icidal ideation. the efficacy of venlafaxine hcl extended-release capsules in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. the efficacy of venlafaxine tablets immediate-release in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see clinical trials ). nevertheless, the physician who elects to use venlafaxine tablets immediate-release/venlafaxine hcl extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

major depressive disorder (mdd) and other psychiatric disorders. short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. the pooled analyses of placebo-controlled trials in children and adolescents with mdd, obsessive compulsive disorder (ocd), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. the pooled analyses of placebo-controlled trials in adults with mdd or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. there was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. there were differences in absolute risk of suicidality across the different indications, with the highest incidence in mdd. the risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. these risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in table 1. table 1: age range drug-placebo difference in number of cases of suicidality per 1000 patients treated increases compared to placebo <18 14 additional cases 18 to 24 5 additional cases decreases compared to placebo 25 to 64 1 fewer case ≥65 6 fewer cases no suicides occurred in any of the pediatric trials. there were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. it is unknown whether the suicidality risk extends to longer-term use, i.e. beyond several months. however, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. all patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. the following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. if the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see precautions and dosage and administration, discontinuation of treatment with venlafaxine hcl , for a description of the risks of discontinuation of venlafaxine hcl). families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. such monitoring should include daily observation by families and caregivers. prescriptions for venlafaxine hcl should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. screening patients for bipolar disorder a major depressive episode may be the initial presentation of bipolar disorder. it is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. whether any of the symptoms described above represent such a conversion is unknown. however, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. it should be noted that venlafaxine hcl is not approved for use in treating bipolar depression. serotonin syndrome the development of a potentially life-threatening serotonin syndrome has been reported with snris and ssris, including venlafaxine hcl, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and st. john’s wort) and with drugs that impair metabolism of serotonin (in particular, maois, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). patients should be monitored for the emergence of serotonin syndrome. the concomitant use of venlafaxine hcl with maois intended to treat psychiatric disorders is contraindicated. venlafaxine hcl should also not be started in a patient who is being treated with maois such as linezolid or intravenous methylene blue. all reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. no reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. there may be circumstances when it is necessary to initiate treatment with a maoi such as linezolid or intravenous methylene blue in a patient taking venlafaxine hcl. venlafaxine hcl should be discontinued before initiating treatment with the maoi (see contraindications and dosage and administration ). if concomitant use of venlafaxine hcl with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and st. john’s wort is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases. treatment with venlafaxine hcl and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. angle-closure glaucoma the pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. sustained hypertension venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) in a premarketing study comparing three fixed doses of venlafaxine (75, 225 and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (sdbp) of 7.2 mm hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in sdbp of 2.2 mm hg in the placebo group. (2) an analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent sdbp ≥ 90 mm hg and ≥ 10 mm hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine: probability of sustained elevation in sdbp (pool of premarketing venlafaxine studies) treatment group incidence of sustained elevation in sdbp venlafaxine < 100 mg/day 3% 101 to 200 mg/day 5% 201 to 300 mg/day 7% > 300 mg/day 13% placebo 2% an analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm hg, sdbp). nevertheless, sustained increases of this magnitude could have adverse consequences. cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. pre-existing hypertension should be controlled before treatment with venlafaxine. it is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. for patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. sexual dysfunction use of snris, including venlafaxine, may cause symptoms of sexual dysfunction (see adverse reactions ). in male patients, snri use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. in female patients, snri use may result in decreased libido and delayed or absent orgasm. it is important for prescribers to inquire about sexual function prior to initiation of venlafaxine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. when evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. discuss potential management strategies to support patients in making informed decisions about treatment.

