Venlafaxine Hydrochloride

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, and libido decreased (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity [ see Contraindications (4.1) ] Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [ see Warnings and Precautions (5.1) ] Serotonin Syndrome [ see Warnings and Precautions (5.2) ] Elevations in Blood Pressure [ see Warnings and Precautions (5.3) ] Abnormal 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)] 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in 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 (30.0%), 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 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 (venlafaxine hydrochloride tablets only) and outpatient studies, fixed-dose, and titration studies. Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-Release Capsules in Premarketing Clinical Studies Indication Venlafaxine Hydrochloride Extended-Release Capsules MDD 705 In addition, in the premarketing assessment of venlafaxine hydrochloride tablet, multiple doses were administered to 2,897 patients in studies for MDD. 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 2.0 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 30.0 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 5.0 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 0.2 Impotence (men) a 5.3 1.0 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) 6.2 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 Venlafaxine Hydrochloride Extended-Release Capsules Placebo Indication ≤ 75mg per day >75mg per day (Duration) SSBP SDBP SSBP SDBP SSBP SDBP MDD (8 to 12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.10 GAD (8 weeks) (6 months) -0.28 1.27 0.02 -0.69 2.40 2.06 1.68 1.28 -1.26 -1.29 -0.92 -0.74 SAD (12 weeks) (6 months) -0.29 -0.98 -1.26 -0.49 1.18 2.51 1.34 1.96 -1.96 -1.84 -1.22 -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 was associated with sustained hypertension (defined as treatment-emergent 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 Indication Dose Range (mg per day) Incidence (%) MDD 75 to 375 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 6.3 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) (6 months) +1.0 +2.3 -4.9 -7.7 SAD (12 weeks) (6 months) +7.9 +5.6 -2.9 -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 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. 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 venlafaxine hydrochloride 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 0.0% of placebo- treated patients. Serum Triglycerides Venlafaxine hydrochloride extended-release capsules was 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 6.4 Pediatric Patients In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed [ see Warnings and Precautions (5.3, 5.10, 5.11) and Use in Specific Populations (8.4) ]. In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. 6.5 Adverse Reactions Identified During Postapproval Use The following adverse reactions have been identified during postapproval 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 system – Dyspnea, 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) ]

4 CONTRAINDICATIONS • Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the venlafaxine hydrochloride extended-release capsules formulation (4.1). • Do not use with an MAOI or within 14 days of stopping an MAOI. Allow 7 days after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI, because of the risk of serotonin syndrome (4.2, 5.2, 7.3). 4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation 4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome [ see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3) ].

11 DESCRIPTION Venlafaxine hydrochloride extended-release capsule, USP is an extended-release capsule for once-a-day oral administration that contains venlafaxine hydrochloride, a serotonin and norepinephrine reuptake inhibitor (SNRI). Venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C 17 H 27 NO 2 HCl. Its molecular weight is 313.86. The structural formula is shown as follows: Venlafaxine hydrochloride, USP is a white to off-white crystalline solid, with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Venlafaxine hydrochloride extended-release capsules, USP contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of colloidal silicon dioxide, ethyl cellulose, gelatin, hypromellose, sodium lauryl sulphate, sugar spheres, talc and titanium dioxide. Additionally, the 37.5 mg capsule contains iron oxide (black, red & yellow), the 75 mg capsule contains FD&C Blue No.1 and FD&C Yellow No.5 and the 150 mg capsule contains FD&C Red No. 40 and FD&C Yellow No. 5. Sugar spheres contains sucrose and corn starch. Venlafaxine hydrochloride extended-release capsules, USP, 37.5 mg, 75 mg and 150 mg meet USP dissolution test 5. Structure

