Effexor (Venlafaxine HCl)

EFFEXOR® EFFEXOR® XR

Wyeth-Ayerst

Venlafaxine HCl

Antidepressant

Action And Clinical Pharmacology: Venlafaxine is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.

The mechanism of venlafaxine’s antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its major 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, 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 MAO inhibitory activity.

Pharmacokinetics: Venlafaxine is well absorbed, with peak plasma concentrations with Effexor tablets occurring approximately 2 hours after dosing. Venlafaxine is extensively metabolized, with O-desmethylvenlafaxine, (ODV, the only major active metabolite) peak plasma levels occurring approximately 4 hours after dosing. Following single doses of 25 to 75 mg, mean (±SD) peak plasma concentrations of venlafaxine range from 37±14 to 102±41 ng/mL, respectively, and are reached in 2±1 hours, and mean peak ODV plasma concentrations range from 61±13 to 168±37 ng/mL and are reached in 4±2 hours. Approximately 87% of a single dose of venlafaxine is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.

After administration of Effexor XR (extended release capsules), the peak plasma concentrations of venlafaxine and ODV are attained within 6.0±1.5 and 8.8±2.2 hours, respectively. The rate of absorption of venlafaxine from the Effexor XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of Effexor XR (15±6 hours) is actually the absorption half-life instead of the true disposition half-life (5±2) hours observed following administration of an Effexor immediate release tablet.

Multiple-Dose Pharmacokinetic Profile (Tablets and Extended Release Capsules): Steady-state concentrations of both venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose.

Venlafaxine and ODV exhibited approximately linear kinetics over the dose range of 75 to 450 mg/day.

The mean±SD steady-state plasma clearances of venlafaxine and ODV are 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 renal clearances are 49±27 and 94±56 mL/h/kg, respectively, which correspond to 5±3.0% and 25±13% of an administered venlafaxine dose recovered in urine as venlafaxine and ODV, respectively.

When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended release capsule, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the 2 treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the extended release capsule. Therefore, the Effexor XR capsules provide a slower rate of absorption, but the same extent of absorption (i.e., AUC), as the venlafaxine immediate release tablet.

Venlafaxine and ODV are 27 and 30% bound to human plasma proteins, respectively. Therefore, administration of venlafaxine to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug. Following i.v. administration, the steady-state volume of distribution of venlafaxine is 4.4±1.9 L/kg, indicating that venlafaxine distributes well beyond the total body water.

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%. The primary metabolite of venlafaxine is ODV, which is an active metabolite. Venlafaxine is also metabolized to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalysed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalysed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and extensive metabolizers. However, despite the metabolic differences between the CYP2D6 poor and extensive metabolizers, the total exposure to the sum of the 2 active species (venlafaxine and ODV, which have comparable activity) was similar in the 2 metabolizer groups.

Food has no significant effect on the absorption of venlafaxine or on the subsequent formation of ODV.

Age and Gender: Population pharmacokinetic analyses of 547 venlafaxine-treated patients from 3 studies involving both venlafaxine immediate release tablets and venlafaxine extended release capsules showed that age and sex do not significantly affect the pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV in subjects over 60 years old; this was possibly caused by the decrease in renal function that typically occurs with aging. Dosage adjustment based upon age or gender is generally not necessary (see Dosage).

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, there is no need for different venlafaxine dosing regimens for these 2 groups.

Hepatic Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV were significantly altered. Venlafaxine elimination half-life was prolonged by about 30%, and clearance was 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 patients with liver disease (see Dosage).

Renal Disease: In patients with moderate to severe impairment of renal function (GFR=10 to 70 mL/min), venlafaxine elimination half-life was prolonged by 50%, and clearance was decreased by about 24% compared to normal subjects. ODV elimination half-life was prolonged by about 40%, but clearance was unchanged.

In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was decreased by about 57%. 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 patients with renal disease (see Dosage).

Clinical Trials: The efficacy of venlafaxine tablets in the treatment of depression was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-II or DSM-III-R category of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia.

The efficacy of venlafaxine extended release capsules as a treatment for depression was established in 2 placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depression. An 8-week study utilizing venlafaxine extended release doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) and a 12-week study utilizing venlafaxine extended release doses in a range 75 to 150 mg/day (Mean dose for completers was 136 mg/day) both demonstrated superiority of venlafaxine extended release over placebo on the HAM-D total score, the HAM-D Depressed Mood Item, the MADRS total score, the CGI Severity of illness scale, and the CGI Global Improvement scale. In both studies, venlafaxine extended release 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.

Indications And Clinical Uses: For the symptomatic relief of depressive illness.

