Effexor XR Side Effects

Generic Name: venlafaxine

Please note - some side effects for Effexor XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Effexor XR - for the Consumer

Effexor XR Extended-Release Capsules

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Effexor XR Extended-Release Capsules:

Abnormal dreams; blurred vision; changes in taste; constipation; decreased sexual desire or ability; dizziness; drowsiness; dry mouth; flushing; headache; increased sweating; loss of appetite; nausea; nervousness; stomach upset; trouble sleeping; vomiting; weakness; weight loss; yawning.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bizarre behavior; blood in the stool; chest pain or discomfort; confusion; decreased concentration; decreased coordination; decreased urination; fainting; fast or irregular heartbeat; fever, chills, or sore throat; hallucinations; memory problems; new or worsening aggressiveness, agitation, anxiety, hostility, impulsiveness, inability to sit still, irritability, panic attacks, or restlessness; persistent or severe ringing in the ears; red, swollen, blistered, or peeling skin; seizures; severe or persistent anxiety, nervousness, or trouble sleeping; severe or persistent cough; severe or persistent headache, dizziness, stomach pain, or weakness; shortness of breath; significant weight loss; suicidal thoughts or attempts; tremor; trouble concentrating; unusual bruising or bleeding; unsteadiness or loss of coordination; unusual or severe mental or mood changes; unusual weakness; vision problems; worsening of depression.

Effexor XR Extended-Release Tablets

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Effexor XR Extended-Release Tablets:

Abnormal dreams; blurred vision; changes in taste; constipation; decreased sexual desire or ability; dizziness; drowsiness; dry mouth; flushing; headache; increased sweating; loss of appetite; nausea; nervousness; stomach upset; trouble sleeping; vomiting; weakness; weight loss; yawning.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bizarre behavior; blood in the stool; chest pain or discomfort; confusion; decreased concentration; decreased coordination; decreased urination; fainting; fast or irregular heartbeat; fever, chills, or sore throat; hallucinations; memory problems; new or worsening aggressiveness, agitation, anxiety, hostility, impulsiveness, inability to sit still, irritability, panic attacks, or restlessness; persistent or severe ringing in the ears; red, swollen, blistered, or peeling skin; seizures; severe or persistent anxiety, nervousness, or trouble sleeping; severe or persistent cough; severe or persistent headache, dizziness, stomach pain, or weakness; shortness of breath; significant weight loss; suicidal thoughts or attempts; tremor; trouble concentrating; unsteadiness or loss of coordination; unusual bruising or bleeding; unusual or severe mental or mood changes; unusual weakness; vision problems; worsening of depression.

Effexor XR Side Effects - for the Professional

Effexor XR

The information included in the Adverse Findings Observed in Short-Term, Placebo‑Controlled Studies with Effexor XR 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), on data up to 8 weeks from a pool of five controlled clinical trials in GAD with Effexor XR®, on data up to 12 weeks from a pool of five controlled clinical trials in Social Anxiety Disorder, 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 Effexor XR in the entire development program for the formulation and with Effexor (immediate release) is included in the Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR subsection.

Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Effexor XR

Approximately 11% of the 357 patients who received Effexor XR® (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 18% of the 1381 patients who received Effexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 15% of the 819 patients who received Effexor XR capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 695 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received Effexor XR 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 (ie, leading to discontinuation in at least 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for any indication) are shown in Table 6.

Tables 7, 8, 9, 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), of GAD (up to 8 weeks; dose range of 37.5 to 225 mg/day), of Social Anxiety 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 Effexor XR (venlafaxine hydrochloride) where the incidence in patients treated with Effexor XR 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, 8, 9, and 10:

Major Depressive Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR 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 Effexor XR-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.

Generalized Anxiety Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for all placebo-controlled trials for the GAD indication (Table 8): Abnormalities of sexual function (abnormal ejaculation and impotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation), problems of special senses (abnormal vision), and sweating.

Social Anxiety Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR patients and at a rate at least twice that of the placebo group for the 5 placebo-controlled trials for the Social Anxiety Disorder indication (Table 9): Asthenia, gastrointestinal complaints (anorexia, constipation, dry mouth, nausea), CNS complaints (insomnia, libido decreased, nervousness, somnolence, tremor), abnormalities of sexual function (abnormal ejaculation, impotence), yawn, and sweating.

In the 6-month trial, the following adverse events occurred twice as often in the 150-225 mg/day Effexor XR group compared to the 75 mg/day Effexor XR group and placebo: vasodilation, libido decreased, tremor, yawn, abnormal vision, and impotence.

