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-[a- [(dimethylamino)methyl]-p- methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 hydrochloride. Its molecular weight is 313.87. The structural formula is shown below.

N (CH3)2

OH

C

H

H3CO

venlafaxine hydrochloride

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 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, and titanium dioxide. The 37.5 mg capsule also contains D&C Red #28, D&C Yellow #10, and FD&C Blue #1.

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 a1-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 immediate release venlafaxine tablets (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 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 patients 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 patients compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic patients 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. Dosage adjustment is necessary in these 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 impaired patients (GFR=10-70 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=10-70 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, flexible-dose 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 75-150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range 75-225 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 (the immediate release form of venlafaxine) 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, 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), or (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, 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 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 (100-200 mg/day, on a bid 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, placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose study in 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 75-225 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 75-225 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. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

Social Anxiety Disorder (Social Phobia)

The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in two double-blind, parallel group, 12-week, multicenter, placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75-225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, Effexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. 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.

CONTRAINDICATIONS

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see "WARNINGS").

WARNINGS

Potential for Interaction with Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an

inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI.

Sustained Hypertension

Venlafaxine is associated with sustained increases in blood pressure in some patients. Among patients treated with 75-375 mg per day of Effexor XR in premarketing studies in patients with major depressive disorder, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) >= 90 mm Hg and >= 10 mm Hg above baseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5-225 mg per day of Effexor XR in premarketing GAD studies, 0.5% (5/1011) experienced sustained hypertension. Among patients treated with 75-225 mg per day of Effexor XR in premarketing Social Anxiety Disorder studies, 1.4% (4/277) experienced sustained hypertension. Experience with the immediate-release venlafaxine showed that sustained hypertension was dose-related, increasing from 3-7% at 100-300 mg per day to 13% at doses above 300 mg per day. An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. In placebo-controlled premarketing studies in patients with major depressive disorder with Effexor XR 75-225 mg/day, a final on-drug mean increase in supine diastolic blood pressure (SDBP) of 1.2 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients. In placebo-controlled premarketing GAD studies with Effexor XR 37.5-225 mg/day up to 8 weeks or up to 6 months, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated patients. In placebo-controlled premarketing Social Anxiety Disorder studies with Effexor XR 75-225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 1.6 mm Hg was observed for Effexor XR-treated patients compared with a mean decrease of 1.1 mm Hg for placebo-treated patients. In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12-16 mm Hg, SDBP) In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12-25 mm Hg, SDBP up to 8 weeks; 8-28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 12 weeks, 0.4% (1/277) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In this patient, the blood pressure increase was modest (13 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Therefore, it is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.

PRECAUTIONS

General

Insomnia and Nervousness

Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, and Social Anxiety Disorder studies, as shown in Table 1.

Table 1

Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder, GAD, and Social Anxiety Disorder Trials

Major Depressive Disorder

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder studies. In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with Effexor XR up to 6 months. In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 3% and 0%, respectively, of the patients treated with Effexor XR up to 12 weeks.

Changes in Appetite and Weight

Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term studies in major depressive disorder. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of Effexor XR treatment. A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in placebo-controlled major depressive disorder trials. Discontinuation rates for anorexia and weight loss associated with Effexor XR were low (1.0% and 0.1%, respectively, of Effexor XR-treated patients in major depressive disorder studies). In the pool of GAD studies, treatment-emergent anorexia was reported in 8% and 2% of patients receiving Effexor XR and placebo up to 8 weeks, respectively. A loss of 7% or more of body weight occurred in 3% of the Effexor XR-treated and 1% of the placebo-treated patients up to 6 months in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 8 weeks (0.9% and 0.3% respectively). In the pool of Social Anxiety Disorder studies, treatment-emergent anorexia was reported in 20% and 2% of patients receiving Effexor XR and placebo up to 12 weeks, respectively. A loss of 7% or more of body weight occurred in none of the Effexor XR-treated or the placebo-treated patients up to 12 weeks in these trials. Discontinuation rates for anorexia and weight loss were low for patients receiving Effexor XR up to 12 weeks (0.4% and 0.0%, respectively).

