Venlafaxine Hydrochloride

1 INDICATIONS AND USAGE Venlafaxine hydrochloride extended-release capsules are indicated in adults for the treatment of: Major Depressive Disorder (MDD) [see Clinical Studies (14.1) ] Generalized Anxiety Disorder (GAD) [see Clinical Studies (14.2) ] Social Anxiety Disorder (SAD) [see Clinical Studies (14.3) ] Panic Disorder (PD) [see Clinical Studies (14.4) ] Venlafaxine hydrochloride extended-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of adults with: Major Depressive Disorder ( MDD ) ( 1 ) Generalized Anxiety Disorder ( GAD ) ( 1 ) Social Anxiety Disorder ( SAD ) ( 1 ) Panic Disorder ( PD ) ( 1 )

2 DOSAGE AND ADMINISTRATION Indication Starting Dose Target Dose Maximum Dose MDD ( 2.2 ) 37.5 to 75 mg/day 75 mg/day 225 mg/day GAD ( 2.3 ) 37.5 to 75 mg/day 75 mg/day 225 mg/day SAD ( 2.4 ) 75 mg/day 75 mg/day 75 mg/day PD ( 2.5 ) 37.5 mg/day 75 mg/day 225 mg/day Take once daily with food. Capsules should be taken whole; do not divide, crush, chew, or dissolve ( 2.1 ). When discontinuing treatment, reduce the dose gradually ( 2.10 , 5.7 ). Renal impairment: reduce the total daily dose by 25% to 50% in patients with renal impairment. Reduce the total daily dose by 50% or more in patients undergoing dialysis or with severe renal impairment ( 2.9 ). Hepatic impairment: reduce the daily dose by 50% in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment or hepatic cirrhosis, it may be necessary to reduce the dose by more than 50% ( 2.8 ). 2.1 General Administration Information Administer venlafaxine hydrochloride extended-release capsules as a single dose with food, either in the morning or in the evening at approximately the same time each day [see Clinical Pharmacology (12.3) ] . Swallow capsules whole with fluid. Do not divide, crush, chew, or place in water. The capsule may also be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets (spheroids). 2.2 Major Depressive Disorder For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 4 days. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more. 2.3 Generalized Anxiety Disorder For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 4 days. 2.4 Social Anxiety Disorder (Social Phobia) The recommended dose is 75 mg per day, administered in a single dose. There was no evidence that higher doses confer any additional benefit. 2.5 Panic Disorder The recommended starting dose is 37.5 mg per day of venlafaxine hydrochloride extended-release capsules for 7 days. Patients not responding to 75 mg per day may benefit from dose increases to a maximum of approximately 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 7 days. 2.6 Screen for Bipolar Disorder Prior to Starting Venlafaxine Hydrochloride Extended-Release Capsules Prior to initiating treatment with venlafaxine hydrochloride extended-release capsules, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6) ] . 2.7 Switching Patients from Effexor Tablets Patients with depression who are currently being treated with Effexor may be switched to venlafaxine hydrochloride extended-release capsules at the nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg venlafaxine hydrochloride extended-release capsules once daily. However, individual dosage adjustments may be necessary. 2.8 Dosage Recommendations for Patients with Hepatic Impairment Reduce the venlafaxine hydrochloride extended-release capsules total daily dose by 50% in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Reduce the total daily dose by 50% or more in patients with severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis [see Use in Specific Populations (8.6) ] . 2.9 Dosage Recommendations for Patients with Renal Impairment Reduce the venlafaxine hydrochloride extended-release capsules total daily dose by 25% to 50% in patients with mild (CLcr 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. Reduce the total daily dose by 50% or more in patients undergoing hemodialysis or with severe renal impairment (CLcr < 30 mL/min). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage is recommended in some patients [see Use in Specific Populations (8.7) ] . 2.10 Discontinuing Treatment with Venlafaxine Hydrochloride Extended-Release Capsules A gradual reduction in the dose, rather than abrupt cessation, is recommended when discontinuing therapy with venlafaxine hydrochloride extended-release capsules. In clinical studies with venlafaxine hydrochloride extended-release capsules, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary. In some patients, discontinuation may need to occur over a period of several months [see Warnings and Precautions (5.7) ] . 2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of venlafaxine hydrochloride extended-release capsules. In addition, at least 7 days must elapse after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI antidepressant [see Contraindications (4) , Warnings and Precautions (5.2) , and Drug Interactions (7.1) ] .