Panic Disorder

Note in particular the following adverse events that occurred in at least 5% of the Effexor XR 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.

Vital Sign Changes

Effexor XR (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. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo‑controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 3 beats per minute, compared with an increase of 1 beat per minute for placebo. Effexor XR 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.

In a flexible-dose study, with Effexor (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

Effexor XR (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. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Effexor XR 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 Effexor (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.

Effexor XR treatment for up to 12 weeks in pooled premarketing Social Anxiety Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 8.2 mg/dL, compared with a mean final increase of 0.4 mg/dL for placebo. Effexor XR treatment for up to 6 months in a premarketing Social Anxiety Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 11.8 mg/dL, compared with a mean final on-therapy increase of 1.8 mg/dL for placebo.

Effexor XR 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. Effexor XR 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 Effexor (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.

Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR

During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies, 819 patients in Phase 3 Social Anxiety Disorder studies, and 1314 patients in Phase 3 panic disorder studies. In addition, in premarketing assessment of Effexor, 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 (Effexor only) and outpatient studies, fixed-dose, and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 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, 8, 9, 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, 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

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, 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, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, serotonin syndrome, 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.

Side Effects by Body System

Gastrointestinal

Gastrointestinal side effects have frequently included nausea (up to 35%), dry mouth (14% to 18%), constipation (12%), anorexia (12% to 23%), vomiting, diarrhea (5% to 12%), eructation, abdominal pain, and flatulence.

Gastrointestinal side effects reported in premarketing Phase 3 trials have included increased appetite, bruxism, colitis, dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration, abdominal distention, 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, and tongue discoloration.

Nervous system

Seizures have been reported in 0.26% of treated patients during premarketing testing. The manufacturer recommends that therapy be discontinued in patients who develop seizures.

The impact of venlafaxine on pain summation may indicate a potential analgesic effect for clinical neuropathic pain.

Nearly all selective serotonin reuptake inhibitors, mixed serotonin/norepinephrine reuptake inhibitors, and tricyclic antidepressants cause sleep abnormalities to some extent. These antidepressants have marked dose-dependent effects on rapid eye movement (REM) sleep, causing reductions in the overall amount of REM sleep over the night and delays the first entry into REM sleep (increased REM sleep onset latency (ROL)), both in healthy subjects and depressed patients. The antidepressants that increase serotonin function appear to have the greatest effect on REM sleep. The reduction in REM sleep is greatest early in treatment, but gradually returns towards baseline during long-term therapy; however, ROL remains long. Following discontinuation of therapy the amount of REM sleep tends to rebound. Some of these drugs (i.e., bupropion, mirtazapine, nefazodone, trazodone, trimipramine) appear to have a modest or minimal effect on REM sleep.

Nervous system side effects have frequently included dizziness (16%), somnolence (up to 14%), insomnia (11% to 25%), fatigue (11%), nervousness (9%), abnormal dreams, sleep abnormalities, tremor, depression, paresthesia, decreased libido, agitation, hypertonia, anxiety, delirium, and twitching. The reported incidence of each of these effects ranges between 10% and 20% of treated patients. Dyskinesia has also been reported.

Venlafaxine has been reported to increase the pain tolerance threshold to electrical sural nerve stimulation and the threshold at which pain increases (pain summation).

One case of serotonin syndrome has been reported which is believed to have been precipitated by the combination of venlafaxine and trazodone.

One small study has suggested that venlafaxine may improve attention, concentration, memory, and reaction time performance after single oral doses.

Nervous system side effects reported in premarketing Phase 3 trials have included amnesia, confusion, depersonalization, hypesthesia, abnormal thinking, trismus, vertigo, akathisia, apathy, ataxia, circumoral paresthesia, central nervous system (CNS) stimulation, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, myoclonus, neuralgia, neuropathy, seizure, abnormal speech, stupor, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, dementia, dystonia, increased energy, facial paralysis, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, increased libido, motion sickness, neuritis, nystagmus, paresis, decreased or increased reflexes, and torticollis. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Impaired coordination and balance have been reported in postmarketing studies.

Cardiovascular

Cardiovascular side effects have frequently included vasodilatation, hypertension, palpitation, postural hypotension, and tachycardia.

Cardiovascular side effects reported in premarketing Phase 3 trials have included angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope, thrombophlebitis, 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, and sinus arrhythmia. Although these events occurred during treatment with venlafaxine, causality has not been determined.