Activation of Mania/Hypomania

During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and 0.0% placebo patients. In premarketing GAD studies, 0.0% of Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, no Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketeddrugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania.

Hyponatremia

Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics.

Mydriasis

Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma should be monitored.

Seizures

During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 277 Effexor XR-treated patients in Social Anxiety Disorder studies. In all premarketing major depressive disorder trials with Effexor, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.

Abnormal Bleeding

There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.

Serum Cholesterol Elevation

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long term treatment.

Suicide

The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the risk of overdose. The same precautions observed when treating patients with major depressive disorder should be observed when treating patients with GAD or Social Anxiety Disorder.

Use in Patients With Concomitant Illness

Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials inmajor depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo- controlled trials in GAD, and for 195 patients who received Effexor XR and 228 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). The mean change from baseline in QTc for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for Effexor XR and decrease of 2.0 msec for placebo). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XR and no change for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Effexor XR and no change for placebo). In a flexible- dose study, with Effexor doses in the range of 200-375 mg/day and mean dose greater than 300 mg/day, Effexor treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses of Effexor above 200 mg/day. Evaluation of the electrocardiograms for 769 patients who received immediate release Effexor in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. In patients with renal impairment (GFR=10-70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see "DOSAGE AND ADMINISTRATION"). Effexor XR, like alldrugs effective in the treatment of major depressive disorder, should be used with caution in such patients.

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor XR (venlafaxine hydrochloride) extended-release capsules:

Interference with Cognitive and Motor Performance

Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities.

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations, since there is a potential for interactions.

Alcohol

Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.

Allergic Reactions

Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing

Patients should be advised to notify their physician if they are breast-feeding an infant.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Alcohol

A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O- desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.

Cimetidine

Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

Diazepam

Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.

Haloperidol

Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.

Lithium

The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium.

Drugs Highly Bound to Plasma Proteins

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.

Drugs that Inhibit Cytochrome P450 Isoenzymes

CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (See "Metabolism and Excretion" under "CLINICAL PHARMACOLOGY"). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce simultaneous inhibition of these two enzymes systems.

Drugs Metabolized by Cytochrome P450 Isoenzymes

CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.

Risperidone

- Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone.)

CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg per day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. The clinical significance of this finding is unknown. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see "Diazepam" above.)

Monoamine Oxidase Inhibitors

See "CONTRAINDICATIONS" and "WARNINGS".

CNS-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment.

Postmarketing Spontaneous Drug Interaction Reports

See "ADVERSE REACTIONS," "Postmarketing Reports." Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.

Mutagenesis

Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also was not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.

Impairment of Fertility

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m2 basis.

Pregnancy

Teratogenic Effects - Pregnancy Category C

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects

If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered.

Labor and Delivery

The effect of venlafaxine on labor and delivery in humans is unknown.

Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Approximately 4% (14/357), 6% (77/1381), and 2% (6/277) of Effexor XR-treated patients in placebo-controlled premarketing major depressive disorder, GAD, and Social Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see "CLINICAL PHARMACOLOGY" ). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see "DOSAGE AND ADMINISTRATION").

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Effexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance.

Physical and Psychological Dependence

In vitro

studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine (See "DOSAGE AND ADMINISTRATION"). While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

OVERDOSAGE

Human Experience

Among the patients included in the premarketing evaluation of Effexor XR, there were 2 reports of acute overdosage with Effexor XR in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took a combination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of Effexor XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. These symptoms resolved over the next week. There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials. Among the patients included in the premarketing evaluation with Effexor, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 mg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), seizures, vertigo, and death have been reported.

Management of Overdosage

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

DOSAGE AND ADMINISTRATION

Effexor XR should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water.

Initial Treatment

Major Depressive Disorder

For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of Effexor XR in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for Effexor XR has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140-180 mg/day (see "Clinical Trials" under "CLINICAL PHARMACOLOGY"). It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for Effexor (the immediate release form of venlafaxine), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of Effexor XR are needed for more severely depressed patients is unknown; however, the experience with Effexor XR doses higher than 225 mg/day is very limited. (See the "Use in Patients with Concomitant Illnesses" section of PRECAUTIONS).

