Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (+-)-1-[a-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below.
N (CH3)2
OH C
H3CO
H
venlafaxine hydrochloride
*HCl
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. Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate.
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, histaminergic, or a-1 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.
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 dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose 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%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV. The degree of binding of venlafaxine to human plasma is 27%+-2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30%+-12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected. Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half- life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean+-SD steady-state plasma clearance of venlafaxine and ODV is 1.3+-0.6 and 0.4+-0.2 L/h/kg, respectively; elimination half-life is 5+-2 and 11+-2 hours, respectively; and steady- state volume of distribution is 7.5+-3.7 L/kg and 5.7+-1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens.
Age and Gender
A 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 due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see "DOSAGE AND ADMINISTRATION").
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").
The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for depression was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression--Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a
dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day. While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. 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 PS 3 and a HAM-D-21 total score of PS 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 3 4 (moderately ill), or (2) 2 consecutive CGI Severity of Illness item scores of 3 4, or (3) a final CGI Severity of Illness item score of 3 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 PS 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 3 20, (2) no more than 2 HAM-D-21 total scores > 10, and (3) no single CGI Severity of Illness item score 3 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 3 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.
Effexor (venlafaxine hydrochloride) is indicated for the treatment of depression. The efficacy of Effexor in the treatment of depression was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category
CONFIDENTIAL 4 16 Mar 01
of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia (see "CLINICAL TRIALS"). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see "CLINICAL TRIALS"). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Effexor (venlafaxine hydrochloride) is contraindicated in patients known to be hypersensitive to it. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see "WARNINGS").
Venlafaxine treatment is associated with sustained increases in blood pressure. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP $90 mm Hg and
$
10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine:
| Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) | |
| Treatment Group | Incidence of Sustained Elevation in SDBP |
| Venlafaxine | |
| < 100 mg/day | 3% |
| 101-200 mg/day | 5% |
| 201-300 mg/day | 7% |
| > 300 mg/day | 13% |
| Placebo | 2% |
An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10-15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine 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.
Anxiety and Insomnia
Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short- term, double-blind, placebo-controlled depression studies:
| Symptom | Venlafaxine n = 1033 | Placebo n = 609 |
| Anxiety | 6% | 3% |
| Nervousness | 13% | 6% |
Insomnia 18% 10%
Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the phase 2-3 depression studies.
Changes in Appetite and Weight
Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. A dose-dependent weight loss was often noted in patients treated with venlafaxine for several weeks. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the phase 2-3 depression trials).
Activation of Mania/Hypomania
During phase 2-3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. Activation of 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, Effexor (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania.
Mydriasis
Mydriasis has been reported in association with venlafaxine; therefore patients with raised intra- ocular pressure or at risk of acute narrow angle glaucoma should be monitored.
Seizures
During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. Effexor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Suicide
The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Effexor should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness
Clinical experience with Effexor in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Effexor 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 premarketing testing. Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-week double-blind placebo- controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in Effexor-treated patients was increased relative to baseline by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor XR (the extended-release form of venlafaxine) 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 Effexor XR-treated patients 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). In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients 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 clinical significance of these changes is unknown. In patients with renal impairment (GFR=10-70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see "DOSAGE AND ADMINISTRATION").
Effexor (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients.
Physicians are advised to discuss the following issues with patients for whom they prescribe Effexor:
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 Effexor therapy does not adversely affect their ability to engage in such activities.
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.
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, since there is a potential for interactions.
Alcohol
Although Effexor 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 Effexor.
Allergic Reactions
Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
There are no specific laboratory tests recommended.
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 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 is 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 (CI/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. O- desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the
pharmacokinetics of lithium.
Drugs Highly Bound to Plasma Protein
Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor 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 and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 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 CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently 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 potent simultaneous inhibition of these two enzyme 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 to 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 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/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 treatment.
Postmarketing Spontaneous Drug Interaction Reports
See "ADVERSE REACTIONS, Postmarketing Reports."
Carcinogenesis
Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. 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 levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels 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.
Mutagenicity
Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose.
Impairment of Fertility
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m2 basis.
Teratogenic Effects--Pregnancy Category C
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the 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 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 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.