There are reports of sustained hypertension (some requiring immediate treatment). Experience with the immediate-release venlafaxine showed that sustained hypertension was dose-related, increasing from 3% to 7% at 100 to 300 mg/day to 13% at doses above 300 mg/day. There are not sufficient data with the use of venlafaxine extended-release at doses above 300 mg/day to determine the incidence of sustained increases in blood pressure at these high doses.

One study has reported average systolic blood pressure increases of 1.7 to 3.4 mm Hg and average diastolic pressure increases of 0.4 to 2.6 mm Hg. The same study reported an increase in the average pulse rate of 1.1 to 4.5 beats per minute.

Another study (n=7) suggests that venlafaxine may promote adverse cardiovascular and cerebrovascular events by increasing platelet activity in susceptible patients.

An increase in heart rate of 4 beats per minute has been reported.

According to a retrospective review, in the overdose setting (up to 3 g of venlafaxine), tachycardia, hypertension, mydriasis, QTc prolongation, and transient arrhythmia can be expected. Tachycardia and QTc prolongation appear to occur in a dose-dependent manner.

In one case report, venlafaxine (75 mg 3 times/day) may have contributed to an elevation in defibrillation threshold in a patient with nonischemic cardiomyopathy and an implantable cardioverter- defibrillator. Additional data are required to confirm this finding.

Genitourinary

One case of unexpected orgasm and subsequent ejaculation with no erection as well as orgasmic episodes with no ejaculation or erection has also been reported. A case of increased libido and spontaneous erections has also been reported.

Although rare, several cases of venlafaxine- induced urinary symptoms including nocturia, enuresis, increased urge/frequency, and incontinence have been reported. Symptoms resolved following discontinuation of therapy.

Genitourinary side effects have frequently included male and female sexual dysfunction such as abnormal ejaculation in up to 16% of male patients, decreased libido (13%), impotence (13%), and organic dysfunction (anorgasmia or abnormal orgasm) in up to 8% of female patients.

Genitourinary side effects reported in premarketing Phase 3 trials have included prostatic disorder (prostatitis, enlarged prostate, and prostate irritability), impaired urination, albuminuria, amenorrhea, cystitis, dysuria, hematuria, leukorrhea, menorrhagia, metrorrhagia, nocturia, breast pain, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage, vaginitis, 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, mastitis, menopause, oliguria, salpingitis, urolithiasis, uterine hemorrhage, uterine spasm, and vaginal dryness. Although these events occurred during treatment with venlafaxine, causality has not been determined.

There is a single case report of breast pain associated with venlafaxine therapy.

Dermatologic

At least 3 cases of venlafaxine- induced alopecia have been reported. In all cases, hair re- growth occurred within 2 to 4 weeks following discontinuation of venlafaxine.

Dermatologic side effects have included sweating in up to approximately 14% of treated patients. Dermatologic side effects reported in premarketing Phase 3 trials have included pruritus, acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria, 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, and decreased sweating. Although these events occurred during treatment with venlafaxine, causality has not been determined. There have been postmarketing reports of toxic epidermal necrolysis.

One case of venlafaxine-induced Stevens-Johnson syndrome has been reported. Symptoms resolved following treatment with IV steroids and antidepressant therapy was safely switched to paroxetine. In addition, at least one case of photo-induced telangiectasia has been associated with venlafaxine use.

Other

Withdrawal effects occur upon abrupt discontinuation of treatment and the severity of symptoms appears to be dependent on length of therapy and dose (including low dose therapy). Symptoms can be minimized by slow tapering or switching to a drug with a longer half-life (e.g., fluoxetine). Withdrawal symptoms were reported to include brief bursts of dizziness associated with headache, anxiety, irritability, agitation, insomnia, paresthesias, nausea, vomiting, diarrhea, tremor, fatigue, sweating, and worsening of depression (similar to symptoms reported after withdrawal from selective serotonin reuptake inhibitors). The onset of withdrawal symptoms ranges from 14 to 48 hours after the last dose of venlafaxine extended-release and symptoms tend to resolve rapidly (range, within 2 to 24 hours) after resumption of therapy. In the event that therapy is not reintroduced, withdrawal symptoms may last from 5 to 7 days before resolving spontaneously.

In one case report, withdrawal- induced full mania developed in a 33- year- old patient following abrupt termination of treatment with venlafaxine extended-release (150 mg daily for 10 weeks).

Other side effects have frequently included asthenia (up to 21%), headache (up to 34%), flu syndrome (6%), and accidental injury (5%).

