ADVERSE REACTIONS 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 * 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 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 2Treatment-Emergent Adverse Experience Incidence in 4 to 8 Week Placebo-Controlled Clinical Trials1 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 dysmenorrhea3. — Incidence less than 1%. 2Incidence based on number of male patients. 3Incidence based on number of female patients. Body System Preferred Term Venlafaxine Tablets 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 3Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial 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). Vital Sign Changes 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 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 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 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 placebocontrolled 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 (see PRECAUTIONS-General-Serum Cholesterol Elevation). 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 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 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 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 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, angle-closure 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.