The effect of Effexor(r) (venlafaxine hydrochloride) on labor and delivery in humans is unknown.
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, 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.
Safety and effectiveness in individuals below 18 years of age have not been established.
Of the 2,897 patients in phase 2-3 depression studies with Effexor, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these 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").
Associated with Discontinuation of Treatment
Nineteen percent (537/2897) of venlafaxine patients in phase 2-3 depression studies discontinued treatment due to an adverse event. The more common events (3 1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included:
| CNS | Venlafaxine | Placebo |
| Somnolence | 3% | 1% |
| Insomnia | 3% | 1% |
| Dizziness | 3% | -- |
| Nervousness | 2% | -- |
| Dry mouth | 2% | -- |
| Anxiety | 2% | 1% |
| Gastrointestinal | ||
| Nausea | 6% | 1% |
| Urogenital | ||
| Abnormal ejaculation * | 3% | -- |
| Other | ||
| Headache | 3% | 1% |
| Asthenia | 2% | -- |
| Sweating | 2% | -- |
* Percentages based on the number of males.
Less than 1%
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
The most commonly observed adverse events associated with the use of Effexor (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men.
Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients
The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Effexor-treated patients who participated in short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a
CONFIDENTIAL 15 16 Mar 01
range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
TABLE 1
Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1
| Body System | Preferred Term | Effexor (n=1033) | Placebo (n=609) |
| Body as a Whole | Headache | 25% | 24% |
| Asthenia | 12% | 6% | |
| Infection | 6% | 5% | |
| Chills | 3% | -- | |
| Chest pain | 2% | 1% | |
| Trauma | 2% | 1% | |
| Cardiovascular | Vasodilatation Increased blood pressure/hypertension | 4% 2% | 3% -- |
| Tachycardia | 2% | -- | |
| Postural hypotension | 1% | -- | |
| Dermatological | Sweating | 12% | 3% |
| Rash | 3% | 2% | |
| Pruritus | 1% | -- |
CONFIDENTIAL 16 16 Mar 01
| Gastrointestinal | Nausea | 37% | 11% |
| Constipation | 15% | 7% | |
| Anorexia | 11% | 2% | |
| Diarrhea | 8% | 7% | |
| Vomiting | 6% | 2% | |
| Dyspepsia | 5% | 4% | |
| Flatulence | 3% | 2% | |
| Metabolic | Weight loss | 1% | -- |
| Nervous System | Somnolence | 23% | 9% |
| Dry mouth | 22% | 11% | |
| Dizziness | 19% | 7% | |
| Insomnia | 18% | 10% | |
| Nervousness | 13% | 6% | |
| Anxiety | 6% | 3% | |
| Tremor | 5% | 1% | |
| Abnormal dreams | 4% | 3% | |
| Hypertonia | 3% | 2% | |
| Paresthesia | 3% | 2% | |
| Libido decreased | 2% | -- | |
| Agitation | 2% | -- | |
| Confusion | 2% | 1% | |
| Thinking abnormal | 2% | 1% | |
| Depersonalization | 1% | -- | |
| Depression | 1% | -- | |
| Urinary retention | 1% | -- | |
| Twitching | 1% | -- | |
| Respiration | Yawn | 3% | -- |
| Special Senses | Blurred vision | 6% | 2% |
| Taste perversion | 2% | -- | |
| Tinnitus | 2% | -- | |
| Mydriasis | 2% | -- | |
| Urogenital System | Abnormal ejaculation/ Orgasm | 12% 2 | -- 2 |
| Impotence | 6% 2 | -- 2 | |
| Urinary frequency | 3% | 2% | |
| Urination impaired | 2% | -- 3 | |
| Orgasm disturbance | 2% 3 | -- 3 |
Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3.
Incidence less than 1%.
Incidence based on number of male patients.
Incidence based on number of female patients.
CONFIDENTIAL 17 16 Mar 01
Dose Dependency of Adverse Events
A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in the table that follows. 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 one Effexor group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value PS 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.