2 DOSAGE AND ADMINISTRATION Indication Starting Dose Target Dose Maximum Dose MDD (2.1) 37.5 to 75 mg/day 75 mg/day 225 mg/day GAD (2.2) 37.5 to 75 mg/day 75 mg/day 225 mg/day SAD (2.3) 75 mg/day 75 mg/day 75 mg/day PD (2.4) 37.5 mg/day 75 mg/day 225 mg/day • Take once daily with food (2). Capsules should be taken whole; do not divide, crush, chew, or dissolve (2). • When discontinuing treatment, reduce the dose gradually (2.8, 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 (2.6) • 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% (2.6). Venlafaxine hydrochloride extended-release capsules should be administered in 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) ]. Each capsule should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water or it may 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). 2.1 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, since steady-state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4 [ see Clinical Pharmacology (12.3) ]. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more. It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg per day for venlafaxine hydrochloride tablets, more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg per day (range of 150 to 375 mg per day). Whether or not higher doses of venlafaxine hydrochloride extended-release capsules are needed for more severely depressed patients is unknown; however, the experience with venlafaxine hydrochloride extended-release capsules doses higher than 225 mg per day is very limited. 2.2 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, since steady-state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4 [see Clinical Pharmacology (12.3)]. 2.3 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. 2.4 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. 2.5 Switching Patients from Venlafaxine Hydrochloride Tablets Depressed patients who are currently being treated at a therapeutic dose with venlafaxine hydrochloride tablets 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. 2.6 Specific Populations Patients with Hepatic Impairment The total daily dose should be reduced by 50% in patients with mild (Child-Pugh=5 to 6) to moderate (Child-Pugh=7 to 9) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh=10 to 15) or hepatic cirrhosis, it may be necessary to reduce the dose by 50% or more [ See Use in Specific Populations (8.7) ]. Patients with Renal Impairment The total daily dose should be reduced by 25% to 50% in patients with mild (CLcr= 60 to 89 mL/min) or moderate (CLcr= 30 to 59 mL/min) renal impairment. In patients undergoing hemodialysis or with severe renal impairment (CLcr < 30 mL/min), the total daily dose should be reduced by 50% or more. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients [ see Use in Specific Populations (8.7) ]. 2.7 Maintenance Treatment There is no body of evidence available from controlled studies to indicate how long patients with MDD, GAD, SAD, or PD should be treated with venlafaxine hydrochloride extended-release capsules. It is generally agreed that acute episodes of MDD require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Venlafaxine hydrochloride extended-release capsules/venlafaxine hydrochloride tablets have demonstrated continuation of response in clinical studies up to 52 weeks, at the same dose at which patients responded during the initial treatment [ see Clinical Studies (14.1) ]. It is not known whether or not the dose of venlafaxine hydrochloride 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. In patients with GAD and SAD, venlafaxine hydrochloride extended-release capsules have been shown to be effective in 6-month clinical studies. The need for continuing medication in patients with GAD and SAD who improve with venlafaxine hydrochloride extended-release capsules treatment should be periodically reassessed. In a clinical study for PD, patients continuing venlafaxine hydrochloride extended-release capsules at the same dose at which they responded during the initial 12 weeks of treatment experienced a statistically significantly longer time to relapse than patients randomized to placebo [ see Clinical Studies (14.4) ]. The need for continuing medication in patients with PD who improve with venlafaxine hydrochloride extended-release capsules treatment should be periodically reassessed. 2.8 Discontinuing venlafaxine hydrochloride extended-release capsules A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. 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 [ see Warnings and Precautions (5.7) ]. 2.9 Switching Patients 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 hydrochloride extended-release capsules. In addition, at least 7 days should be allowed after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI intended to treat psychiatric disorders [ see Contraindications (4.2), Warnings and Precautions (5.2), and Drug Interactions (7.2) ]. Use of venlafaxine hydrochloride extended-release capsules with other MAOIs such as Linezolid or Intravenous Methylene Blue Do not start venlafaxine hydrochloride extended-release capsules in a patient who is being treated with linezolid or intravenous methylene blue, because there is an 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 4.2) ]. In some cases, a patient already receiving venlafaxine hydrochloride extended-release capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue 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 hydrochloride extended-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. Monitor the patient 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 hydrochloride extended-release capsules can be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [ see Warnings and Precautions (5.2) ]. 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 concomitantly with venlafaxine hydrochloride extended-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE Venlafaxine hydrochloride extended-release capsules, USP are serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of: • Major Depressive Disorder (MDD) • Generalized Anxiety Disorder (GAD) • Social Anxiety Disorder (SAD) • Panic Disorder (PD) 1.1 Major Depressive Disorder Venlafaxine hydrochloride extended-release capsules, USP are indicated for the treatment of major depressive disorder (MDD). Efficacy was established in three short-term (4, 8, and 12 weeks) and two long-term, maintenance trials. 1.2 Generalized Anxiety Disorder Venlafaxine hydrochloride extended-release capsules, USP is indicated for the treatment of Generalized Anxiety Disorder (GAD). Efficacy was established in two 8-week and two 26-week placebo-controlled trials. 1.3 Social Anxiety Disorder Venlafaxine hydrochloride extended-release capsules, USP are indicated for the treatment of Social Anxiety Disorder (SAD), also known as social phobia. Efficacy was established in four 12-week and one 26-week, placebo-controlled trials. 1.4 Panic Disorder Venlafaxine hydrochloride extended-release capsules, USP are indicated for the treatment of Panic Disorder (PD), with or without agoraphobia. Efficacy was established in two 12-week placebo-controlled trials.

9.2 Abuse While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical studies. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

9.1 Controlled Substance Venlafaxine hydrochloride extended-release capsule is not a controlled substance.

9.3 Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine [ see Dosage and Administration (2.8) ].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Venlafaxine hydrochloride extended-release capsule is not a controlled substance. 9.2 Abuse While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical studies. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). 9.3 Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine [ see Dosage and Administration (2.8) ].

10 OVERDOSAGE 10.1 Human Experience During the premarketing evaluations of venlafaxine hydrochloride extended-release capsules (for MDD, GAD, SAD and PD) and venlafaxine hydrochloride tablets (for MDD), there were twenty reports of acute overdosage with venlafaxine hydrochloride (6 and 14 reports in venlafaxine hydrochloride extended-release capsules and venlafaxine hydrochloride tablets patients, respectively), either alone or in combination with other drugs and/or alcohol. Somnolence was the most commonly reported symptom. Among the other reported symptoms were paresthesia of all four limbs, moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. In most cases, no signs or symptoms were associated with overdose. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. One patient who ingested 2.75 g of venlafaxine was observed to have two generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in two of the other patients. Actions taken to treat the overdose included no treatment, hospitalization and symptomatic treatment, and hospitalization plus treatment with activated charcoal. All patients recovered. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher preexisting burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. 10.2 Management of Overdosage Consult a Certified Poison Control Center for up-to-date guidance and advice (1-800-222-1222 or www.poison.org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Provide supportive and symptomatic measures.

