at doses of 50 mg per day to 400 mg per day) in adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder. In the first study, patients received 100 mg (n = 114), 200 mg (n = 116), or 400 mg (n = 113) of desvenlafaxine extended-release tablets once daily, or placebo (n = 118). In a second study, patients received either 200 mg (n = 121) or 400 mg (n = 124) of desvenlafaxine extended-release tablets once daily, or placebo (n = 124). In two additional studies, patients received 50 mg (n = 150 and n = 164) or 100 mg (n = 147 and n = 158) of desvenlafaxine extended-release tablets once daily, or placebo (n = 150 and n = 161).

Desvenlafaxine extended-release tablets showed superiority over placebo as measured by improvement in the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) total score in four studies and overall improvement, as measured by the Clinical Global Impressions Scale — Improvement (CGI-I), in three of the four studies. In studies directly comparing 50 mg per day and 100 mg per day there was no suggestion of a greater effect with the higher dose and adverse reactions and discontinuations were more frequent at higher doses [see Dosage and Administration ( 2.1)].

Table 9: Primary Efficacy (HAM-D 17 ) Results for Short-term Studies
Desvenlafaxine Extended-Release Tablets
Study No. Primary Endpoint: HAM-D 17 Placebo 50 mg/day 100 mg/day 200 mg/day 400 mg/day
1 Baseline Score (SD a) 23.1 (2.5) 23.2 (2.5) 22.9 (2.4) 23.0 (2.2)
Difference from Placebo (95% CI c) -2.9 b (-5.1, -0.8) -2.0 -3.1 b (-5.2, -0.9)
2 Baseline Score (SD a) 25.3 (3.3) 24.8 (2.9) 25.2 (3.2)
Difference from Placebo (95% CI c) -3.3 b (-5.3, -1.2) -2.8 b (-4.8, -0.7)
3 Baseline Score (SD a) 23.0 (2.6) 23.4 (2.6) 23.4 (2.6)
Difference from Placebo (95% CI c) -1.9 b (-3.5, -0.3) -1.5
4 Baseline Score (SD a) 24.3 (2.6) 24.3 (2.4) 24.4 (2.7)
Difference from Placebo (95% CI c) -2.5 b (-4.1, -0.9) -3.0 b (-4.7, -1.4)
a Standard deviation; b Adjusted p-value < 0.05; c Difference between least squares means at final evaluation, calculated as drug response minus placebo response; unadjusted 95% confidence intervals

Analyses of the relationships between treatment outcome and age and treatment outcome and gender did not suggest any differential responsiveness on the basis of these patient characteristics. There was insufficient information to determine the effect of race on outcome in these studies.

In a longer-term trial (Study 5), adult outpatients meeting DSM-IV criteria for major depressive disorder, who responded to 8 weeks of open-label acute treatment with 50 mg per day desvenlafaxine and subsequently remained stable for 12 weeks on desvenlafaxine, were assigned randomly in a double-blind manner to remain on active treatment or switch to placebo for up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a HAM-D 17 total score of ≤11 and CGI-I ≤2 at the day 56 evaluation; stability was defined as HAM-D 17 total score of ≤11 and CGI-I ≤2 at week 20 and not having a HAM-D 17 total score of ≥16 or a CGI-I score ≥4 at any office visit. Relapse during the double-blind phase was defined as follows: (1) a HAM-D 17 total score of ≥16 at any office visit, (2) discontinuation for unsatisfactory efficacy response, (3) hospitalized for depression, (4) suicide attempt, or (5) suicide. Patients receiving continued desvenlafaxine treatment experienced statistically significantly longer time to relapse compared with placebo. At 26 weeks, the Kaplan-Meier estimated proportion of relapse was 14% with desvenlafaxine treatment versus 30% with placebo.

Figure 4. Estimated Proportion of Relapses vs. Number of Days since Randomization (Study 5)

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In another longer-term trial (Study 6), adult outpatients meeting DSM-IV criteria for major depressive disorder and who responded to 12 weeks of acute treatment with desvenlafaxine were assigned randomly to the same dose (200 or 400 mg per day) they had received during acute treatment or to placebo for up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a HAM-D 17 total score of ≤11 at the day 84 evaluation. Relapse during the double-blind phase was defined as follows: (1) a HAM-D 17 total score of >16 at any office visit, (2) a CGI-I score of ≥6 (versus day 84) at any office visit, or (3) discontinuation from the trial due to unsatisfactory response. Patients receiving continued desvenlafaxine treatment experienced statistically significantly longer time to relapse over the subsequent 26 weeks compared with those receiving placebo. At 26 weeks, the Kaplan-Meier estimated proportion of relapse was 29% with desvenlafaxine treatment versus 49% with placebo.

Figure 5. Estimated Proportion of Relapses vs. Number of Days since Randomization (Study 6)

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In a postmarketing study, the efficacy of desvenlafaxine extended-release tablets at a dose lower than 50 mg per day was evaluated in an 8-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study in adult outpatients with Major Depressive Disorder. The treatment arms were 25 mg (n=232), 50 mg (n=236), and placebo (n=231). The 50 mg dose was superior to placebo, as measured by the mean change from baseline on the HAMD-17. The 25 mg dose was not superior to placebo.

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