3 DOSAGE FORMS AND STRENGTHS Venlafaxine hydrochloride extended-release capsules, USP are available in the following strengths: 37.5 mg extended-release capsule: white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘3’) of opaque grey color cap and opaque peach color body imprinted with “E” on cap and “73” on the body with edible black ink. 75 mg extended-release capsule: white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘1’) of opaque peach color cap and opaque peach color body imprinted with “E” on cap and “74” on the body with edible black ink. 150 m g extended-release capsule: white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘0’) of opaque dark orange color cap and opaque dark orange color body imprinted with “E” on cap and “89” on the body with edible black ink. Extended-release capsules: 37.5 mg, 75 mg, and 150 mg ( 3 ).

4 CONTRAINDICATIONS Venlafaxine hydrochloride extended-release capsules are contraindicated in patients: with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation [see Adverse Reactions (6.2) ] . taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome [see Dosage and Administration (2.11) , Warnings and Precautions (5.2) , and Drug Interactions (7.1) ] . Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the venlafaxine hydrochloride extended-release capsules formulation ( 4 ). Concomitant use of monoaminoxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI ( 4 , 5.2 , 7.1 ).

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue venlafaxine hydrochloride extended-release capsules and serotonergic agents and initiate supportive treatment ( 4 , 5.2 , 7.1 ). Elevated Blood Pressure : Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3 ). Increased Risk of Bleeding : Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk ( 5.4 ). Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles, treated with antidepressants ( 5.5 ). Activation of Mania or Hypomania : Screen patients for bipolar disorder ( 5.6 ). Discontinuation Syndrome : Taper dose and monitor for discontinuation symptoms ( 5.7 ). Seizures: Can occur. Use cautiously in patients with seizure disorder ( 5.8 ). Hyponatremia : Can occur in association with SIADH ( 5.9 ). Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.12 ). Sexual Dysfunction : Venlafaxine hydrochloride extended-release capsules may cause symptoms of sexual dysfunction ( 5.13 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥ 65 years old 6 fewer patients * Venlafaxine hydrochloride extended-release capsules are not approved in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing venlafaxine hydrochloride extended-release capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including venlafaxine hydrochloride extended-release capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7.1) ] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of venlafaxine hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate venlafaxine hydrochloride extended-release capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine hydrochloride extended-release capsules, discontinue venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7.1) ] . Monitor all patients taking venlafaxine hydrochloride extended-release capsules for the emergence of serotonin syndrome. Discontinue treatment with venlafaxine hydrochloride extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension [see Adverse Reactions (6.1) ] . Monitor blood pressure before initiating treatment with venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with venlafaxine hydrochloride extended-release capsules. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with venlafaxine hydrochloride extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure. Across all clinical studies with Effexor, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsules treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups [see Adverse Reactions (6.1) ]. Treatment with venlafaxine hydrochloride extended-release capsules was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits [see Adverse Reactions (6.1) ] . An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. 5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including venlafaxine hydrochloride extended-release capsules, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1) ] . Inform patients about the increased risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing venlafaxine hydrochloride extended-release capsules. 5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine hydrochloride extended-release capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including venlafaxine hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles. 5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with venlafaxine hydrochloride extended-release capsules or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in venlafaxine hydrochloride extended-release capsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with venlafaxine hydrochloride extended-release capsules, screen for any personal or family history of bipolar disorder, mania, or hypomania. Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Hydrochloride Extended-Release Capsules Treated Patients in the Premarketing Studies Indication Venlafaxine Hydrochloride Extended-Release Capsules Placebo MDD 0.3 0 GAD 0 0.2 SAD 0.2 0 PD 0.1 0 5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in venlafaxine hydrochloride extended-release capsules dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of venlafaxine hydrochloride extended-release capsules. During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures. Patients should be monitored for these symptoms when discontinuing treatment with venlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose, rather than abrupt cessation, is recommended. 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 healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months [see Dosage and Administration (2.10) ] . 5.8 Seizures Cases of seizure have been reported with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules has not been systematically evaluated in patients with seizure disorder. Venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder. 5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including venlafaxine hydrochloride extended-release capsules. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] . Consider discontinuation of venlafaxine hydrochloride extended-release capsules in patients with symptomatic hyponatremia, and institute appropriate medical intervention. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.10 Weight and Height Changes in Pediatric Patients Weight Changes The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5% or more) in the placebo-controlled pediatric studies in MDD, GAD, and SAD are shown in Tables 3 and 4. Table 3: Average Change in Body Weight (kg) From Beginning of Treatment in Pediatric Patients a in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n = 333) +0.77 (n = 333) SAD (16 weeks) -0.75 (n = 137) +0.76 (n = 148) a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. Table 4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p < 0.001 versus placebo Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) SAD (16 weeks) 47 b (n = 137) 14 (n = 148) Weight loss was not limited to patients with anorexia [see Warnings and Precautions (5.11) ] . The risks associated with longer term venlafaxine hydrochloride extended-release capsules use were assessed in an open-label MDD study of children and adolescents who received venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents in the study had increases in weight that were less than expected, based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [ Use in Specific Populations (8.4) ] . Height Changes Table 5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were most notable in patients younger than 12 years old. Table 5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p = 0.041 Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 b (n = 122) 1 (n = 132) SAD (16 weeks) 1 (n = 109) 1 (n = 112) In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected, based on data from age- and sex-matched peers. The difference between observed and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old) [see Use in Specific Populations (8.4) ] . 5.11 Appetite Changes in Pediatric Patients Decreased appetite (reported as anorexia) was more commonly observed in venlafaxine hydrochloride extended-release capsules treated patients versus placebo-treated patients in the premarketing evaluation of venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [see Use in Specific Populations (8.4) ] . Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules a The discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine hydrochloride extended-release capsules or placebo. b Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. Indication Venlafaxine Hydrochloride Extended-Release Capsules Placebo (Duration) Incidence Discontinuation Incidence Discontinuation MDD and GAD (pooled, 8 weeks) 10 0 3 - SAD (16 weeks) 22 0.7 3 0 5.12 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in venlafaxine hydrochloride extended-release capsules-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-release capsules should be considered. 5.13 Sexual Dysfunction Use of SNRIs, including venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1) ] . 