Venlafaxine (Page 5 of 8)
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.
Electroconvulsive Therapy
There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine tablets, USP treatment.
Postmarketing Spontaneous Drug Interaction Reports
See ADVERSE REACTIONS, Postmarketing Reports.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Mutagenicity
Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose.
Impairment of Fertility
Reproduction and fertility studies of venlafaxine in rats showed no adverse effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mg/day on a mg/m2 basis.
However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day.
Pregnancy
Teratogenic Effects
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects
Neonates exposed to venlafaxine tablets, USP, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS, Drug Interactions, CNS-Active Drugs). When treating a pregnant woman with venlafaxine tablets, USP during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).
Labor and Delivery
The effect of venlafaxine tablets, USP on labor and delivery in humans is unknown.
Nursing Mothers
Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from venlafaxine tablets, USP, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.
Anyone considering the use of venlafaxine tablets, USP in a child or adolescent must balance the potential risks with the clinical need.
Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsule’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with venlafaxine tablets, USP, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of venlafaxine hydrochloride extended-release capsule treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.
In the studies conducted in pediatric patients (ages 6 to 17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension and PRECAUTIONS, General, Serum Cholesterol Elevation).
Geriatric Use
Of the 2,897 patients in Phase 2 and Phase 3 depression studies with venlafaxine tablets, USP, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including venlafaxine tablets, USP, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION).
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:
| Venlafaxine | Placebo | |
| CNS | ||
| 3% | 1% |
| 3% | 1% |
| 3% | – |
| 2% | – |
| 2% | – |
| 2% | 1% |
| Gastrointestinal | ||
| 6% | 1% |
| Urogenital | ||
| 3% | – |
| Other | ||
| 3% | 1% |
| 2% | – |
| 2% | – |
* Percentages based on the number of males.
– Less than 1%
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, USP (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine tablets, USP 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, USP-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, USP-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 tablets, USP (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% | – | |
| Urogenital System | Abnormal ejaculation/orgasm | 12%2 | –2 |
| Impotence | 6%2 | –2 | |
| Urinary frequency | 3% | 2% | |
| Urination impaired | 2% | – | |
| Orgasm disturbance | 2%3 | –3 |
1 Events reported by at least 1% of patients treated with venlafaxine tablets, USP are included, and are rounded to the nearest %. Events for which the venlafaxine tablets, USP 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%.
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 tablets, USP 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine tablets, USP 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, USP 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
| Venlafaxine Tablets, USP (mg/day) | ||||
| Body System/Preferred Term | 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 tablets, USP 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, USP was 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, USP, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with venlafaxine tablets, USP was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL.
Patients treated with venlafaxine tablets, USP 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 tablets, USP 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, USP. 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, USP 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, USP was 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 tablets, USP 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.
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