VENEXOR

Venlafaxine hydrochloride is a structurally novel antidepressant for oral administration.

It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the molecular formula of C 17 H 27 NO 2 HCl.

Its molecular weight is 313.87.

The structural formula is shown below.

Venlafaxine hydrochloride

Venlafaxine hydrochloride, USP is a white to off-white crystalline powder.

It is soluble in methanol and in water.

Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

Each venlafaxine tablet, USP intended for oral administration contains venlafaxine hydrochloride equivalent to 25 mg or 37.5 mg or 50 mg or 75 mg or 100 mg of venlafaxine.

In addition, each tablet contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate.

Structured formula for venlafaxine.

Venlafaxine tablets, USP are indicated for the treatment of major depressive disorder.

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

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 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 venlafaxine hydrochloride extended-release capsules 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 venlafaxine tablets 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.

Nevertheless, the physician who elects to use venlafaxine tablets/venlafaxine hydrochloride extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

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 α-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.

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 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.

ODV exhibited linear kinetics over the dose range of 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.

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.

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

Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects.

ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects.

A large degree of intersubject variability was noted.

Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.

In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively).

Venlafaxine oral bioavailability was increased to 3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects.

In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects.

Dosage adjustment is necessary in these hepatically impaired patients See DOSAGE AND ADMINISTRATION.

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 to 70 mL/min), compared to normal subjects.

In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects.

Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normal subjects.

In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects.

Dosage adjustment is necessary in these patients See DOSAGE AND ADMINISTRATION.

The efficacy of venlafaxine tablets as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials.

Four of these were 6 week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with venlafaxine tablets in a range of to 225 mg/day (t.i.d. schedule), the third involving fixed venlafaxine tablets 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 adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose venlafaxine tablets doses were titrated in a range of to 375 mg/day (t.i.d. schedule).

In these 5 studies, venlafaxine tablets were shown to be significantly superior to placebo on at least 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 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 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, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8 week open trial on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsules dose or to placebo, for up to 26 weeks of observation for relapse.

Response during the open phase was defined as a CGI Severity of Illness item score of ≤ 3 and a HAM-D-21 total score of ≤ 10 at the day 56 evaluation.

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

Patients receiving continued venlafaxine hydrochloride extended-release capsules treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.

In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score ≤ 12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: no HAM-D-21 total score ≥ 20; no more than 2 HAM-D-21 total scores > 10; and no single CGI Severity of Illness item score ≥ 4 (moderately ill)] during an initial 26 weeks of treatment on venlafaxine tablets (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same venlafaxine tablets dose or to placebo.

The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥ 4, was for up to 52 weeks.

Patients receiving continued venlafaxine tablets treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

Nineteen percent (537/2897) of venlafaxine patients in Phase and Phase 3 depression studies discontinued treatment due to an adverse event.

The more common events (≥ 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 Percentages based on the number of males. — Less than 1% Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% − Nervousness 2% − Dry mouth 2% − Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal 3% − ejaculation Other Headache 3% 1% Asthenia 2% − Sweating 2% − Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of venlafaxine tablets (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine tablets 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 Venlafaxine Tablets -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 venlafaxine tablets-treated patients who participated in short-term (4 to 8 week) placebo-controlled trials in which patients were administered doses in a range of 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 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 2 Treatment-Emergent Adverse Experience Incidence in to 8 Week Placebo-Controlled Clinical Trials 1 1 Events reported by at least 1% of patients treated with venlafaxine tablets are included, and are rounded to the nearest %.

Events for which the venlafaxine tablets 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 dysmenorrhea 3. — Incidence less than 1%.

Incidence based on number of male patients.

Incidence based on number of female patients.

Placebo (n=1033) (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 4% 3% Increased blood pressure/hypertension 2% — Tachycardia 2% — Postural hypotension 1% — Dermatological Sweating 12% 3% Rash 3% 2% Pruritus 1% — 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% — Orgasm disturbance 2% 3 — 3 Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing venlafaxine tablets 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine tablets 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 venlafaxine tablets 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.

TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial $NoTableFooter $NoFootNote Venlafaxine Tablets (mg/day) Body System/ Preferred Term Placebo 75 225 375 (n=92) (n=89) (n=89) (n=88) Body as a Whole Abdominal pain 3.3% 3.4% 2.2% 8% 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% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous System Agitation 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% 26.1% Tremor 0% 1.1% 2.2% 10.2% Respiratory System Yawn 0% 4.5% 5.6% 8% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/orgasm 0% 4.5% 2.2% 12.5% Impotence 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).

Venlafaxine tablets 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.

In a flexible-dose study, with doses in the range of to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo.

In controlled clinical trials, venlafaxine tablets were 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.

Of the serum chemistry and hematology parameters monitored during clinical trials with venlafaxine tablets, a statistically significant difference with placebo was seen only for serum cholesterol.

In premarketing trials, treatment with venlafaxine tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL.

Patients treated with venlafaxine tablets for at least 3 months in placebo-controlled 12 month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients.

This increase was duration dependent over the study period and tended to be greater with higher doses.

Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥ 50 mg/dL from baseline and to a value ≥ 261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥ 50 mg/dL from baseline and to a value ≥ 261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0% of placebo-treated patients.

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 per minute for venlafaxine tablets.

In a flexible-dose study, with doses in the range of to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo.

Other Events Observed During the Premarketing Evaluation of Venlafaxine During its premarketing assessment, multiple doses of venlafaxine tablets were administered to 2897 patients in Phase and Phase 3 studies.

