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adverse reactions
ADVERSE REACTIONS The information included in the Adverse Findings Observed in Short-Term, Placebo-Controlled Studies With Venlafaxine Hydrochloride Extended-Release Capsules subsection is based on data from a pool of three 8 and 12 week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), and on data up to 12 weeks from a pool of four controlled clinical trials in panic disorder. Information on additional adverse events associated with venlafaxine hydrochloride extended-release capsules in the entire development program for the formulation and with venlafaxine hydrochloride tablets (immediate release) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Venlafaxine Hydrochloride Tablets and Venlafaxine Hydrochloride Extended-Release Capsules subsection (see also WARNINGS and PRECAUTIONS ). Adverse Findings Observed in Short-Term, Placebo-Controlled Studies With Venlafaxine Hydrochloride Extended-Release Capsules Adverse Events Associated With Discontinuation of Treatment Approximately 11% of the 357 patients who received venlafaxine hydrochloride extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received venlafaxine hydrochloride extended-release capsules in placebo-controlled clinical trials for panic disorder discontinued treatment due to an adverse experience, compared with 6% of the 662 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the venlafaxine hydrochloride extended-release capsule-treated patients at a rate at least twice that of placebo) are shown in Table 6 . Table 6: Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials Two of the major depressive disorder studies were flexible dose and one was fixed dose. Two of the panic disorder studies were flexible dose and two were fixed dose. Percentage of Patients Discontinuing Due to Adverse Event Adverse Event Major Depressive Disorder Indication In U.S. placebo-controlled trials for major depressive disorder, the following were also common events leading to discontinuation and were considered to be drug-related for venlafaxine hydrochloride extended-release capsule-treated patients (% venlafaxine hydrochloride extended-release capsules [n = 192], % Placebo [n = 202]): hypertension (1%, < 1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%). Panic Disorder Indication Venlafaxine Hydrochloride Extended-Release Capsules Placebo Venlafaxine Hydrochloride Extended-Release Capsules Placebo n = 357 n = 285 n = 1001 n = 662 Body as a Whole Asthenia -- -- 1% 0% Headache -- -- -- -- Digestive System Nausea 4% < 1% 2% < 1% Anorexia 1% < 1% -- -- Dry Mouth 1% 0% -- -- Vomiting -- -- -- -- Nervous System Dizziness 2% 1% -- -- Insomnia 1% < 1% 1% < 1% Somnolence 2% < 1% -- -- Nervousness -- -- -- -- Tremor -- -- -- -- Skin Sweating -- -- -- -- Urogenital System Impotence Incidence is based on the number of men (venlafaxine hydrochloride extended-release capsules = 454, placebo = 357). -- -- -- -- Adverse Events Occurring at an Incidence of 2% or More Among Venlafaxine Hydrochloride Extended-Release Capsule-Treated Patients Tables 7 and 10 enumerate the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day), and of panic disorder (up to 12 weeks; dose range of 37.5 to 225 mg/day), respectively, in 2% or more of patients treated with venlafaxine hydrochloride extended-release capsules where the incidence in patients treated with venlafaxine hydrochloride extended-release capsules was greater than the incidence for the respective placebo-treated patients. The 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. Commonly Observed Adverse Events From Tables 7 and 10 Major Depressive Disorder Note in particular the following adverse events that occurred in at least 5% of the venlafaxine hydrochloride extended-release capsule patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication ( Table 7 ): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional events occurred in at least 5% of venlafaxine hydrochloride extended-release capsule-treated patients (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. Panic Disorder Note in particular the following adverse events that occurred in at least 5% of the venlafaxine hydrochloride extended-release capsule patients and at a rate at least twice that of the placebo group for 4 placebo-controlled trials for the panic disorder indication ( Table 10 ): gastrointestinal complaints (anorexia, constipation, dry mouth), CNS complaints (somnolence, tremor), abnormalities of sexual function (abnormal ejaculation), and sweating. Table 7: Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Venlafaxine Hydrochloride Extended-Release Capsule Clinical Trials in Patients With Major Depressive Disorder Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated with venlafaxine hydrochloride extended-release capsules, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis. < 1% indicates an incidence greater than zero but less than 1%. Body System % Reporting Event Venlafaxine Hydrochloride Extended-Release Capsules Placebo Preferred Term (n = 357) (n = 285) Body as a Whole Asthenia 8% 7% Cardiovascular System Vasodilatation Mostly “hot flashes.” 4% 2% Hypertension 4% 1% Digestive System Nausea 31% 12% Constipation 8% 5% Anorexia 8% 4% Vomiting 4% 2% Flatulence 4% 3% Metabolic/Nutritional Weight Loss 3% 0% Nervous System Dizziness 20% 9% Somnolence 17% 8% Insomnia 17% 11% Dry Mouth 12% 6% Nervousness 10% 5% Abnormal Dreams Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 7% 2% Tremor 5% 2% Depression 3% < 1% Paresthesia 3% 1% Libido Decreased 3% < 1% Agitation 3% 1% Respiratory System Pharyngitis 7% 6% Yawn 3% 0% Skin Sweating 14% 3% Special Senses Abnormal Vision Mostly “blurred vision” and “difficulty focusing eyes.” 4% < 1% Urogenital System Abnormal Ejaculation (male) Mostly “delayed ejaculation.” , Incidence is based on the number of male patients. 