7 DRUG INTERACTIONS • Serotonergic Drugs (e.g., MAOIs, triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St. John's wort): Potential for serotonin syndrome. Careful patient observation is advised (4.2, 5.2, 7.3) 7.1 Central Nervous System (CNS)-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when venlafaxine hydrochloride extended-release capsules is taken in combination with other CNS- active drugs. 7.2 Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with pharmacological properties similar to venlafaxine hydrochloride extended-release capsules (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI [ see Dosage and Administration (2.9), Contraindications (4.2) and Warnings and Precautions (5.2) ]. 7.3 Serotonergic Drugs Based on the mechanism of action of venlafaxine hydrochloride extended-release capsules and the potential for serotonin syndrome, caution is advised when venlafaxine hydrochloride extended-release capsule is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's wort. If concomitant treatment with venlafaxine hydrochloride extended-release capsules and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine hydrochloride extended-release capsules with tryptophan supplements is not recommended [ see Dosage and Administration (2.9), Contraindications (4.2), and Warnings and Precautions (5.2) ]. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. The use of psychotropic drugs that interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding [ see Warnings and Precautions (5.4) ]. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine hydrochloride extended-release capsules are initiated or discontinued. 7.5 Weight Loss Agents The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. Venlafaxine hydrochloride extended-release capsule is not indicated for weight loss alone or in combination with other products. 7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-Release Capsules Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV). Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations; EM's, extensive metabolizers; PM's, poor metabolizers * No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3) Figure 1 7.7 Effects of Venlafaxine Hydrochloride Extended-Release Capsules on Other Drugs Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites. Abbreviations: AUC, area under the curve; Cmax, peak plasma concentrations; OH, hydroxyl * Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for Cmax and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5.0), respectively. Note: *: Administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Figure 2 7.8 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. 12.2 Pharmacodynamics Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H1-histaminergic, or α 1 -adrenergic receptors in vitro . Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Cardiac Electrophysiology The effect of venlafaxine on the QT interval was evaluated in a randomized, double-blind, placebo-and positive-controlled three-period crossover thorough QT study in 54 healthy adult subjects. No significant QT prolongation effect of venlafaxine 450 mg was detected. 12.3 Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple- dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg per day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption and Distribution Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%. Administration of venlafaxine hydrochloride extended-release capsules (150 mg once daily) generally resulted in lower C max and later T max values than for venlafaxine hydrochloride tablets administered twice daily (Table 16). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the venlafaxine hydrochloride extended-release capsule. Therefore, venlafaxine hydrochloride extended-release capsules provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 16: Comparison of C max and T max Values for Venlafaxine and ODV Following Oral Administration of Venlafaxine Hydrochloride Extended-Release Capsules and Venlafaxine Hydrochloride Tablets Venlafaxine Cmax (ng/mL) Tmax (h) ODV Cmax (ng/mL) Tmax (h) Venlafaxine Hydrochloride Extended-Release Capsules (150 mg once daily) 150 5.5 260 9 Venlafaxine Hydrochloride Tablets (75 mg twice daily) 225 2 290 3 Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg venlafaxine hydrochloride extended-release capsules. Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride extended-release capsules to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug. Metabolism and Elimination Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 levels (extensive metabolizers) [ see Use in Specific Populations 8.7 ]. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.

12.1 Mechanism of Action The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

12.2 Pharmacodynamics Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H1-histaminergic, or α 1 -adrenergic receptors in vitro . Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Cardiac Electrophysiology The effect of venlafaxine on the QT interval was evaluated in a randomized, double-blind, placebo-and positive-controlled three-period crossover thorough QT study in 54 healthy adult subjects. No significant QT prolongation effect of venlafaxine 450 mg was detected.

12.3 Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple- dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg per day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively). Absorption and Distribution Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%. Administration of venlafaxine hydrochloride extended-release capsules (150 mg once daily) generally resulted in lower C max and later T max values than for venlafaxine hydrochloride tablets administered twice daily (Table 16). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the venlafaxine hydrochloride extended-release capsule. Therefore, venlafaxine hydrochloride extended-release capsules provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 16: Comparison of C max and T max Values for Venlafaxine and ODV Following Oral Administration of Venlafaxine Hydrochloride Extended-Release Capsules and Venlafaxine Hydrochloride Tablets Venlafaxine Cmax (ng/mL) Tmax (h) ODV Cmax (ng/mL) Tmax (h) Venlafaxine Hydrochloride Extended-Release Capsules (150 mg once daily) 150 5.5 260 9 Venlafaxine Hydrochloride Tablets (75 mg twice daily) 225 2 290 3 Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg venlafaxine hydrochloride extended-release capsules. Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride extended-release capsules to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug. Metabolism and Elimination Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 levels (extensive metabolizers) [ see Use in Specific Populations 8.7 ]. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.