venlafaxine tablets, other snris, or ssris, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding (see precautions ). when treating pregnant women with venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. dosage for patients with hepatic impairment given the decrease in clearance and increase in elimination half-life for both venlafaxine and odv that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see clinical pharmacology ), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. dosage for patients with renal impairment given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and odv that is observed in patients with renal impairment (gfr = 10 to 70 ml/min) compared to normals (see clinical pharmacology ), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. it is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. dosage for elderly patients no dose adjustment is recommended for elderly patients on the basis of age. as with any antidepressant, however, caution should be exercised in treating the elderly. when individualizing the dosage, extra care should be taken when increasing the dose. maintenance treatment it is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. in one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hcl extended-release capsules were assigned randomly to placebo or to the same dose of venlafaxine hcl extended-release capsules (75, 150, or 225 mg/day, qam) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. a second longer-term study has demonstrated the efficacy of venlafaxine tablets immediate-release in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine tablets immediate-release for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see clinical trials ). based on these limited data, it is not known whether or not the dose of venlafaxine tablets immediate-release/venlafaxine hcl extended-release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. discontinuing venlafaxine tablets symptoms associated with discontinuation of venlafaxine tablets, other snris and ssris, have been reported (see precautions ). patients should be monitored for these symptoms when discontinuing treatment. a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. if intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. subsequently, the physician may continue decreasing the dose but at a more gradual rate. switching a patient to or from a monoamine oxidase inhibitor (maoi) intended to treat psychiatric disorders: at least 14 days should elapse between discontinuation of an maoi intended to treat psychiatric disorders and initiation of therapy with venlafaxine tablets. conversely, at least 7 days should be allowed after stopping venlafaxine tablets before starting an maoi intended to treat psychiatric disorders (see contraindications ). use of venlafaxine tablets with other maois, such as linezolid or methylene blue: do not start venlafaxine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. in a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see contraindications ). in some cases, a patient already receiving therapy with venlafaxine tablets may require urgent treatment with linezolid or intravenous methylene blue. if acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. the patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. therapy with venlafaxine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see warnings ). the risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with venlafaxine tablets is unclear. the clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see warnings ).

patients (i.e. incidence for venlafaxine hcl 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 hcl-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 hcl-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 hcl (n=1033) placebo (n=609) 1 events reported by at least 1% of patients treated with venlafaxine hcl are included, and are rounded to the nearest %. events for which the venlafaxine hcl incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased and dysmenorrhea 3 . - incidence less than 1%. 2 incidence based on number of male patients. 3 incidence based on number of female patients. body as a whole headache 25% 24% asthenia 12% 6% infection 6% 5% chills 3% - chest pain 2% 1% trauma 2% 1% cardiovascular vasodilatation 4% 3% increased blood pressure/hypertension 2% - tachycardia 2% - postural hypotension 1% - dermatological sweating 12% 3% rash 3% 2% pruritus 1% - gastrointestinal nausea 37% 11% constipation 15% 7% anorexia 11% 2% diarrhea 8% 7% vomiting 6% 2% dyspepsia 5% 4% flatulence 3% 2% metabolic weight loss 1% - nervous system somnolence 23% 9% dry mouth 22% 11% dizziness 19% 7% insomnia 18% 10% nervousness 13% 6% anxiety 6% 3% tremor 5% 1% abnormal dreams 4% 3% hypertonia 3% 2% paresthesia 3% 2% libido decreased 2% - agitation 2% - confusion 2% 1% thinking abnormal 2% 1% depersonalization 1% - depression 1% - urinary retention 1% - twitching 1% - respiration yawn 3% - special senses blurred vision 6% 2% taste perversion 2% - tinnitus 2% - mydriasis 2% - urogenital system abnormal ejaculation/orgasm 12% 2 - 2 impotence 6% 2 - 2 urinary frequency 3% 2% urination impaired 2% - orgasm disturbance 2% 3 - 3 dose dependency of adverse events a comparison of adverse event rates in a fixed-dose study comparing venlafaxine hcl 75, 225 and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine hcl 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 hcl group. tests for potential dose relationships for these events (cochran-armitage test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating and abnormal ejaculation. table 3: treatment-emergent adverse experience incidence in a dose comparison trial body system/preferred term placebo (n=92) venlafaxine hcl (mg/day) 75 (n=89) 225 (n=89) 375 (n=88) body as a whole abdominal pain 3.3% 3.4% 2.2% 8% asthenia 3.3% 16.9% 14.6% 14.8% chills 1.1% 2.2% 5.6% 6.8% infection 2.2% 2.2% 5.6% 2.3% cardiovascular system hypertension 1.1% 1.1% 2.2% 4.5% vasodilatation 0% 4.5% 5.6% 2.3% digestive system anorexia 2.2% 14.6% 13.5% 17% dyspepsia 2.2% 6.7% 6.7% 4.5% nausea 14.1% 32.6% 38.2% 58% vomiting 1.1% 7.9% 3.4% 6.8% nervous system agitation 0% 1.1% 2.2% 4.5% anxiety 4.3% 11.2% 4.5% 2.3% dizziness 4.3% 19.1% 22.5% 23.9% insomnia 9.8% 22.5% 20.2% 13.6% libido decreased 1.1% 2.2% 1.1% 5.7% nervousness 4.3% 21.3% 13.5% 12.5% somnolence 4.3% 16.9% 18% 26.1% tremor 0% 1.1% 2.2% 10.2% respiratory system yawn 0% 4.5% 5.6% 8% skin and appendages sweating 5.4% 6.7% 12.4% 19.3% special senses abnormality of accommodation 0% 9.1% 7.9% 5.6% urogenital system abnormal ejaculation/orgasm 0% 4.5% 2.2% 12.5% impotence 0% 5.8% 2.1% 3.6% (number of men) (n=63) (n=52) (n=48) (n=56) adaptation to certain adverse events over a 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth). vital sign changes venlafaxine hcl 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 hcl 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 hcl, a statistically significant difference with placebo was seen only for serum cholesterol. in premarketing trials, treatment with venlafaxine tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dl. patients treated with venlafaxine tablets for at least 3 months in 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% of placebo-treated patients (see precautions, general , serum cholesterol elevation ). ecg changes in an analysis of ecgs obtained in 769 patients treated with venlafaxine hcl 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 hcl. 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 hcl immediate-release were administered to 2897 patients in phase 2 and phase 3 studies. in addition, in premarketing assessment of venlafaxine hcl extended-release, multiple doses were administered to 705 patients in phase 3 major depressive disorder studies and venlafaxine hcl immediate-release was administered to 96 patients. during its premarketing assessment, multiple doses of venlafaxine hcl extended-release 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 hcl immediate-release 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. to report suspected adverse reactions, contact amneal pharmaceuticals at 1-877-835-5472 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