The effectiveness of venlafaxine in long-term use (i.e., for more than 4 to 6 weeks-immedate release tablets, or 8 to 12 weeks-extended release capsules) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use venlafaxine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications: In patients with known hypersensitivity to venlafaxine or to any of the components of the formulations.

MAO Inhibitors: There have been reports of serious, sometimes fatal reactions in patients receiving antidepressants with pharmacological properties similar to those of venlafaxine in combination with a MAO inhibitor. Therefore, venlafaxine should not be used in combination with MAO inhibitors or within 2 weeks of terminating treatment with MAO inhibitors. Treatment with MAO inhibitors should not be started until 2 weeks after discontinuation of venlafaxine therapy.

Manufacturers’ Warnings In Clinical States: Sustained Hypertension: Treatment with venlafaxine tablets was associated with modest but sustained increases in blood pressure during premarketing studies.

An analysis of the blood pressure increases in patients with sustained hypertension and in the 19 patients who were discontinued from treatment because of hypertension.

In placebo-controlled premarketing depression studies with venlafaxine extended release, a final on-therapy mean increase in supine diastolic pressure (SDBP).

Less than 3% of venlafaxine extended release patients treated with doses of 75 to 300 mg/day had sustained elevations in blood pressure (defined as treatment-emergent SDBP 90 mm Hg and 10 mm Hg above baseline for 3 consecutive on-therapy visits). An insufficient number of patients received doses of venlafaxine extended release >300 mg/day to evaluate systematically sustained blood pressure increases. Less than 1% of venlafaxine extended release-treated patients in double-blind, placebo-controlled premarketing depression studies discontinued treatment because of elevated blood pressure compared with 0.4% of placebo-treated patients.

Sustained increases could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have their blood pressure monitored regularly. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered after a benefit-risk assessment is made.

Precautions: General: Suicide: The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization. In order to reduce the risk of overdose, prescriptions for venlafaxine tablets/capsules should be written for the smallest quantity of tablets/capsules consistent with good patient management.

Seizures: During premarketing testing, seizures were reported in 8 out of 3 082 venlafaxine tablet-treated patients (0.26%). In 5 of the 8 cases with immediate release tablets, patients were receiving doses of 150 mg/day or less. No seizures were seen in 705 venlafaxine extended release capsule-treated patients. However, patients with a history of convulsive disorders were excluded from most of these studies. Venlafaxine should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures.

Activation of Mania/Hypomania: During Phase II and III trials, mania or hypomania occurred in 0.5% of venlafaxine tablet-treated patients and in 0.3% of venlafaxine capsule-treated patients. Mania or hypomania occurred in 0.6% of all venlafaxine-treated patients. Mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, venlafaxine should be used cautiously in patients with a history of mania.

Patients with Concomitant Illness: Clinical experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Patients should be questioned about any prescription or “over the counter drugs” that they are taking, or planning to take, since there is a potential for interactions.

Cardiac Disease: 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 the product’s clinical trials.

Evaluation of the ECG for 769 patients who received venlafaxine immediate release tablets in 4- to 6-week double-blind trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo.

The electrocardiograms for 357 patients who received venlafaxine extended release and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for venlafaxine extended release-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine extended release and decrease of 1.9 msec for placebo). Three of 705 venlafaxine extended release-treated patients in phase III studies experienced QTc prolongation to 500 msec during treatment. Baseline QTc was >450 msec for all 3 patients. No case of sudden unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTc prolongation, was reported in venlafaxine extended release premarketing studies.

The mean heart rate was increased by about 4 beats/minute during treatment with venlafaxine. Venlafaxine treatment has been associated with sustained hypertension (see Warnings).

Hepatic and Renal Disease: In patients with hepatic or renal impairment (GFR=10 to 70 mL/min), the pharmacokinetic disposition of both venlafaxine and ODV are significantly altered. Dosage adjustment is necessary in these patients (see Dosage).

Insomnia and Nervousness: Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine than with placebo (see Adverse Effects).

Changes in Appetite and Weight: Treatment-emergent anorexia was more commonly reported for venlafaxine-treated than placebo-treated patients (see Adverse Effects). Significant weight loss, especially in underweight depressed patients, may be an undesirable result of treatment.

Occupational Hazards: 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 judgement, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

Pregnancy, Labor and Delivery: There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Lactation: It is not known whether venlafaxine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, lactating women should not nurse their infants while receiving venlafaxine.

Children: Safety and efficacy in children below the age of 18 have not been established.