20191102

5

3 DOSAGE FORMS AND STRENGTHS • Venlafaxine hydrochloride extended-release capsules are available as 37.5 mg, 75 mg and 150 mg strengths (3). • Each capsule contains venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg or 150 mg of venlafaxine (3). Venlafaxine hydrochloride extended-release capsules are available in the following strengths: • 37.5 mg capsules (grey cap and peach body printed with "37.5" on the body and "1018" on the cap with red ink) • 75 mg capsules (pink cap and body printed with "75" on the body and "1019" on the cap with red ink) • 150 mg capsules (orange cap and body printed with "150" on the body and "1020" on the cap with white ink)

Venlafaxine Hydrochloride Venlafaxine Hydrochloride VENLAFAXINE HYDROCHLORIDE VENLAFAXINE SILICON DIOXIDE ETHYLCELLULOSE, UNSPECIFIED FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE GELATIN, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED SODIUM LAURYL SULFATE SUCROSE TALC TITANIUM DIOXIDE grey cap and peach body hard gelatin capsule 37;5;1018 Venlafaxine Hydrochloride Venlafaxine Hydrochloride VENLAFAXINE HYDROCHLORIDE VENLAFAXINE SILICON DIOXIDE ETHYLCELLULOSE, UNSPECIFIED FD&C BLUE NO. 1 FD&C YELLOW NO. 5 GELATIN, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED SODIUM LAURYL SULFATE SUCROSE TALC TITANIUM DIOXIDE pink cap and body hard gelatin capsule 75;1019 Venlafaxine Hydrochloride Venlafaxine Hydrochloride VENLAFAXINE HYDROCHLORIDE VENLAFAXINE SILICON DIOXIDE ETHYLCELLULOSE, UNSPECIFIED FD&C RED NO. 40 FD&C YELLOW NO. 5 GELATIN, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED SODIUM LAURYL SULFATE SUCROSE TALC TITANIUM DIOXIDE orange cap and body hard gelatin capsule 150;1020

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Tumors were not increased by venlafaxine treatment in mice or rats. Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m 2 basis. 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 concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite (ODV) were lower in rats than in patients receiving the maximum recommended dose. O desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study. Mice received ODV at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The exposure at the 300 mg/kg/day dose is 9 times that of a human dose of 225 mg/day. Rats received ODV at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The exposure at the highest dose is approximately 8 (males) or 11 (females) times that of a human dose of 225 mg/day. Mutagenesis Venlafaxine and the major human metabolite, ODV, were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay or in the in vivo chromosomal aberration assay in rats. Impairment of Fertility Reproduction and fertility studies of venlafaxine in rats showed no adverse effects of venlafaxine 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/m 2 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.

ANDA090899

Venlafaxine Hydrochloride

Venlafaxine Hydrochloride

0904-6468

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel Venlafaxine Hydrochloride Extended-Release Capsules, USP 37.5 mg* 100 Capsules carton label

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with venlafaxine hydrochloride extended-release capsules and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions" is available for venlafaxine hydrochloride extended-release capsules. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and should be asked to alert their prescriber if these occur while taking venlafaxine hydrochloride extended-release capsules. Suicidal Thoughts and Behaviors Advise patients, their families and caregivers to look for the emergence of suicidality, worsening of depression, and other psychiatric symptoms (anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, psychomotor restlessness, hypomania, mania, other unusual changes in behavior), especially early during treatment and when the dose is adjusted up or down. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring [ see Boxed Warning and Warnings and Precautions (5.1) ]. Concomitant Medication Advise patients taking venlafaxine hydrochloride extended-release capsules not to use concomitantly other products containing venlafaxine or desvenlafaxine. Healthcare professionals should instruct patients not to take venlafaxine hydrochloride extended-release capsules with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI [ see Contraindications (4.2) ]. Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome, with the concomitant use of venlafaxine hydrochloride extended-release capsules and triptans, tramadol, amphetamines, tryptophan supplements, with antipsychotics or other dopamine antagonists, or other serotonergic agents [s ee Warnings and Precautions (5.2) and Drug Interactions (7.3) ]. Elevated Blood Pressure Advise patients that they should have regular monitoring of blood pressure when taking venlafaxine hydrochloride extended-release capsules [ see Warnings and Precautions (5.3) ]. Abnormal Bleeding Patients should be cautioned about the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [ see Warnings and Precautions (5.4) ]. Angle Closure Glaucoma Patients should be advised that taking venlafaxine hydrochloride extended-release capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.5)] . Activation of Mania/Hypomania Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania [ see Warnings and Precautions (5.6) ]. Cardiovascular/Cerebrovascular Disease Caution is advised in administering venlafaxine hydrochloride extended-release capsules to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders [ see Adverse Reactions (6.1) ]. Serum Cholesterol and Triglyceride Elevation Advise patients that elevations in total cholesterol, LDL and triglycerides may occur and that measurement of serum lipids may be considered [ see Warnings and Precautions (6.3) ]. Discontinuation [Symptoms] Advise patients not to stop taking venlafaxine hydrochloride extended-release capsules without talking first with their healthcare professional. Patients should be aware that discontinuation effects may occur when stopping venlafaxine hydrochloride extended-release capsules [ see Warnings and Precautions ( 5.7) and Adverse Reactions (6.1) ]. Interference with Cognitive and Motor Performance Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine hydrochloride extended-release capsules therapy does not adversely affect their ability to engage in such activities. Alcohol Advise patients to avoid alcohol while taking venlafaxine hydrochloride extended-release capsules [ see Drug Interactions (7.6) ]. Allergic Reactions Advise patients to notify their physician if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing. Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [ see Use in Specific Populations (8.1) ]. Nursing Advise patients to notify their physician if they are breast-feeding an infant [ see Use in Specific Populations (8.3) ]. Residual Spheroids Venlafaxine hydrochloride extended-release capsule contains spheroids, which release the drug slowly into the digestive tract. The insoluble portion of these spheroids is eliminated, and patients may notice spheroids passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the spheroids. Manufactured by: TORRENT PHARMACEUTICALS LTD., Indrad-382 721, Dist. Mehsana, INDIA. For: TORRENT PHARMA INC., 150 Allen Road, Suite 102 Basking Ridge, NJ 07920. Distributed By: MAJOR® PHARMACEUTICALS 17177 N Laurel Park Dr., Suite 233 Livonia, MI 48152 8065460 Revised February 2018 logo