TABLE 2
Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial
| Body System/ Preferred Term | Placebo (n=92) | 75 (n=89) | Effexor (mg/day) 225 (n=89) | 375 (n=88) |
| Body as a Whole | ||||
| Abdominal pain | 3.3% | 3.4% | 2.2% | 8.0% |
| Asthenia | 3.3% | 16.9% | 14.6% | 14.8% |
| Chills | 1.1% | 2.2% | 5.6% | 6.8% |
| Infection | 2.2% | 2.2% | 5.6% | 2.3% |
| Cardiovascular System | ||||
| Hypertension | 1.1% | 1.1% | 2.2% | 4.5% |
| Vasodilatation | 0.0% | 4.5% | 5.6% | 2.3% |
| Digestive System | ||||
| Anorexia | 2.2% | 14.6% | 13.5% | 17.0% |
| Dyspepsia | 2.2% | 6.7% | 6.7% | 4.5% |
| Nausea | 14.1% | 32.6% | 38.2% | 58.0% |
| Vomiting | 1.1% | 7.9% | 3.4% | 6.8% |
| Nervous System | ||||
| Agitation | 0.0% | 1.1% | 2.2% | 4.5% |
| Anxiety | 4.3% | 11.2% | 4.5% | 2.3% |
| Dizziness | 4.3% | 19.1% | 22.5% | 23.9% |
| Insomnia | 9.8% | 22.5% | 20.2% | 13.6% |
| Libido decreased | 1.1% | 2.2% | 1.1% | 5.7% |
| Nervousness | 4.3% | 21.3% | 13.5% | 12.5% |
| Somnolence | 4.3% | 16.9% | 18.0% | 26.1% |
| Tremor | 0.0% | 1.1% | 2.2% | 10.2% |
| Respiratory System | ||||
| Yawn | 0.0% | 4.5% | 5.6% | 8.0% |
| Skin and Appendages | ||||
| Sweating | 5.4% | 6.7% | 12.4% | 19.3% |
CONFIDENTIAL 18 16 Mar 01
Special Senses
Abnormality of 0.0% 9.1% 7.9% 5.6% Accommodation
Urogenital System
Abnormal Ejaculation/orgasm
0.0% 4.5% 2.2% 12.5%
Impotence 0.0% 5.8% 2.1% 3.6%
(Number of men) (n=63) (n=52) (n=48) (n=56)
Adaptation to Certain Adverse Events
Over a 6-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
Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per 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").
Laboratory Changes
Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a statistically significant difference with placebo was seen only for serum cholesterol, i.e., patients treated with Effexor had mean increases from baseline of 3 mg/dL, a change of unknown clinical significance.
ECG Changes
In an analysis of ECGs obtained in 769 patients treated with Effexor 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 per minute for Effexor (see "PRECAUTIONS, General, Use in Patients with Concomitant Illness").
Other Events Observed during the Premarketing Evaluation of Venlafaxine
During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in phase 2 and 3 studies. In addition, in premarketing assessment of Effexor XR (the extended release form of venlafaxine), multiple doses were administered to 705 patients in phase 3 depression studies and Effexor was administered to 96 patients. During its premarketing
CONFIDENTIAL 19 16 Mar 01
assessment for Generalized Anxiety Disorder, multiple doses of Effexor XR were administered to 476 patients in phase 3 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 (Effexor 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 4174 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. All reported events are included except those already listed in Table 1 and those events for which a drug cause was remote. 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 listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent:chest pain substernal, neck pain; Infrequent:face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt; Rare:appendicitis, bacteremia, carcinoma, cellulitis, withdrawal syndrome. Cardiovascular system - Frequent:migraine; Infrequent:angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare:aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mitral valve disorder, mucocutaneous hemorrhage, myocardial infarct, pallor.