Geriatrics: Of the 2 897 patients in Phase II and III trials with venlafaxine tablets, 357 (12%) were 65 years of age or older. Forty-three (4%) of the patients in trials with venlafaxine extended release capsules, were 65 years of age or older. No overall differences in effectiveness and safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

Discontinuation Symptoms: While the discontinuation effects of venlafaxine have not been systematically evaluated in controlled clinical trials, a retrospective survey of new events occurring during taper or following discontinuation revealed the following 6 events that occurred at an incidence of at least 5%, and for which the incidence for venlafaxine was at least twice the placebo incidence: asthenia, dizziness, headache, insomnia, nausea and nervousness.

With venlafaxine extended release, the following 6 events occurred with an incidence of at least 3% , and for which the incidence of venlafaxine extended release was at least twice the placebo incidence: dizziness, dry mouth, insomnia, nausea, nervousness and sweating.

Therefore, it is recommended that the dosage be tapered gradually and the patient monitored (see Dosage).

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

Lithium: The steady-state pharmacokinetics of venlafaxine administered as 50 mg every 8 hours was not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. Venlafaxine had no effect on the pharmacokinetics of lithium.

Diazepam: The steady-state pharmacokinetics of venlafaxine administered as 50 mg every 8 hours was not affected when a single 10 mg oral dose of diazepam was administered to 18 healthy male subjects. Venlafaxine had no effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam. Additionally, venlafaxine administration did not affect the psychomotor and psychometric effects induced by diazepam.

Cimetidine: Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs in 18 healthy male subjects resulted in inhibition of first-pass metabolism of venlafaxine. 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, there was no effect on the pharmacokinetics of ODV. 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, for elderly patients and for patients with hepatic or renal dysfunction, the interaction associated with the concomitant use of cimetidine and venlafaxine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

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.

Imipramine: Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, AUC, Cmax and Cmin of desipramine (the active metabolite of imipramine) increased by approximately 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). The clinical significance of elevated 2-OH-desipramine levels is unknown.

Imipramine partially inhibited the CYP2D6-mediated formation of ODV. However, the total concentration of active compounds (venlafaxine plus ODV) was not affected by coadministration with imipramine, and no dosage adjustment is required.

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).

Drugs Highly Bound to Plasma Proteins: Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine 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. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6 mediated metabolism and venlafaxine. Drug interactions that reduce the metabolism of venlafaxine to ODV (see Imipramine above) potentially increase the plasma concentrations of venlafaxine and lower the concentrations of the active metabolite. However, the pharmacokinetic profile of venlafaxine in subjects concomitantly receiving a CYP2D6-inhibitor would not be substantially different than the pharmacokinetic profile in subjects who are CYP2D6 poor metabolizers, and no dosage adjustment is required.

CYP3A3/4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A3/4. Because CYP3A3/4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A3/4-mediated metabolism and venlafaxine is small. However, because the 2 primary metabolic pathways for venlafaxine are through CYP2D6 and, to a lesser extent, CYP3A3/4, concomitant intake of inhibitors of both of these isoenzymes is not recommended during treatment with venlafaxine. However, interactions between concomitant intake of inhibitors of both CYP2D6 and CYP3A3/4 with venlafaxine has not been studied.

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 vivo by a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

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.

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).

MAO Inhibitors: See Contraindications.

Other CNS-Active Drugs: The risk of using venlafaxine in combination with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.

Electroconvulsive Therapy: There are no clinical data on the use of electroconvulsive therapy combined with venlafaxine treatment.

Drug Abuse and Dependence: 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. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

While venlafaxine tablets and capsules have not been systematically studied in clinical trials for their 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).

Adverse Reactions: Commonly Observed Adverse Reactions: The most commonly observed adverse events associated with the use of venlafaxine (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine at least twice that for placebo), derived from the 2% incidence in Table III, were:

Effexor: asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, blurred vision, and abnormal ejaculation/orgasm and impotence in men.

Effexor XR: abnormal dreams, anorexia, dizziness, dry mouth, nausea, nervousness, somnolence, sweating, and tremor as well as abnormal ejaculation/orgasm in men.

Adverse Reactions Associated with Discontinuation of Treatment: Nineteen percent (537/2 897) of venlafaxine and 12% (88/705) of venlafaxine extended release-treated patients in Phase II and III depression studies discontinued treatment due to an adverse reaction.

Incidence in Controlled Trials: Table III enumerates adverse events that occurred at an incidence of 2% or more, and were more frequent than in the placebo group, among venlafaxine-treated patients.

Effexor: Patients participated in 4- to 8-week placebo-controlled trials in which doses in the range of 75 to 375 mg/day were administered.