Medication Guide Venlafaxine Hydrochloride (VEN-la-FAX-een HYE-droe-KLOR-ide) Extended-Release Capsules, USP Read the Medication Guide that comes with venlafaxine hydrochloride extended-release capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about venlafaxine hydrochloride extended-release capsules? Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: • Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. • Watch for these changes and call your healthcare provider right away if you notice: • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. • Pay particular attention to such changes when venlafaxine hydrochloride extended-release capsules are started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: • attempts to commit suicide • acting on dangerous impulses • acting aggressive or violent • thoughts about suicide or dying • new or worse depression • new or worse anxiety or panic attacks • feeling agitated, restless, angry or irritable • trouble sleeping • an increase in activity or talking more than what is normal for you • other unusual changes in behavior or mood • Visual problems • eye pain • changes in vision • swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Venlafaxine hydrochloride extended-release capsules may be associated with these serious side effects : 2. Serotonin Syndrome This condition can be life-threatening and may include : • agitation, hallucinations, coma or other changes in mental status • coordination problems or muscle twitching (overactive reflexes) • racing heartbeat, high or low blood pressure • sweating or fever • nausea, vomiting, or diarrhea • muscle rigidity 3. Changes in blood pressure. Venlafaxine hydrochloride extended-release capsules may: • increase your blood pressure. Control high blood pressure before starting treatment and monitor blood pressure regularly 4. Enlarged pupils (mydriasis). 5. Anxiety and insomnia. 6. Changes in appetite or weight. 7. Manic/hypomanic episodes: • greatly increased energy • severe trouble sleeping • racing thoughts • reckless behavior • unusually grand ideas • excessive happiness or irritability • talking more or faster than usual 8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: • headache • weakness or feeling unsteady • confusion, problems concentrating or thinking or memory problems 9. Seizures or convulsions. 10. Abnormal bleeding : Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin ® , Jantoven ® ), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 11. Elevated cholesterol. 12 . Lung disease and pneumonia : Venlafaxine hydrochloride extended-release capsules may cause rare lung problems. Symptoms include: • worsening shortness of breath • cough • chest discomfort 13. Severe allergic reactions: • trouble breathing • swelling of the face, tongue, eyes or mouth • rash, itchy welts (hives) or blisters, alone or with fever or joint pain. Do not stop venlafaxine hydrochloride extended-release capsules without first talking to your healthcare provider . Stopping venlafaxine hydrochloride extended-release capsules too quickly or changing from another antidepressant too quickly may cause serious symptoms including: • anxiety, irritability • feeling tired, restless or problems sleeping • headache, sweating, dizziness • electric shock-like sensations, shaking, confusion, nightmares • vomiting, nausea, diarrhea What are venlafaxine hydrochloride extended-release capsules? Venlafaxine hydrochloride extended-release capsules are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Venlafaxine hydrochloride extended-release capsules are also used to treat: Generalized Anxiety Disorder (GAD) • Social Anxiety Disorder (SAD) • Panic Disorder (PD) Talk to your healthcare provider if you do not think that your condition is getting better with venlafaxine hydrochloride extended-release capsules treatment. Who should not take venlafaxine hydrochloride extended-release capsules? Do not take venlafaxine hydrochloride extended-release capsules if you: • are allergic to venlafaxine hydrochloride extended-release capsules or any of the ingredients in venlafaxine hydrochloride extended-release capsules . See the end of this Medication Guide for a complete list of ingredients in venlafaxine hydrochloride extended-release capsules. • have uncontrolled angle-closure glaucoma • take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. • Do not take an MAOI within 7 days of stopping venlafaxine hydrochloride extended-release capsules unless directed to do so by your physician. • Do not start venlafaxine hydrochloride extended-release capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take venlafaxine hydrochloride extended-release capsules close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: • high fever • uncontrolled muscle spasms • stiff muscles • rapid changes in heart rate or blood pressure • confusion • loss of consciousness (pass out) What should I tell my healthcare provider before taking venlafaxine hydrochloride extended-release capsules? Ask if you are not sure. Before starting venlafaxine hydrochloride extended-release capsules , tell your healthcare provider if you: • Are taking certain drugs such as: • Amphetamines • Medicines used to treat migraine headaches such as: • triptans • Medicines used to treat mood, anxiety, psychotic or thought disorders, such as: • tricyclic antidepressants • lithium • SSRIs • SNRIs • antipsychotic drugs • Medicines used to treat pain such as: • tramadol • Medicines used to thin your blood such as: • warfarin • Medicines used to treat heartburn such as: • Cimetidine • Over-the-counter medicines or supplements such as: • Aspirin or other NSAIDs • Tryptophan • St. John's Wort • have heart problems • have diabetes • have liver problems • have kidney problems • have thyroid problems • have or had seizures or convulsions • have bipolar disorder or mania • have low sodium levels in your blood • have high blood pressure • have high cholesterol • have or had bleeding problems • are pregnant or plan to become pregnant. It is not known if venlafaxine hydrochloride extended-release capsules will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy • are breast-feeding or plan to breast-feed. Some venlafaxine hydrochloride extended-release capsules may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking venlafaxine hydrochloride extended-release capsules . Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Venlafaxine hydrochloride extended-release capsules and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take venlafaxine hydrochloride extended-release capsules with your other medicines. Do not start or stop any medicine while taking venlafaxine hydrochloride extended-release capsules without talking to your healthcare provider first. If you take venlafaxine hydrochloride extended-release capsules , you should not take any other medicines that contain (venlafaxine) including: venlafaxine hydrochloride. How should I take venlafaxine hydrochloride extended-release capsules? • Take venlafaxine hydrochloride extended-release capsules exactly as prescribed. Your healthcare provider may need to change the dose of venlafaxine hydrochloride extended-release capsules until it is the right dose for you. • Venlafaxine hydrochloride extended-release capsules are to be taken with food. • If you miss a dose of venlafaxine hydrochloride extended-release capsules , take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of venlafaxine hydrochloride extended-release capsules at the same time. • If you take too much venlafaxine hydrochloride extended-release capsules , call your healthcare provider or poison control center right away, or get emergency treatment. • When switching from another antidepressant to venlafaxine hydrochloride extended-release capsules your doctor may want to lower the dose of the initial antidepressant first to avoid side effects What should I avoid while taking venlafaxine hydrochloride extended-release capsules? Venlafaxine hydrochloride extended-release capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how venlafaxine hydrochloride extended-release capsule affects you. Do not drink alcohol while using venlafaxine hydrochloride extended-release capsules . What are the possible side effects of venlafaxine hydrochloride extended-release capsules? Venlafaxine hydrochloride extended-release capsules may cause serious side effects, including: • See "What is the most important information I should know about venlafaxine hydrochloride extended-release capsules ?" • Increased cholesterol-have your cholesterol checked regularly • Newborns whose mothers take venlafaxine hydrochloride extended-release capsules in the third trimester may have problems right after birth including: • problems feeding and breathing • seizures • shaking, jitteriness or constant crying • Angle-closure glaucoma Common possible side effects in people who take venlafaxine hydrochloride extended-release capsules include : • unusual dreams • sexual problems • loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth • feeling tired, fatigued or overly sleepy • change in sleep habits, problems sleeping • yawning • tremor or shaking • dizziness, blurred vision • sweating • feeling anxious, nervous or jittery • headache • increase in heart rate Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of venlafaxine hydrochloride extended-release capsules . For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store venlafaxine hydrochloride extended-release capsules? • Store venlafaxine hydrochloride extended-release capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15°to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. • Keep venlafaxine hydrochloride extended-release capsules in a dry place. Keep venlafaxine hydrochloride extended-release capsules and all medicines out of the reach of children. General information about venlafaxine hydrochloride Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use venlafaxine hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not give venlafaxine hydrochloride extended-release capsules to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about venlafaxine hydrochloride extended-release capsules . If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about venlafaxine hydrochloride extended-release capsules that is written for healthcare professionals. For more information call 1-800-912-9561. What are the ingredients in venlafaxine hydrochloride extended-release capsules? Active ingredient: venlafaxine hydrochloride, USP Inactive ingredients : • Extended-Release Capsules : colloidal silicon dioxide, ethyl cellulose, gelatin, hypromellose, sodium lauryl sulphate, sugar spheres, talc and titanium dioxide. Additionally, the 37.5 mg capsule contains iron oxide (black, red & yellow), the 75 mg capsule contains FD&C Blue No.1 and FD&C Yellow No.5 and the 150 mg capsule contains FD&C Red No. 40 and FD&C Yellow No. 5. Sugar spheres contains sucrose and corn starch. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Trademarks are the property of their respective owners. Manufactured by: TORRENT PHARMACEUTICALS LTD., Indrad-382 721, Dist. Mehsana, INDIA. For: TORRENT PHARMA INC., 150 Allen Road, Suite 102 Basking Ridge, NJ 07920. Distributed By: MAJOR® PHARMACEUTICALS 17177 N Laurel Park Dr., Suite 233 Livonia, MI 48152 8065461 Revised February 2018 logo