Other side effects reported in premarketing Phase 3 trials have included edema, hyperacusis, otitis media, parosmia, loss of taste, deafness, labyrinthitis, otitis externa, substernal chest pain, chills, fever, neck pain, face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, appendicitis, bacteremia, carcinoma, and cellulitis. Although these events occurred during treatment with venlafaxine, causality has not been determined.

One case of anasarca was reported in a patient receiving venlafaxine. Following discontinuation of venlafaxine, symptoms resolved within approximately 72 hours. The authors state that it is possible that the anasarca was due to an allergic or delayed- type hypersensitivity reaction given the circumstances.

There are numerous case reports of withdrawal symptoms following abrupt discontinuation of treatment, and a single case report of severe tinnitus associated with venlafaxine.

Hepatic

Hepatic side effects have included toxic hepatitis. In one case, toxic hepatitis associated with low dose (37.5 mg/day) venlafaxine was reported in a patient with a history of chronic hepatitis.

Endocrine

Endocrine side effects have included flushing.

Endocrine side effects reported in premarketing Phase 3 trials have rarely included galactorrhea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, and thyroiditis. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Psychiatric

Psychiatric side effects have included visual hallucinations, hypomania, and mania.

Psychiatric side effects reported in premarketing Phase 3 trials have included emotional lability, delusions, euphoria, hallucinations, manic reaction, psychosis, suicidal ideation, abnormal/changed behavior, homicidal ideation, paranoid reaction, and psychotic depression. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Hematologic

Hematologic side effects have included have frequently included abnormal bleeding (most commonly ecchymosis).

Hematologic side effects reported in premarketing Phase 3 trials have included anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, basophilia, increased bleeding time, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, and thrombocytopenia. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Musculoskeletal

Musculoskeletal side effects have included rhabdomyolysis.

Musculoskeletal side effects reported in premarketing Phase 3 trials have included arthralgia, arthritis, arthrosis, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis, bone pain, pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, and tendon rupture. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Ocular

Ocular side effects have included abnormal vision, primarily blurred vision, in approximately 6% of patients. Angle-closure glaucoma has been reported rarely.

Ocular side effects reported in premarketing Phase 3 trials have included abnormality of accommodation, mydriasis, conjunctivitis, diplopia, dry eyes, eye pain, photophobia, visual field defect, blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, exophthalmos, eye hemorrhage, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis, miosis, papilledema, decreased pupillary reflex, scleritis, and uveitis. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Metabolic

A recent short-term study (6 weeks) has reported an average weight loss of 2 to 3 pounds in patients treated with venlafaxine.

Numerous cases of hyponatremia have been reported following treatment with a selective serotonin reuptake inhibitor (SSRI). Risk factors for the development of SSRI- associated hyponatremia including advanced age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium levels have been identified. Hyponatremia tends to develop within the first few weeks of treatment (range 3 to 120 days) and typically resolves within 2 weeks (range 48 hours to 6 weeks) after therapy has been discontinued with some patients requiring treatment. The proposed mechanism for the development of hyponatremia involves the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) via release of antidiuretic hormone.

Use of venlafaxine has been associated with small but statistically significant increases in total cholesterol, high- density lipoprotein cholesterol and low- density lipoprotein cholesterol.

Metabolic side effects have included weight loss (3%).

Metabolic side effects reported in premarketing Phase 3 trials have included weight gain, increased alkaline phosphatase, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemia, increased SGOT (AST), increased SGPT (ALT), thirst, bilirubinemia, increased BUN, increased creatinine, diabetes mellitus, glycosuria, gout, abnormal healing, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hyponatremia, hypophosphatemia, hypoproteinemia, and uremia. Although these events occurred during treatment with venlafaxine, causality has not been determined.

There have been a minimum of approximately fifteen cases of hyponatremia in which at least one was life threatening, including at least one case of recurrent venlafaxine- induced hyponatremia after rechallenge.

Renal

Renal side effects reported in premarketing Phase 3 trials have included kidney calculus, kidney pain, abnormal kidney function, and pyelonephritis. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Respiratory

Respiratory side effects have frequently included pharyngitis, sinusitis, and yawning.

Respiratory side effects reported in premarketing Phase 3 trials have included increased cough, dyspnea, asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration, atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, and sleep apnea. Although these events occurred during treatment with venlafaxine, causality has not been determined.

Although rare, interstitial pneumonitis secondary to venlafaxine therapy has been reported. The onset of venlafaxine- associated interstitial pneumonitis has ranged from 1 to 18 months after initial exposure to the drug and symptomatic improvement occurred after discontinuation of venlafaxine and treatment with corticosteroids.

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