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Effexor XR

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Effexor XR

CLINICAL PHARMACOLOGY

Mechanism Of Action

The exact mechanism of the antidepressant action of venlafaxine in humans 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 demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

Pharmacodynamics

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 per 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 (steadystate) 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 and Distribution

Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the 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 approximately 45%.

Administration of Effexor XR (150 mg once daily) generally resulted in lower Cmax and later Tmax values than for Effexor (immediate release) administered twice daily (Table 16). 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. Therefore, Effexor XR provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet.

Table 16: Comparison of Cmax and Tmax Values for Venlafaxine and ODV Following Oral Administration of Effexor XR and Effexor (Immediate Release)

  Venlafaxine C max (ng/mL) Tmax (h) ODV C max (ng/mL) Tmax (h)
Effexor XR (150 mg once daily) 150 5.5 260 9
Effexor (75 mg twice daily) 225 2 290 3

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

Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug.

Metabolism and Elimination

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other 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 levels (extensive metabolizers) [see Use In Specific Populations].

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.

Clinical Studies

Major Depressive Disorder

The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, Effexor XR demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, Effexor XR also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing Effexor in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of Effexor over placebo based on the HAM-D-21 total score. The mean dose in completers was 350 mg per day (study 3).

In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on Effexor XR (75, 150, or 225 mg, once daily every morning) 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-label 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 statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4).

In a second longer term trial, adult outpatients with MDD, recurrent type, who had responded (HAM-D21 total score ≤ 12 at the day 56 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 HAMD-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 [100 to 200 mg per day, on a twice daily 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 statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5).

Table 17: Major Depressive Disorder Studies:

Study number Treatment Group Mean Baseline Score (SD) Primary Efficacy Measure: HAM-D Score
LSMean Change from Baseline Placebo Subtracted Differencea (95%CI)
Study 1 Effexor(XR 75225 mg/day)* 24.5 -11.7 -4.45
(-6.66,-2.25)
Placebo 23.6 -7.24 -
Study 2 Effexor(XR 75225 mg/day)* 24.5 -15.11 -6.40
(-8.45,-4.34)
Placebo 24.9 -8.71
Study 3 Effexor(IR 150375 mg/day)* 28.2 (0.5) -14.9 -10.2
(-14.4,-6.0)
Placebo 28.6 (0.6) -4.7 -
SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline
* Doses statistically significantly superior to placebo.

Generalized Anxiety Disorder

The efficacy of Effexor XR as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD.

In one 8-week study, Effexor XR demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by 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. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied.

Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating Effexor XR doses of 75 to 225 mg per day (study 4), 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 per day dose, this dose was not as consistently effective as the higher doses.

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

Table 18: Generalized Anxiety Disorder Studies

Study Number Treatment Group Primary Efficacy Measure: HAM-A Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo Subtracted Differencea (95% CI)
Study 1 Ven XR 75 mg 24.7 -11.1 (0.95) -1.5 (-3.8, 0.8)
Ven XR 150 mg 24.5 -11.7 (0.87) -2.2 (-4.5, 0.1)
Eff XR 225 mg 23.6 -12,1 (0.81) -2.6 (-4.9, -0.3)
Placebo 24.1 -9.5 (0.85)
Study 2 Ven XR 75 mg 23.7 -10.6 (0.82) -2.6 (-4.6, -0.5)
Ven XR 150 mg 23.0 -9.8 (0.86) -1.7 (-3.8, 0.3)
Placebo 23.7 -8.0 (0.73)
Study 3 Ven XR 37.5 mg 26.6 (0.4) -13.8 -2.8 (-5.1, -0.6)
Ven XR 75 mg 26.3 (0.4) -15.5 -4.6 (-6.9, -2.3)
Ven XR150 mg 26.3 (0.4) -16.4 -5.5 (-7.8, -3.1)
Placebo 26.7 (0.5) -11.0
Study 4 Ven XR 75-225 mg 25.0 -13.4 (0.79) -4.7 (-6.6, -2.9)
Placebo 24.9 -8.7 (0.70)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline
* Doses statistically significantly superior to placebo.

Social Anxiety Disorder (also known as Social Phobia)

The efficacy of Effexor XR as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1-4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5).

In these five studies, Effexor XR was statistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to the 75 mg per day group in the 6-month study.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

Table 19: Social Anxiety Disorder Studies

Study Number Treatment Group Primary Efficacy Measure: LSAS Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo Subtracted Differencea (95% CI)
Study 1 Ven XR (75-225 mg) 91.1 -31.0(2.22) 11.2 (-5.3, -17.1)
Placebo 86.7 -19.9 (2.22) -
Study 2 Ven XR (75-225 MG) 90.8 -32.8 (2.69) -10.7 (-3.7,-176)
Placebo 87.4 -22.1 (2.66) -
Study 3 Ven XR (75-225 MG) 83.2 -36.0 (2.35) -16.9(-22.6, -11.2)
Placebo 83.6 -19.1 (2.40) -12.7 (-6.5, -19.0)
Study 4 Ven XR (75-225 mg) 86.2 -35.0 (2.64) -14.6 (-21.8, -7.4)
Placebo 86.1 -22.2 (2,47)  
Study 5 Ven XR 75 mg 91.8 -38.1 (3.16) -14.6 (-21.8, -7.4)
Ven XR (150-225 mg) 86.2 -37.6 (3.05) -14.1 (-21.3, -6.9)
Placebo 89.3 -23.5 (3.08)  
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline
* Doses statistically significantly superior to placebo.

Panic Disorder

The efficacy of Effexor XR as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2).

Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, Effexor XR was statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with Effexor XR (75 to 225 mg per day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12 week open-label period, patients receiving continued Effexor XR experienced a statistically significantly longer time to relapse.

Table 20: Panic Disorder Studies

Study Number Treatment Group Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks
Percent of patients Free of Full symptom panic attack Adjusted Odds Ratioa to placebo Adjusted Odds Ratioa 95% Confidence Interval
Study 1 Ven XR 75 mg* 54.1% (85/157) 2. 268 (1.43, 3.59)
Ven XR 150 mg* 61.4% (97/158) 3.035 (1.91, 4.82)
Placebo 34.4% (53/154) -- --
Study 2 Ven XR 75 mg* 64.1% (100/156) 2.350 (1.46, 3.78)
Ven XR 225 mg* 70.0% (112/160) 2.890 (1.80, 4.64)
Placebo 46.5% (73/157) -- --
a Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model. 95%CI: 95% confidence interval without adjusting for multiple dose arms.
* Doses statistically significantly superior to placebo.

Pediatric Patients

Two placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients.

Last reviewed on RxList: 1/12/2015
This monograph has been modified to include the generic and brand name in many instances.

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