Effexor XR: Patients participated in 8- to 12-week placebo-controlled trials in which doses in the range of 75 to 225 mg/day were administered.

Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

The prescriber should be aware that the cited frequencies for venlafaxine extended release cannot be compared with figures obtained from other clinical investigations of venlafaxine which involved different treatments, uses and investigators. The cited figures for venlafaxine extended release, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

Dose Dependency of Adverse Events: The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least 1 venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating and abnormal ejaculation.

Adaptation to Certain Adverse Events: In premarketing experience with venlafaxine tablets over a 6-week period, and venlafaxine extended release capsules over a 12-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth).

Vital Sign Changes: Treatment with venlafaxine tablets (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats/minute, compared to no change for placebo. It was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see Warnings).

Treatment with venlafaxine extended release capsules for up to 12 weeks in premarketing depression trials was associated with a mean increase in pulse rate of approximately 2 beats/minute, compared with 1 beat/minute for placebo. It was associated with mean increases in diastolic blood pressure ranging from 0.7 to 0.9 mm Hg, compared with mean decreases ranging from 0.5 to 1.4 mm Hg for placebo (see Warnings).

Laboratory Changes: Of the serum chemistry and hematology parameters monitored during clinical trials with venlafaxine, a statistically significant difference with placebo was seen only for serum cholesterol, i.e., patients treated with venlafaxine had mean increases from baseline of 3 mg/dL. In premarketing placebo-controlled depression trials for up to 12 weeks, venlafaxine extended release was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL. The serum cholesterol changes induced by venlafaxine are of unknown clinical significance.

ECG Changes: In an analysis of ECGs obtained in 769 patients treated with venlafaxine tablets and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, i.e., a mean increase from baseline of 4 beats/minute for venlafaxine tablets.

An analysis of ECGs obtained in 357 patients treated with venlafaxine extended release and 285 patients treated with placebo in controlled clinical trials, revealed a mean increase in corrected QT (QTc) interval relative to placebo (see Precautions). A mean increase in heart rate of approximately 4 beats/minute for venlafaxine extended release compared with 1 beat/minute for placebo was observed.

Other Events Observed During the Premarketing Evaluation of Venlafaxine: During its premarketing assessment, multiple doses of venlafaxine extended release were administered to 705 patients in phase III depression studies and venlafaxine tablets were administered to 96 patients. In addition, in premarketing assessment of venlafaxine tablets, multiple doses were administered to 2 897 patients in phase II and III depression studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine tablets only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 3 698 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it.

Events are further categorized by body system and the frequent adverse events are provided below. Frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing).

Body as a Whole: chest pain, chills, fever.

Cardiovascular: migraine, postural hypotension, tachycardia.

Digestive: eructation, increased appetite.

Hemic and Lymphatic: ecchymosis.

Musculoskeletal: myalgia.

Nervous: amnesia, emotional lability, hypesthesia, sleep disturbance, thinking abnormal, trismus.

Special Senses: ear pain, taste perversion.

Urogenital: menstrual disorder*, prostatitis*, urinary tract infection, urination impaired, vaginitis*.

*Based on the number of men and women as appropriate.

Symptoms And Treatment Of Overdose: Human Experience: In postmarketing experience, venlafaxine, taken alone, has not been clearly associated with lethal overdose. However, fatal reactions have been reported in patients taking overdoses of venlafaxine in combination with alcohol and/or other drugs.

Symptoms: Effexor: There were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions 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 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 µg/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.

Effexor XR: Among the patients included in the premarketing evaluation of venlafaxine extended release capsules, there were 2 reports of acute overdosage with venlafaxine extended release, either alone or in combination with other drugs. One patient took a combination of 6 g of venlafaxine extended release and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.5 g of venlafaxine extended release. This patient reported paresthesia of all four limbs but recovered without sequelae.

Treatment: Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitoring of cardiac rhythm and vital signs is recommended. General supportive and symptomatic measures are also recommended. Use of activated charcoal, induction of emesis, or gastric lavage should be considered. Due to the large volume of distribution of venlafaxine, 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 centre on the treatment of any overdose.

Dosage And Administration: Adults: Effexor: The recommended treatment dose is 75 mg/day, administered in 2 or 3 divided doses, taken with food. If the expected clinical improvement does not occur after a few weeks, a gradual dose increase to 150 mg/day may be considered. If needed, the dose may be further increased up to 225 mg/day. Increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of the usefulness of doses greater than 225 mg/day for moderately depressed patients. More severely depressed inpatients have responded to higher doses, between 350 and 375 mg/day, given in 3 divided doses. Maximum: The maximum dose recommended is 375 mg/day (in an inpatient setting).