CONFIDENTIAL 20 16 Mar 01
Digestive system - Frequent:eructation; Infrequent:bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, stomatitis, mouth ulceration; Rare:cheilitis, cholecystitis, cholelithiasis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, oral moniliasis, proctitis, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare:goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent:ecchymosis; Infrequent:anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare:basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura. Metabolic and nutritional - Frequent:edema, weight gain; Infrequent:alkaline phosphatase increased, glycosuria, hypercholesteremia, hyperglycemia, hyperuricemia, hypoglycemia, hypokalemia, SGOT increased, thirst; Rare:alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, dehydration, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperlipemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia SGPT increased, uremia. Musculoskeletal system - Infrequent:arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare:pathological fracture, myopathy, osteoporosis, osteosclerosis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent:emotional lability, trismus, vertigo; Infrequent:apathy, ataxia, circumoral paresthesia, CNS stimulation, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, paranoid reaction, psychosis, seizure, abnormal speech, stupor; Rare:akathisia, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain- Barre Syndrome, hypokinesia, neuritis, nystagmus, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis. Respiratory system - Frequent:bronchitis, dyspnea; Infrequent:asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare:atelectasis, hemoptysis, hypoventilation, hypoxia, larnyx edema, pleurisy, pulmonary embolus, sleep apnea.
CONFIDENTIAL 21 16 Mar 01
Skin and appendages - Infrequent:acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare:erythremia nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae. Special senses - Frequent:abnormality of accommodation, abnormal vision; Infrequent:cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, exophthalmos, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare:blepharitis, chromatopsia, conjunctival edema, deafness, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system - Frequent:metrorrhagia, * prostatitis, * vaginitis *; Infrequent:albuminuria, amenorrhea, * cystitis, dysuria, hematuria, female lactation, * leukorrhea, * menorrhagia, * nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage *; Rare:abortion, * anuria, breast discharge, breast engorgement, breast enlargement, endometriosis, * fibrocystic breast, calcium crystalluria, cervicitis, * ovarian cyst, * prolonged erection, * gynecomastia (male), * hypomenorrhea, * kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause, * pyelonephritis, oliguria, salpingitis, * urolithiasis, uterine hemorrhage, * uterine spasm. *
*Based on the number of men and women as appropriate.
Postmarketing Reports
Voluntary reports of other adverse events temporally associated with the use of Effexor that have been received since market introduction and that may have no causal relationship with the use of Effexor include the following: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities (such as atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, ventricular tachycardia), epidermal necrosis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including tardive dyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), pancreatitis, panic, prolactin increased, renal failure, serotonin syndrome, shock-like electrical sensations (in some cases, subsequent to the
CONFIDENTIAL 22 16 Mar 01
discontinuation of Effexor or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly). There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.
Effexor (venlafaxine hydrochloride) is not a controlled substance.
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. While the discontinuation effects of Effexor have not been systematically evaluated in controlled clinical trials, a retrospective survey of new events occurring during taper or following discontinuation revealed the following six events that occurred at an incidence of at least 5% and for which the incidence for Effexor was at least twice the placebo incidence: asthenia, dizziness, headache, insomnia, nausea, and nervousness. Therefore, it is recommended that the dosage be tapered gradually and the patient monitored (see "DOSAGE AND ADMINISTRATION"). While Effexor 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 Effexor (e.g., development of tolerance, incrementation of dose, drug- seeking behavior).
There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), 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 Effexor 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.
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).
The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, 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 usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses.
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 to normal subjects (see "CLINICAL PHARMACOLOGY"), it is recommended that the total daily dose be reduced by 50% in patients with moderate hepatic impairment. 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.
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 to normals (see "CLINICAL PHARMACOLOGY"), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients.
No dose adjustment is recommended for elderly patients on the basis of 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.
It is generally agreed that acute episodes of depression 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 an antidepressant response in patients with recurrent depression 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"). 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.
When discontinuing Effexor 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 for 6 weeks or more should have their dose tapered gradually over a 2-week period.
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI (see "CONTRAINDICATIONS" and "WARNINGS").
Effexor(r) (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped tablet with "25" and a " reverse side. NDC 0008-0701-01, bottle of 100 tablets. NDC 0008-0701-02, carton of 10 Redipak(r) blister strips of 10 tablets each. 37.5 mg, peach, shield-shaped tablet with "37.5" and a " " on one side and "781" on scored reverse side. NDC 0008-0781-01, bottle of 100 tablets. NDC 0008-0781-02, carton of 10 Redipak(r) blister strips of 10 tablets each.