14 CLINICAL STUDIES 14.1 Major Depressive Disorder The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, venlafaxine hydrochloride extended-release capsules also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing venlafaxine hydrochloride tablets in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of venlafaxine hydrochloride tablets over placebo based on the HAM-D-21 total score. The mean dose in completers was 350 mg per day (study 3). In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, once daily every morning) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsules dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued venlafaxine hydrochloride extended-release capsule treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4). In a second longer term trial, adult outpatients with MDD, recurrent type, who had responded (HAM-D 21 total score ≤ 12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥ 20; (2) no more than 2 HAM D-21 total scores > 10, and (3) no single CGI Severity of Illness item score ≥ 4 (moderately ill)] during an initial 26 weeks of treatment on venlafaxine hydrochloride tablets [100 to 200 mg per day, on a twice daily schedule] were randomized to continuation of their same venlafaxine hydrochloride tablets dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥ 4, was for up to 52 weeks. Patients receiving continued venlafaxine hydrochloride tablets treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5). Table 17: Major Depressive Disorder Studies Study number Treatment Group Primary Efficacy Measure: HAM-D Score Mean Baseline Score (SD) LS Mean Change From Baseline Placebo Subtracted Difference SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval. (95%CI) Study 1 Venlafaxine Hydrochloride Extended-Release Capsules (75 to 225 mg/day)* 24.5 -11.7 -4.45 (-6.66, -2.25) Placebo 23.6 -7.24 - Study 2 Venlafaxine Hydrochloride Extended-Release Capsules (75 to 225 mg/day)* 24.5 -15.11 -6.40 (-8.45, -4.34) Placebo 24.9 -8.71 Study 3 Venlafaxine Hydrochloride Tablets (150 to 375 mg/day)* 28.2 (0.5) -14.9 -10.2 (-14.4, -6.0) Placebo 28.6 (0.6) -4.7 - 14.2 Generalized Anxiety Disorder The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD. In one 8-week study, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied. Two 6-month studies, one evaluating venlafaxine hydrochloride extended-release capsules doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating venlafaxine hydrochloride extended-release capsules doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. Table 18: Generalized Anxiety Disorder Studies SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline * Doses statistically significantly superior to placebo. Study number Treatment Group Primary Efficacy Measure: HAM-A Score Mean Baseline Score (SD) LS Mean Change From Baseline Placebo Subtracted Difference a (95% CI) Study 1 Ven XR 75mg 24.7 -11.1 (0.95) -1.5 (-3.8, 0.8) Ven XR 150 mg 24.5 -11.7 (0.87) -2.2 (-4.5, 0.1) Venlafaxine Hydrochloride Extended-Release Capsules 225 mg 23.6 - 12.1 (0.81) -2.6 (-4.9, -0.3) Placebo 24.1 - 9.5 (0.85) Study 2 Ven XR 75mg 23.7 -10.6 (0.82) -2.6 (-4.6, -0.5) Ven XR 150 mg 23.0 -9.8 (0.86) -1.7 (-3.8, 0.3) Placebo 23.7 -8.0 (0.73) Study 3 Ven XR 37.5mg 26.6 (0.4) -13.8 -2.8 (-5.1, -0.6) Ven XR 75 mg 26.3 (0.4) -15.5 -4.6 (-6.9, -2.3) Ven XR 150 mg 26.3 (0.4) -16.4 -5.5 (-7.8, -3.1) Placebo 26.7 (0.5) -11.0 Study 4 Ven XR 75 to 225 mg 25.0 -13.4 (0.79) -4.7 (-6.6, -2.9) Placebo 24.9 -8.7 (0.70) 14.3 Social Anxiety Disorder (also known as Social Phobia) The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1 to 4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5). In these five studies, venlafaxine hydrochloride extended-release capsules were statistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to the 75 mg per day group in the 6-month study. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. Table 19: Social Anxiety Disorder Studies SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline * Doses statistically significantly superior to placebo. Study number Treatment Group Primary Efficacy Measure: HAM-D Score Mean Baseline Score (SD) LS Mean Change From Baseline Placebo Subtracted Difference a (95%CI) Study 1 Ven XR (75 to 225mg) 91.1 -31.0(2.22) 11.2 (-5.3, -17.1) Placebo 86.7 -19.9(2.22) - Study 2 Ven XR (75 to 225MG) 90.8 -32.8(2.69) -10.7 (-3.7,-17.6) Placebo 87.4 -22.1(2.66) - Study 3 Ven XR (75 to 225MG) 83.2 -36.0(2.35) -16.9(-22.6, -11.2) Placebo 83.6 -19.1(2.40) -12.7 (-6.5, -19.0) Study 4 Ven XR (75 to 225MG) 86.2 -35.0(2.64) -14.6 (-21.8, -7.4) Placebo 86.1 -22.2(2.47) Study 5 Ven XR 75 mg Ven XR (150 to 225mg) 91.8 86.2 -38.1(3.16) -37.6(3.05) -14.6 (-21.8, -7.4) -14.1 (-21.3, -6.9) Placebo 89.3 -23.5(3.08) 14.4 Panic Disorder The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2). Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full- symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, venlafaxine hydrochloride extended-release capsule was statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with venlafaxine hydrochloride extended-release capsules (75 to 225 mg per day) were randomly assigned to continue the same venlafaxine hydrochloride extended-release capsules dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12 week open-label period, patients receiving continued venlafaxine hydrochloride extended-release capsules experienced a statistically significantly longer time to relapse. Table 20: Panic Disorder Studies: a Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model. 95% CI: 95% confidence interval without adjusting for multiple dose arms. * Doses statistically significantly superior to placebo. Study Treatment Group Number Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks Percent of patients Free of Full symptom panic attack Adjusted Odds Ratio a to placebo Adjusted Odds Ratio a 95% Confidence Interval Study 1 Ven XR 75 mg* Ven XR 150 mg* Placebo 54.1% (85/157) 61.4% (97/158) 34.4% (53/154) 2. 268 3.035 -‑ (1.43, 3.59) (1.91, 4.82) -‑ Study 2 Ven XR 75 mg* Ven XR 225 mg* Placebo 64.1% (100/156) 70.0% (112/160) 46.5% (73/157) 2.350 2.890 -‑ (1.46, 3.78) (1.80, 4.64) -‑ 14.5 Pediatric Patients Two placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies 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.