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 hydrochloride extended-release capsules 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Hypersensitivity [see Contraindications (4) ] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1) ] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Elevated Blood Pressure [see Warnings and Precautions (5.3) ] Increased Risk of Bleeding [see Warnings and Precautions (5.4) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.5) ] Activation of Mania/Hypomania [see Warnings and Precautions (5.6) ] Discontinuation Syndrome [see Warnings and Precautions (5.7) ] Seizure [see Warnings and Precautions (5.8) ] Hyponatremia [see Warnings and Precautions (5.9) ] Weight and Height Changes in Pediatric Patients [see Warnings and Precautions (5.10) ] Appetite Changes in Pediatric Patients [see Warnings and Precautions (5.11) ] Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.12) ] Sexual Dysfunction [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, impotence (men), and libido decreased ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Most Common Adverse Reactions The most commonly observed adverse reactions in the clinical study database in venlafaxine hydrochloride extended-release capsules treated patients in MDD, GAD, SAD, and PD (incidence ≥5% and at least twice the rate of placebo) were: nausea (30%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%), and decreased libido (5.1%). Adverse Reactions Reported as Reasons for Discontinuation of Treatment Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the 3,558 patients who received venlafaxine hydrochloride extended-release capsules (37.5 to 225 mg) discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated patients in those studies. The most common adverse reactions leading to discontinuation in ≥1% of the venlafaxine hydrochloride extended-release capsules treated patients in the short-term studies (up to 12 weeks) across indications are shown in Table 7. Table 7: Incidence (%) of Patients Reporting Adverse Reactions Leading to Discontinuation in Placebo-controlled Clinical Studies (up to 12 Weeks Duration) Body System Adverse Reaction Venlafaxine Hydrochloride Extended-Release Capsules n = 3,558 Placebo n = 2,197 Body as a whole Asthenia 1.7 0.5 Headache 1.5 0.8 Digestive system Nausea 4.3 0.4 Nervous system Dizziness 2.2 0.8 Insomnia 2.1 0.6 Somnolence 1.7 0.3 Skin and appendages 1.5 0.6 Sweating 1 0.2 Common Adverse Reactions in Placebo-controlled Studies The number of patients receiving multiple doses of venlafaxine hydrochloride extended-release capsules during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all 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. Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-Release Capsules in Premarketing Clinical Studies a In addition, in the premarketing assessment of Effexor, multiple doses were administered to 2,897 patients in studies for MDD. Indication Venlafaxine Hydrochloride Extended-Release Capsules MDD 705 a GAD 1,381 SAD 819 PD 1,314 The incidences of common adverse reactions (those that occurred in ≥2% of venlafaxine hydrochloride extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride extended-release capsules treated patients in short-term, placebo-controlled, fixed- and flexible-dose clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9. The adverse reaction profile did not differ substantially between the different patient populations. Table 9: Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (≥2% and > placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications a Percentages based on the number of men (venlafaxine hydrochloride extended-release capsules, n = 1,440; placebo, n = 923) b Percentages based on the number of women (venlafaxine hydrochloride extended-release capsules, n = 2,118; placebo, n = 1,274) Body System Adverse Reaction Venlafaxine Hydrochloride Extended-Release Capsules n = 3,558 Placebo n = 2,197 Body as a whole Asthenia 12.6 7.8 Cardiovascular system Hypertension 3.4 2.6 Palpitation 2.2 2 Vasodilatation 3.7 1.9 Digestive system Anorexia 9.8 2.6 Constipation 9.3 3.4 Diarrhea 7.7 7.2 Dry mouth 14.8 5.3 Nausea 30 11.8 Vomiting 4.3 2.7 Nervous system Abnormal dreams 2.9 1.4 Dizziness 15.8 9.5 Insomnia 17.8 9.5 Libido decreased 5.1 1.6 Nervousness 7.1 5 Paresthesia 2.4 1.4 Somnolence 15.3 7.5 Tremor 4.7 1.6 Respiratory system Yawn 3.7 0.2 Skin and appendages Sweating (including night sweats) 11.4 2.9 Special senses Abnormal vision 4.2 1.6 Urogenital system Abnormal ejaculation/orgasm (men) a 9.9 0.5 Anorgasmia (men) a 3.6 0.1 Anorgasmia (women) b 2 0.2 Impotence (men) a 5.3 1 Other Adverse Reactions Observed in Clinical Studies Body as a Whole – Photosensitivity reaction, chills Cardiovascular System – Postural hypotension, syncope, hypotension, tachycardia Digestive System – Gastrointestinal hemorrhage [see Warnings and Precautions (5.4) ] , bruxism Hemic/Lymphatic System – Ecchymosis [see Warnings and Precautions (5.4) ] Metabolic/Nutritional – Hypercholesterolemia, weight gain [see Warnings and Precautions (5.10) ] , weight loss [see Warnings and Precautions (5.10) ] Nervous System – Seizures [see Warnings and Precautions (5.8) ] , manic reaction [see Warnings and Precautions (5.6) ] , agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy Skin and Appendages – Urticaria, pruritus, rash, alopecia Special Senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion Urogenital System – Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia) Vital Sign Changes In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with venlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SDBP of ≥15 mm Hg along with a blood pressure ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SSBP of ≥20 mm Hg with a blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups. Table 10: Final On-therapy Mean Changes from Baseline in Supine Systolic (SSBP) and Diastolic (SDBP) Blood Pressure (mm Hg) in Placebo-controlled Studies Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo ≤75 mg per day > 75 mg per day SSBP SDBP SSBP SDBP SSBP SDBP MDD (8 to 12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.1 GAD (8 weeks) -0.28 0.02 2.4 1.68 -1.26 -0.92 (6 months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 SAD (12 weeks) -0.29 -1.26 1.18 1.34 -1.96 -1.22 (6 months) -0.98 -0.49 2.51 1.96 -1.84 -0.65 PD (10 to 12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99 Venlafaxine hydrochloride extended-release capsules treatment were associated with sustained hypertension (defined as Supine Diastolic Blood Pressure [SDBP] ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. Table 11: Sustained Elevations in SDBP in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies a Maximum recommended dosage for venlafaxine hydrochloride extended-release capsules is 225 mg once daily. Indication Dose Range (mg per day) Incidence (%) MDD 75 to 375 a 19/705 (3) GAD 37.5 to 225 5/1011 (0.5) SAD 75 to 225 5/771 (0.6) PD 75 to 225 9/973 (0.9) Venlafaxine hydrochloride extended-release capsules were associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 12) [see Warnings and Precautions (5.3 , 5.4) ] . Table 12: Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Placebo-controlled Studies (up to 12 Weeks Duration) Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo MDD (12 weeks) 2 1 GAD (8 weeks) 2 <1 SAD (12 weeks) 3 1 PD (12 weeks) 1 <1 Laboratory Changes Serum Cholesterol Venlafaxine hydrochloride extended-release capsules were associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13). Table 13: Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo MDD (12 weeks) +1.5 -7.4 GAD (8 weeks) +1 -4.9 (6 months) +2.3 -7.7 SAD (12 weeks) +7.9 -2.9 (6 months) +5.6 -4.2 PD (12 weeks) +5.8 -3.7 Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 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 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. Venlafaxine hydrochloride extended-release capsules 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. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with 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% of placebo-treated patients. Serum Triglycerides Venlafaxine hydrochloride extended-release capsules were associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14). Table 14: Mean Final On-therapy Increases in Triglyceride Concentrations (mg/dL) in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo SAD (12 weeks) 8.2 0.4 SAD (6 months) 11.8 1.8 PD (12 weeks) 5.9 0.9 PD (6 months) 9.3 0.3 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of venlafaxine hydrochloride extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole – Anaphylaxis, angioedema Cardiovascular System – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy Digestive System – Pancreatitis Hemic/Lymphatic System – Mucous membrane bleeding [see Warnings and Precautions (5.4) ] , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9) ] , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions (5.9) ] , abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal – Rhabdomyolysis Nervous System – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.2) ] , serotonergic syndrome [see Warnings and Precautions (5.2) ] , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia Respiratory, Thoracic and Mediastinal Disorders – Anosmia, dyspnea, hyposmia, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions (5.12) ] Skin and Appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special Senses – Angle-closure glaucoma [see Warnings and Precautions (5.5) ]

16 HOW SUPPLIED/STORAGE AND HANDLING Venlafaxine Hydrochloride Extended-Release Capsules USP, 150 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘0’) of opaque dark orange color cap and opaque dark orange color body imprinted with “E” on cap and “89” on the body with edible black ink. NDC: 71335-1642-1: 30 Capsules in a BOTTLE NDC: 71335-1642-2: 60 Capsules in a BOTTLE NDC: 71335-1642-3: 90 Capsules in a BOTTLE NDC: 71335-1642-4: 100 Capsules in a BOTTLE Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504