In addition, in premarketing assessment of venlafaxine hydrochloride extended-release capsules, multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and venlafaxine tablets were administered to 96 patients.

During its premarketing assessment, multiple doses of venlafaxine hydrochloride extended-release capsules were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies.

The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and doubleblind 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 5356 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 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: accidental injury, chest pain substernal, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome;

• Rare: appendicitis, bacteremia, c.

There were 14 reports of acute overdose with venlafaxine tablets, 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 tablets 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 mcg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mcg/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 of the other patients.

In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs.

The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting.

Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants.

Epidemiological studies have shown that venlafaxine-treated patients have a higher preexisting burden of suicide risk factors than SSRI-treated patients.

The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear.

Prescriptions for venlafaxine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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).

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages to 24) with major depressive disorder (MDD) and other psychiatric disorders.

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1 Age Range Drug.

• Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases to 24 5 additional cases Decreases Compared to Placebo to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for venlafaxine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that venlafaxine tablets are not approved for use in treating bipolar depression.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including venlafaxine tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of venlafaxine tablets with MAOIs intended to treat psychiatric disorders is contraindicated.

Venlafaxine tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine tablets.

Venlafaxine tablets should be discontinued before initiating treatment with the MAOI See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION.

If concomitant use of venlafaxine tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St.

John's Wort is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with venlafaxine tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

The pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Venlafaxine treatment is associated with sustained increases in blood pressure in some patients.

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 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group.

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 to 200 mg/day 5% 201 to 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 to 15 mm Hg, SDBP).

Nevertheless, sustained increases of this magnitude could have adverse consequences.

Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience.

Preexisting hypertension should be controlled before treatment with venlafaxine.

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.

Sexual Dysfunction Use of

SNRIs, including venlafaxine tablets, may cause symptoms of sexual dysfunction See ADVERSE REACTIONS.

In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.

In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of venlafaxine tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.

When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.

Discuss potential management strategies to support patients in making informed decisions about treatment.

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

The use of

MAOIs intended to treat psychiatric disorders with venlafaxine tablets or within 7 days of stopping treatment with venlafaxine tablets is contraindicated because of an increased risk of serotonin syndrome.

The use of venlafaxine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated See WARNINGS and DOSAGE AND ADMINISTRATION.

Starting venlafaxine tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome See WARNINGS and DOSAGE AND ADMINISTRATION.

The recommended starting dose for venlafaxine tablets 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.

Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to venlafaxine tablets, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

When treating pregnant women with venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects, it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment.

Since there was much individual variability in clearance between subjects 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 to 70 mL/min) compared to normals, 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% 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 major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode.

In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended-release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride extended-release capsules (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 venlafaxine tablets 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 venlafaxine tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) .

Based on these limited data, it is not known whether or not the dose of venlafaxine tablets/venlafaxine hydrochloride extended-release capsules 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.

Symptoms associated with discontinuation of venlafaxine tablets, other SNRIs, and SSRIs, have been reported.

Patients should be monitored for these symptoms when discontinuing treatment.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric.

Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with venlafaxine tablets.

Conversely, at least 7 days should be allowed after stopping venlafaxine tablets before starting an MAOI intended to treat psychiatric disorders See CONTRAINDICATIONS.

MAOls, Such as Linezolid or Methylene Blue Do not start venlafaxine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered See CONTRAINDICATIONS.

In some cases, a patient already receiving therapy with venlafaxine tablets may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with venlafaxine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue See WARNINGS.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with venlafaxine tablets is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use See WARNINGS.

Tablets, USP equivalent to 37.5 mg of venlafaxine are peach-colored, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "65" and other side is plain and are supplied as follows: NDC 68071-3431-0 in bottles of 100 tablets Storage Store at 20° to 25°C (68° to 77°F) in a dry place.

Dispense in a well-closed container as defined in the USP.

KEEP THIS AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.

Guide available at or call 1-877-993-8779.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.

Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.

Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Interference with Cognitive and Motor Performance

Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals.

The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance.

However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine tablets therapy does not adversely affect their ability to engage in such activities.

Patients should be advised that taking venlafaxine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy.

Open-angle glaucoma is not a risk factor for angle closure glaucoma.

Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

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

Patients should be advised to notify their physician if they are breastfeeding an infant.

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

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of venlafaxine tablets and triptans, tramadol, tryptophan supplements or other serotonergic agents See CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs, Serotonergic Drugs.

Patients should be cautioned about the concomitant use of venlafaxine tablets and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

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

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

Venlafaxine and

ODV have been reported to be excreted in humanmilk.

Because of the potential for serious adverse reactions in nursing infants from venlafaxine tablets, 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 the pediatric population have not been established.

Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.

Anyone considering the use of venlafaxine tablets in a child or adolescent must balance the potential risks with the clinical need.

Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsule's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height.

Should the decision be made to treat a pediatric patient with venlafaxine tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term.

The safety of venlafaxine hydrochloride extended-release capsules treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.

In the studies conducted in pediatric patients (ages to 17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients.

Consequently, the precautions for adults apply to pediatric patients See WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation.

Of the 2,897 patients in Phase and Phase 3 depression studies with venlafaxine tablets, 12% 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.

SSRIs and

SNRIs, including venlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.

The pharmacokinetics of venlafaxine and

ODV are not substantially altered in the elderly.

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.