8.5 Geriatric Use The percentage of patients in clinical studies for venlafaxine hydrochloride extended-release capsules for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 15. Table 15: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indication In addition, in the premarketing assessment of venlafaxine hydrochloride tablets, 12% (357/2,897) of patients were ≥ 65 years of age. Indication Venlafaxine Hydrochloride Extended-Release Capsules MDD 4 (14/357) GAD 6 (77/1,381) SAD 1 (10/819) PD 2 (16/1,001) No overall differences in effectiveness or safety were observed between geriatric 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 hydrochloride extended-release capsules, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [ see Warnings and Precautions (5.9) ]. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [ see Clinical Pharmacology (12.3) ] (see Figure 3). 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 (2.6) ].

8.2 Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown.

8.3 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 hydrochloride extended-release capsules, 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.

8.4 Pediatric Use 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 hydrochloride extended-release capsules in a child or adolescent must balance the potential risks with the clinical need [ see Boxed Warning, Warnings and Precautions (5.1, 5.10, 5.11) and Adverse Reactions (6.4) ]. 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 Warnings and Precautions (5.10) ] . Should the decision be made to treat a pediatric patient with venlafaxine hydrochloride extended-release capsules, regular monitoring of weight and height is recommended during treatment, particularly if treatment is to be continued long-term [ see Warnings and Precautions (5.10, 5.11) ]. The safety of venlafaxine hydrochloride extended-release capsules 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 and Precautions (5.3,6.3) ].

8.1 Pregnancy Teratogenic Effects – Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended 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 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. In reproductive developmental studies in rats and rabbits with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, evidence of teratogenicity was not observed at exposure margins of 13 in rats and 0.3 in rabbits. There are no adequate and well-controlled studies in pregnant women. Venlafaxine hydrochloride extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs, or SSRIs, 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 Warnings and Precautions (5.2) and Drug Interactions (7.3) ]. When treating a pregnant woman with venlafaxine hydrochloride extended-release capsules during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1). • Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother (8.3) 8.1 Pregnancy Teratogenic Effects – Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended 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 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. In reproductive developmental studies in rats and rabbits with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, evidence of teratogenicity was not observed at exposure margins of 13 in rats and 0.3 in rabbits. There are no adequate and well-controlled studies in pregnant women. Venlafaxine hydrochloride extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Non-teratogenic Effects Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs, or SSRIs, 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 Warnings and Precautions (5.2) and Drug Interactions (7.3) ]. When treating a pregnant woman with venlafaxine hydrochloride extended-release capsules during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. 8.2 Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown. 8.3 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 hydrochloride extended-release capsules, 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. 8.4 Pediatric Use 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 hydrochloride extended-release capsules in a child or adolescent must balance the potential risks with the clinical need [ see Boxed Warning, Warnings and Precautions (5.1, 5.10, 5.11) and Adverse Reactions (6.4) ]. 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 Warnings and Precautions (5.10) ] . Should the decision be made to treat a pediatric patient with venlafaxine hydrochloride extended-release capsules, regular monitoring of weight and height is recommended during treatment, particularly if treatment is to be continued long-term [ see Warnings and Precautions (5.10, 5.11) ]. The safety of venlafaxine hydrochloride extended-release capsules 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 and Precautions (5.3,6.3) ]. 8.5 Geriatric Use The percentage of patients in clinical studies for venlafaxine hydrochloride extended-release capsules for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 15. Table 15: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indication In addition, in the premarketing assessment of venlafaxine hydrochloride tablets, 12% (357/2,897) of patients were ≥ 65 years of age. Indication Venlafaxine Hydrochloride Extended-Release Capsules MDD 4 (14/357) GAD 6 (77/1,381) SAD 1 (10/819) PD 2 (16/1,001) No overall differences in effectiveness or safety were observed between geriatric 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 hydrochloride extended-release capsules, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [ see Warnings and Precautions (5.9) ]. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [ see Clinical Pharmacology (12.3) ] (see Figure 3). 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 (2.6) ]. 8.6 Age and Gender A population pharmacokinetic analysis of 404 venlafaxine hydrochloride tablets-treated patients from two studies involving both twice daily and three times daily regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary [ see Dosage and Administration (2.6) ] (see Table 15). 8.7 Use in Patient Subgroups Figure 3: Pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) in special populations. Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations; *Similar effect is expected with strong CYP2D6 inhibitors Figure 3

16 HOW SUPPLIED/STORAGE AND HANDLING Venlafaxine hydrochloride extended-release capsules, USP are available as follows: 37.5 mg, size "4" hard gelatin capsule with grey cap and peach body printed with "37.5" on the body and "1018" on the cap with red ink containing white to off white pellets. Carton of 100 tablets (10 tablets each blister card x 10) NDC 0904-6468-61 75 mg, size "1" hard gelatin capsule with pink cap and body printed with "75" on the body and "1019" on the cap with red ink containing white to off white pellets. Carton of 100 tablets (10 tablets each blister card x 10) NDC 0904-6469-61 150 mg, size "0" hard gelatin capsule with orange cap and body printed with "150" on the body and "1020" on the cap with white ink containing white to off white pellets. Carton of 100 tablets (10 tablets each blister card x 10) NDC 0904-6470-61 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container with a child-resistant closure.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning • Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants (5.1) • Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1) • Venlafaxine hydrochloride extended-release capsulesare not approved for use in pediatric patients (8.4) Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [ see Warnings and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy monitor closely for clinical worsening and emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [ see Warnings and Precautions (5.1) and Patient Counseling Information (17) ] .