16% < 1% Impotence 4% < 1% Anorgasmia (female) Mostly “delayed orgasm” or “anorgasmia.” , Incidence is based on the number of female patients. 3% < 1% Table 10: Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Venlafaxine Hydrochloride Extended-Release Capsule Clinical Trials in Panic Disorder Patients Adverse events for which the venlafaxine hydrochloride extended-release capsules reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, abnormal vision, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, nervousness, pain, paresthesia, pharyngitis, rash, rhinitis, and vomiting. < 1% means greater than zero but less than 1%. % Reporting Event Body System Preferred Term Venlafaxine Hydrochloride Extended-Release Capsules (n = 1001) Placebo (n = 662) Body as a Whole Asthenia 10% 8% Cardiovascular System Hypertension 4% 3% Vasodilatation Mostly “hot flushes.” 3% 2% Digestive System Nausea 21% 14% Dry Mouth 12% 6% Constipation 9% 3% Anorexia Mostly “decreased appetite” and “loss of appetite.” 8% 3% Nervous System Insomnia 17% 9% Somnolence 12% 6% Dizziness 11% 10% Tremor 5% 2% Libido Decreased 4% 2% Skin Sweating 10% 2% Urogenital System Abnormal Ejaculation Includes “delayed or retarded ejaculation” and “anorgasmia.” , Percentage based on the number of males (venlafaxine hydrochloride extended-release capsules = 335, placebo = 238). 8% < 1% Impotence 4% < 1% Orgasmic Dysfunction Includes “anorgasmia” and “delayed orgasm.” , Percentage based on the number of females (venlafaxine hydrochloride extended-release capsules = 666, placebo = 424). 2% < 1% Vital Sign Changes Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo (see WARNINGS , Sustained Hypertension and Elevations in Systolic and Diastolic Blood Pressure for effects on blood pressure). In a flexible-dose study, with venlafaxine hydrochloride tablet (immediate release) 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. Laboratory Changes Serum Cholesterol Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with venlafaxine hydrochloride tablets (immediate-release) 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 ). Serum Triglycerides Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in pooled premarketing Panic Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 5.9 mg/dL, compared with a mean final increase of 0.9 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 6 months in a premarketing Panic Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 9.3 mg/dL, compared with a mean final on-therapy decrease of 0.3 mg/dL for placebo. ECG Changes In a flexible-dose study, with venlafaxine hydrochloride tablet (immediate release) 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 , Use in Patients With Concomitant Illness .) Other Adverse Events Observed During the Premarketing Evaluation of Venlafaxine Hydrochloride Tablets and Venlafaxine Hydrochloride Extended-Release Capsules During their premarketing assessment, multiple doses of venlafaxine hydrochloride extended-release capsules 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 1314 patients in Phase 3 panic disorder studies. In addition, in premarketing assessment of venlafaxine hydrochloride tablets, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. 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 7212 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 Tables 7 and 10 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis, granuloma. Cardiovascular system - Frequent: migraine, tachycardia; Infrequent: angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), postural hypotension, syncope; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia, thrombophlebitis. Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, rectal disorder, salivary gland enlargement, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: galactorrhoea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia. Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipidemia, 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 spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: bone pain, pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking abnormal, 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, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis. Respiratory system - Frequent: cough increased, 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 - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: conjunctivitis, diplopia, dry eyes, eye pain, otitis media, parosmia, photophobia, taste loss; Rare: blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, hyperacusis, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual field defect. Urogenital system - Frequent: albuminuria, urination impaired; Infrequent: amenorrhea, * cystitis, dysuria, hematuria, kidney calculus, kidney pain, leukorrhea, * menorrhagia, * metrorrhagia, * nocturia, breast pain, polyuria, pyuria, prostatic disorder (prostatitis, enlarged prostate, and prostate irritability), * urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage, * vaginitis * ; Rare: abortion, * anuria, breast discharge, breast engorgement, balanitis, * breast enlargement, endometriosis, * female lactation, * fibrocystic breast, calcium crystalluria, cervicitis, * orchitis, * ovarian cyst, * bladder pain, prolonged erection, * gynecomastia (male), * hypomenorrhea, * kidney function abnormal, mastitis, menopause, * pyelonephritis, oliguria, salpingitis, * urolithiasis, uterine hemorrhage, * uterine spasm, * vaginal dryness. * * Based on the number of men and women as appropriate. Postmarketing Reports Adverse Events 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 extrasystoles, 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). Drug Interactions 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.