VENLAFAXINE HYDROCHLORIDE

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 C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below. Venlafaxine hydrochloride is a white crystalline powder. It is freely soluble in water and dilute hydrochloric acid, soluble in ethanol and chloroform and insoluble in ether. Each venlafaxine hydrochloride tablet 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 yellow, ferric oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. VenlafaxineHcl Structural Formula

Venlafaxine hydrochloride tablets are indicated for the treatment of major depressive disorder. The efficacy of venlafaxine hydrochloride tablets 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 (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 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 hydrochloride 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 (see CLINICAL TRIALS). Nevertheless, the physician who elects to use venlafaxine hydrochloride tablets/venlafaxine hydrochloride extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Initial Treatment The recommended starting dose for venlafaxine hydrochloride 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 (see PRECAUTIONS, General, Use in Patients with Concomitant Illness). Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to venlafaxine hydrochloride tablets, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with venlafaxine hydrochloride tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering venlafaxine hydrochloride tablets in the third trimester. Dosage for Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), 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. Dosage for Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 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% 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. Dosage for Elderly 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. Maintenance Treatment 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 hydrochloride 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 hydrochloride tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of venlafaxine hydrochloride 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. Discontinuing Venlafaxine Hydrochloride Tablets Symptoms associated with discontinuation of venlafaxine hydrochloride tablets, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). 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 PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with venlafaxine hydrochloride tablets. In addition, at least 7 days should be allowed after stopping venlafaxine hydrochloride tablets before starting an MAOI (see CONTRAINDICATIONS ).

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation. Venlafaxine hydrochloride Tablets must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with SNRI or SSRI treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine hydrochloride tablets before starting an MAOI (see DOSAGE AND ADMINISTRATION).

Associated with Discontinuation of Treatment Nineteen percent (537/2897) of venlafaxine patients in Phase 2 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 Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% - Nervousness 2% - Dry mouth 2% - Anxiety 2% 1% Gastrointestinal Nausea 6% Urogenital Abnormal 3% - ejaculation* Other Headache 3% 1% Asthenia 2% - Sweating 2% - *Percentages based on the number of males. Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of venlafaxine hydrochloride tablets (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine hydrochloride 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 Hydrochloride 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 hydrochloride 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 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 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials 1 Body System Preferred term Venlafaxine Hydrochloride Tablets (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 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% - Abnormal ejaculation/Orgasm 12% 2 - 2 Impotence 6% 2 - 2 Urinary frequency 3% 2% Urination impaired 2% - Orgasm disturbance 2% 3 - 3 1 2%Events reported by at least 1% of patients treated with venlafaxine hydrochloride tablets are included, and are rounded to the nearest %. Events for which the venlafaxine hydrochloride 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‡. - Incidence less than 1%. 2 Incidence based on number of male patients. 3 Incidence based on number of female patients. Dose Dependency of Adverse Events A comparison of adverse event rates in a fixed-dose study comparing venlafaxine hydrochloride tablets 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine hydrochloride 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 hydrochloride 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 Body System / Preferred Term Venlafaxine Hydrochloride Tablets (mg/day) Venlafaxine Hydrochloride Tablets (mg/day) Venlafaxine Hydrochloride Tablets (mg/day) Venlafaxine Hydrochloride Tablets (mg/day) Placebo (n=92) 75 (n=89) 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% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% 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 Venlafaxine hydrochloride 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 200 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 hydrochloride 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). Laboratory Changes Of the serum chemistry and hematology parameters monitored during clinical trials with venlafaxine hydrochloride tablets, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with venlafaxine hydrochloride tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated with venlafaxine hydrochloride 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 0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation). ECG Changes In an analysis of ECGs obtained in 769 patients treated with venlafaxine hydrochloride 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 hydrochloride tablets. In a flexible-dose study, with doses in the range of 200 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 (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 venlafaxine hydrochloride tablets were administered to 2897 patients in Phase 2 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 hydrochloride 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 double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine hydrochloride 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 2 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, carcinoma, cellulitis. 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, cardiovascular disorder (mitral valve and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, 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, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction, 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, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, petechial rash, 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, eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis. Urogenital system—Frequent: metrorrhagia*, prostatic disorder (prostatitis and enlarged prostate)*, vaginitis*; Infrequent: albuminuria, amenorrhea*, cystitis, dysuria, hematuria, leukorrhea*, menorrhagia*, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal hemorrhage*; Rare: abortion*, anuria, balanitis*, 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, female lactation*, mastitis, menopause*, oliguria, orchitis*, pyelonephritis, salpingitis*, urolithiasis, uterine hemorrhage*, uterine spasm*, vaginal dryness*. *Based on the number of men and women as appropriate. Postmarketing Reports Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, 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), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine 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.

Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] in a dry place. Dispense in a well-closed container as defined in the USP.