50 mg, peach, shield-shaped tablet with "50" and a " " on one side and "703" on scored reverse side. NDC 0008-0703-01, bottle of 100 tablets. NDC 0008-0703-02, carton of 10 Redipak(r) blister strips of 10 tablets each. 75 mg, peach, shield-shaped tablet with "75" and a " " on one side and "704" on scored reverse side. NDC 0008-0704-01, bottle of 100 tablets. NDC 0008-0704-02, carton of 10 Redipak(r) blister strips of 10 tablets each. 100 mg, peach, shield-shaped tablet with "100" and a " " on one side and "705" on scored reverse side. NDC 0008-0705-01, bottle of 100 tablets. NDC 0008-0705-02, carton of 10 Redipak(r) blister strips of 10 tablets each. The appearance of these tablets is a trademark of Wyeth-Ayerst Laboratories.
[Wyeth logo] Based on CI 6027- 2 Revised January 12, 2000 Printed in USA
Effexor(r) XR (venlafaxine hydrochloride) Extended-Release Capsules
Effexor XR is an extended-release capsule for oral administration that contains venlafaxine hydrochloride, a structurally novel antidepressant. Venlafaxine hydrochloride is chemically unrelated to tricyclic, tetracyclic, or other available antidepressants and to other agents used to treat Generalized Anxiety Disorder. 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.
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.
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").
Depression
The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for depression was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depression. 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 depression 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 PS 3 and a HAM-D-21 total score of PS 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 3 4 (moderately ill), or (2) 2 consecutive CGI Severity of Illness item scores of 3 4, or (3) a final CGI Severity of Illness item score of 3 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 PS 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 3 20, (2) no more than 2 HAM-D-21 total scores > 10, and (3) no single CGI sSeverity of Illness item score 3 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 3 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.
Depression
Effexor XR (venlafaxine hydrochloride) extended-release capsules is indicated for the treatment of depression. The efficacy of Effexor XR in the treatment of depression was established in 8- and 12-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see "Clinical Trials"). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
CONFIDENTIAL 6 16 Mar 01
The efficacy of Effexor (the immediate release form of venlafaxine) in the treatment of depression in inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4-week controlled trial (see "Clinical Trials"). The safety and efficacy of Effexor XR in hospitalized depressed patients have not been adequately studied. The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see "Clinical Trials"). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Generalized Anxiety Disorder
Effexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-month placebo-controlled trials in outpatients diagnosed with GAD according to DSM-IV criteria (See "Clinical Trials"). Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials in patients with GAD, the physician who elects to use Effexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (See "DOSAGE AND ADMINISTRATION").
Effexor XR (venlafaxine hydrochloride) extended-release capsules is contraindicated in patients known to be hypersensitive to venlafaxine hydrochloride.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see "WARNINGS").
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 depression studies, 3% (19/705) experienced sustained hypertension [defined as treatment-emergent supine diastolic blood pressure (SDBP) 3 90 mm Hg and 3 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. 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 depression studies 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 premarketing depression 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). 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.
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 depression and GAD studies, as shown in Table 1.
Table 1
Incidence of Insomnia and Nervousness in Placebo-Controlled Depression and GAD Trials
Depression GAD
Placebo
Effexor XR
Placebo
Symptom n = 357 n = 285 n = 1381 n = 555
| Insomnia | 17% | 11% | 15% | 10% |
| Nervousness | 10% | 5% | 6% | 4% |
Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in Phase 3 depression studies. In Phase 3 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.
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 depression studies. 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 depression 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 Phase 3 depression 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).
Activation of Mania/Hypomania
During premarketing depression 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 all premarketing depression 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 marketed antidepressants. As with all antidepressants, Effexor XR should be used cautiously in patients with a history of mania.
Mydriasis
Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or 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 depression studies or among 1381 Effexor XR-treated patients in GAD studies. In all premarketing depression 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.
Suicide
The possibility of a suicide attempt is inherent in depression 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 depression should be observed when treating patients with GAD.
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 for 357 patients who received Effexor XR and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in depression and the electrocardiograms for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD were analyzed. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in depression 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 clinical significance of these changes is unknown. The mean change from baseline in corrected QT interval (QTc) for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the depression 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 clinical significance of these changes is unknown. 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 all antidepressants, should be used with caution in such patients.