Generalized Anxiety Disorder

For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Generalized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in GAD was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the "Use in Patients with Concomitant Illnesses" section of PRECAUTIONS).

Social Anxiety Disorder (Social Phobia)

For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered in a single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with Social Anxiety Disorder, the initial dose of Effexor XR was 75 mg/day and the maximum dose was 225 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Although a dose-response relationship for effectiveness in patients with Social Anxiety Disorder was not clearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days. (See the 'Use in Patients with Concomitant Illnesses' section of PRECAUTIONS).

Switching Patients from Effexor Tablets

Depressed patients who are currently being treated at a therapeutic dose with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg/day), e.g., 37.5 mg venlafaxine two-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary.

Patients with Hepatic Impairment

Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see "CLINICAL PHARMACOLOGY"), it is recommended that the starting dose be reduced by 50% in patients with moderate hepatic impairment. Because there was much individual variability in clearance between patients with cirrhosis, individualization of dosage may be desirable in some patients.

Patients with Renal Impairment

Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10-70 mL/min) compared with normal subjects (see "CLINICAL PHARMACOLOGY"), it is recommended that the total daily dose be reduced by 25%-50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% and that the dose be withheld until the dialysis treatment is completed (4 hrs). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.

Elderly Patients

No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Maintenance Treatment

There is no body of evidence available from controlled trials to indicate how long patients withmajor depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder should be treated with Effexor XR. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Effexor in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or Effexor for a period of up to 52 weeks on the same dose (100-200 mg/day, on a bid schedule) (see "Clinical Trials" under "CLINICAL PHARMACOLOGY"). Based on these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in 6-month clinical trials. The need for continuing medication in patients with GAD who improve with Effexor XR treatment should be periodically reassessed. In patients with Social Anxiety Disorder, there are no efficacy data beyond 12 weeks of treatment with Effexor XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with Effexor XR treatment should be periodically reassessed.

Discontinuing Effexor XR

When discontinuing Effexor XR after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Patients who have received Effexor XR for 6 weeks or more should have their dose tapered over at least a 2-week period. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary. Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials ofmajor depressive disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. It is therefore recommended that the dosage of Effexor XR be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. Discontinuation effects are well known to occur with antidepressants.

Switching Patients To or From a Monoamine Oxidase Inhibitor

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor XR. In addition, at least 7 days should be allowed after stopping Effexor XR before starting an MAOI (see "CONTRAINDICATIONS" and "WARNINGS").

HOW SUPPLIED

Effexor(r) XR (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cap/peach body with " " and "Effexor XR" on the cap and "37.5" on the body. NDC 0008-0837-01, bottle of 100 capsules. NDC 0008-0837-03, carton of 10 Redipak(r) blister strips of 10 capsules each.

Store at controlled room temperature, 20deg C to 25deg C (68deg F to 77deg F). Bottles: Protect from light. Dispense in light-resistant container.

Blisters: Protect from light. Use blister carton to protect contents from light.

75 mg, peach cap and body with " " and "Effexor XR" on the cap and "75" on the body. NDC 0008-0833-01, bottle of 100 capsules. NDC 0008-0833-03, carton of 10 Redipak(r) blister strips of 10 capsules each.

Store at controlled room temperature, 20deg C to 25deg C (68deg F to 77deg F).

150 mg, dark orange cap and body with " " and "Effexor XR" on the cap and "150" on the body. NDC 0008-0836-01, bottle of 100 capsules. NDC 0008-0836-03, carton of 10 Redipak(r) blister strips of 10 capsules each.

Store at controlled room temperature, 20deg C to 25deg C (68deg F to 77deg F).

The appearance of these capsules is a trademark ofWyeth Pharmaceuticals. Wyeth Laboratories

A Wyeth-Ayerst Company Philadelphia, PA 19101

Filename: 20699S022FDAP1labelclean.doc