Effexor XR: The recommended dose for venlafaxine extended release is 75 mg/day, administered once daily with food, either in the morning or in the evening. Each capsule should be swallowed whole with water. It should not be divided, crushed, chewed, or placed in water. While the relationship between dose and antidepressant response for venlafaxine extended release has not been adequately explored patients not responding to the initial 75 mg may benefit from dose increases. Depending on tolerability and the need for further clinical effect, the dose should be increased by up to 75 mg/day up to a maximum of 225 mg/day for moderately depressed outpatients. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days. There is very limited experience with venlafaxine extended release at doses higher than 225 mg/day, or in severely depressed inpatients.

It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for venlafaxine tablets, more severely depressed inpatients responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day).

Switching Patients from Effexor Tablets: Depressed patients who are currently being treated at a therapeutic dose with venlafaxine tablets may be switched to venlafaxine extended release at the nearest equivalent dose (mg/day), e.g., 37.5 mg venlafaxine 2-times-a-day to 75 mg venlafaxine extended release 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 Pharmacology), it is recommended that the total daily dose be reduced by about 50% in patients with moderate hepatic impairment. For such patients, it may be desirable to start at 37.5 mg/day. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.

Patients with Renal Impairment: Given the decrease in clearance for venlafaxine and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR=10 to 70 mL/min) compared to normal subjects (see Pharmacology), it is recommended that the total daily dose be decreased by 25 to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hours). For such patients, it may be desirable to start at 37.5 mg/day. Since there is so much individual variability in clearance among patients with renal impairment, individualization of dosing may be desirable.

Geriatrics: No dose adjustment is recommended for elderly patients solely on the basis of their age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Maintenance/Continuation/Extended Treatment: There is no body of evidence available to answer the question of how long a patient should continue to be treated with venlafaxine. It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Discontinuing Venlafaxine: When venlafaxine therapy that has been administered for more than 1 week is stopped, it is generally recommended that the dose be tapered gradually to minimize the risk of discontinuation symptoms. Patients who have received venlafaxine for 6 weeks or more should have their dose tapered gradually over a 2-week period. Individualization of tapering may be necessary.

Switching Patients to or from a MAO Inhibitor: At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of therapy with venlafaxine. In addition, at least 14 days should be allowed after stopping venlafaxine before starting an MAO inhibitor (see Contraindications).

Availability And Storage: Effexor: 37.5 mg: Each shield-shaped, peach-colored, compressed tablet, with a score, with “W” on one side and “37.5” on the other side, contains: venlafaxine HCl equivalent to venlafaxine base 37.5 mg. Nonmedicinal ingredients: cosmetic brown iron oxide, ferric oxide yellow, lactose hydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. Gluten-free. Bottles of 100.

75 mg: Each shield-shaped, peach-colored, compressed tablet, with a score, with “W” on one side and “75” on the other side, contains: venlafaxine HCl equivalent to venlafaxine base 75 mg. Nonmedicinal ingredients: cosmetic brown iron oxide, ferric oxide yellow, lactose hydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. Gluten-free. Bottles of 100.

Effexor XR: 37.5 mg: Each extended release, hard gelatin capsule, with gray cap and peach body, with “W” and “Effexor XR” on the cap and “37.5” on the body, in red ink, contains: venlafaxine HCl equivalent to venlafaxine base 37.5 mg. Nonmedicinal ingredients: ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, talc, titanium dioxide and White Tek SB-0007 and/or Opacode Red S-1-15034 ink. Bottles of 100 and 500.

75 mg: Each extended release, hard gelatin capsule, with peach cap and body, with “W” and “Effexor XR” on the cap and “75” on the body, in red ink, contains: venlafaxine HCl equivalent to venlafaxine base 75 mg. Nonmedicinal ingredients: ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, talc, titanium dioxide and White Tek SB-0007 and/or Opacode Red S-1-15034 ink. Bottles of 100 and 500.

150 mg: Each extended release, hard gelatin capsule, with dark orange cap and body, with “W” and “Effexor XR” on the cap and “150” on the body, in white ink, contains: venlafaxine HCl equivalent to venlafaxine base 150 mg. Nonmedicinal ingredients: ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, talc, titanium dioxide and White Tek SB-0007 and/or Opacode Red S-1-15034 ink. Bottles of 100 and 500.

Store at room temperature (15 to 30°C), in a dry place.

EFFEXOR® EFFEXOR® XR Wyeth-Ayerst Venlafaxine HCl Antidepressant

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