t 92% of a single-dose of venlafaxine is absorbed. approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated odv (29%), conjugated odv (26%), or other minor inactive metabolites (27%). renal elimination of venlafaxine and its metabolites is the primary route of excretion. the relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. food has no significant effect on the absorption of venlafaxine or on the formation of odv. the degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/ml. the degree of odv binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/ml. protein-binding-induced drug interactions with venlafaxine are not expected. steady-state concentrations of both venlafaxine and odv in plasma were attained within 3 days of multiple-dose therapy. venlafaxine and odv exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and odv after multiple-dosing. mean ± sd steady-state plasma clearance of venlafaxine and odv is 1.3 ± 0.6 and 0.4 ± 0.2 l/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 l/kg and 5.7 ± 1.8 l/kg, respectively. when equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (auc) and fluctuation in plasma levels of venlafaxine and odv were comparable following both regimens. age and gender a pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or odv were unaltered due to age or gender differences. dosage adjustment based upon the age or gender of a patient is generally not necessary (see dosage and administration ). liver disease in 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and odv was significantly altered after oral administration of venlafaxine. venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. odv elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. a large degree of intersubject variability was noted. three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. in a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in child-pugh a (n = 8) and child-pugh b (n = 11) subjects (mildly and moderately impaired, respectively). venlafaxine oral bioavailability was increased 2 to 3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. in hepatically impaired subjects, odv oral elimination half-life was prolonged by about 40%, while oral clearance for odv was similar to that for normal subjects. a large degree of intersubject variability was noted. dosage adjustment is necessary in these hepatically impaired patients (see dosage and administration ). renal disease in a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (gfr = 10 to 70 ml/min), compared to normal subjects. in dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. similarly, odv elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (gfr = 10 to 70 ml/min) compared to normal subjects. in dialysis patients, odv elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. a large degree of intersubject variability was noted. dosage adjustment is necessary in these patients (see dosage and administration ).

20° to 25°c (68° to 77°f) [see usp controlled room temperature], in a dry place. dispense in a well-closed container as defined in the usp. distributed by: amneal pharmaceuticals llc bridgewater, nj 08807 rev. 01-2023-06