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«Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in ...»

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Effexor XR®

(venlafaxine hydrochloride)

Extended-Release Capsules

Rx only

Suicidality and Antidepressant Drugs

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. Anyone considering the use of

Effexor XR or any other antidepressant in a child, adolescent, or young adult must balance

this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.

Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor XR is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use)

DESCRIPTION

Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1­ (4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p­ methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl.

Its molecular weight is 313.87. The structural formula is shown below.

Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

Effexor XR is formulated as an extended-release capsule for once-a-day oral administration.

Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 1 Reference ID: 3537473 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.

Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is

1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).

Absorption Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%.

Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for Effexor (immediate release) [Cmax's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV]. When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet.

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule.

Metabolism and Excretion Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other 2 Reference ID: 3537473 minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6;





this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent.

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.

Special Populations Age and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION).

Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups.

Liver Disease: In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine.

Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.

In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted.

Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION).

Renal Disease: In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally 3 Reference ID: 3537473 impaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION).

Clinical Trials Major Depressive Disorder The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexibledose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder.

A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Effexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, Effexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score.

A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing Effexor (immediate release) in a range of 150 to 375 mg/day (t.i.d.

schedule) demonstrated superiority of Effexor over placebo. The mean dose in completers was 350 mg/day.

Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation.

Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason.

Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.

In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 4 Reference ID: 3537473 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores 10, and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (immediate release) [100 to 200 mg/day, on a b.i.d. schedule] were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

Generalized Anxiety Disorder The efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month, placebocontrolled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in adult outpatients meeting DSM-IV criteria for GAD.

One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose.

A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day dose range utilized in these two studies.

Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and the other evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses.



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