Effexor XR

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hypersensitivity [see Contraindications (4) ] • Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1) ] • Serotonin Syndrome [see Warnings and Precautions (5.2) ] • Elevated Blood Pressure [see Warnings and Precautions (5.3) ] • Increased Risk of Bleeding [see Warnings and Precautions (5.4) ] • Angle-Closure Glaucoma [see Warnings and Precautions (5.5) ] • Activation of Mania/Hypomania [see Warnings and Precautions (5.6) ] • Discontinuation Syndrome [see Warnings and Precautions (5.7) ] • Seizure [see Warnings and Precautions (5.8) ] • Hyponatremia [see Warnings and Precautions (5.9) ] • Weight and Height Changes in Pediatric Patients [see Warnings and Precautions (5.10) ] • Appetite Changes in Pediatric Patients [see Warnings and Precautions (5.11) ] • Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.12) ] • Sexual Dysfunction [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, impotence (men), and libido decreased ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Most Common Adverse Reactions The most commonly observed adverse reactions in the clinical study database in Effexor XR 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 Effexor XR (37.5-225 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 Effexor XR 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 Effexor XR 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 Effexor XR during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Table 8: Patients Receiving Effexor XR in Premarketing Clinical Studies Indication Effexor XR MDD 705 In addition, in the premarketing assessment of Effexor, 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 Effexor XR treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in Effexor XR 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 Body System Adverse Reaction Effexor XR 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) Percentages based on the number of men (Effexor XR, n = 1,440; placebo, n = 923) 9.9 0.5 Anorgasmia (men) 3.6 0.1 Anorgasmia (women) Percentages based on the number of women (Effexor XR, n = 2,118; placebo, n = 1,274) 2.0 0.2 Impotence (men) 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) 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 Effexor XR. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the Effexor XR 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 Effexor XR 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 Effexor XR Placebo Indication ≤75 mg per day >75 mg per day (Duration) SSBP SDBP SSBP SDBP SSBP SDBP MDD (8-12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.10 GAD (8 weeks) -0.28 0.02 2.40 1.68 -1.26 -0.92 (6 months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 SAD (12 weeks) -0.29 -1.26 1.18 1.34 -1.96 -1.22 (6 months) -0.98 -0.49 2.51 1.96 -1.84 -0.65 PD (10-12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99 Effexor XR treatment was associated with sustained hypertension (defined as Supine Diastolic Blood Pressure [SDBP] ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient number of patients received mean doses of Effexor XR 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 Effexor XR Premarketing Studies Indication Dose Range (mg per day) Incidence (%) MDD 75-375 Maximum recommended dosage for Effexor XR is 225 mg once daily. 19/705 (3) GAD 37.5-225 5/1011 (0.5) SAD 75-225 5/771 (0.6) PD 75-225 9/973 (0.9) Effexor XR was 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 Effexor XR Premarketing Placebo-controlled Studies (up to 12 Weeks Duration) Indication (Duration) Effexor XR Placebo MDD (12 weeks) 2 1 GAD (8 weeks) 2 <1 SAD (12 weeks) 3 1 PD (12 weeks) 1 <1 Laboratory Changes Serum Cholesterol Effexor XR was 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 Effexor XR Premarketing Studies Indication (Duration) Effexor XR Placebo MDD (12 weeks) +1.5 -7.4 GAD (8 weeks) +1.0 -4.9 (6 months) +2.3 -7.7 SAD (12 weeks) +7.9 -2.9 (6 months) +5.6 -4.2 PD (12 weeks) +5.8 -3.7 Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo. Patients treated with Effexor (immediate-release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients. Serum Triglycerides Effexor XR 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 Effexor XR Premarketing Studies Indication (Duration) Effexor XR Placebo SAD (12 weeks) 8.2 0.4 SAD (6 months) 11.8 1.8 PD (12 weeks) 5.9 0.9 PD (6 months) 9.3 0.3 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Effexor XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole – Anaphylaxis, angioedema Cardiovascular System – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy Digestive System – Pancreatitis Hemic/Lymphatic System – Mucous membrane bleeding [see Warnings and Precautions (5.4) ] , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9) ] , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions (5.9) ] , abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal – Rhabdomyolysis Nervous System – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.2) ] , serotonergic syndrome [see Warnings and Precautions (5.2) ] , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia Respiratory, Thoracic and Mediastinal Disorders – Anosmia, dyspnea, hyposmia, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions (5.12) ] Skin and Appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special Senses – Angle-closure glaucoma [see Warnings and Precautions (5.5) ]

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

11 DESCRIPTION Effexor XR 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 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. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide. Venlafaxine Hydrochloride Structural Formula

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

1 INDICATIONS AND USAGE Effexor XR is indicated in adults for the treatment of: • Major Depressive Disorder (MDD) [see Clinical Studies (14.1) ] • Generalized Anxiety Disorder (GAD) [see Clinical Studies (14.2) ] • Social Anxiety Disorder (SAD) [see Clinical Studies (14.3) ] • Panic Disorder (PD) [see Clinical Studies (14.4) ] Effexor XR is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of adults with: • Major Depressive Disorder (MDD) ( 1 ) • Generalized Anxiety Disorder (GAD) ( 1 ) • Social Anxiety Disorder (SAD) ( 1 ) • Panic Disorder (PD) ( 1 )

9.2 Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. 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, providers 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 Effexor XR contains venlafaxine which is not a controlled substance.

9.3 Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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 (2.10) and Warnings and Precautions (5.7) ] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Effexor XR contains venlafaxine which is not a controlled substance. 9.2 Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. 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, providers 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 Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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 (2.10) and Warnings and Precautions (5.7) ] .

10 OVERDOSAGE Human Experience During the premarketing evaluations of Effexor XR (for MDD, GAD, SAD, and PD) and Effexor (for MDD), there were twenty reports of acute overdosage with Effexor (6 and 14 reports in Effexor XR and Effexor 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 Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage No specific antidotes for Effexor XR are known. In managing overdosage, consider the possibility of multiple drug involvement. Consider contacting a Poison Center (1-800-222-1222) or a medical toxicologist for overdosage management recommendations for Effexor XR.

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Effexor XR Table 15: Clinically Important Drug Interactions with Effexor XR Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SNRIs, including Effexor XR, with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of Effexor XR is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.11) , Contraindications (4) and Warnings and Precautions (5.2) ]. Other Serotonergic Drugs Clinical Impact Concomitant use of Effexor XR with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when Effexor XR is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Effexor XR and/or concomitant serotonergic drugs [see Dosage and Administration (2.11) and Warnings and Precautions (5.2) ]. Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of Effexor XR with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of Effexor XR on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when Effexor XR is initiated or discontinued [see Warnings and Precautions (5.4) ] . Effect of CYP3A Inhibitors Clinical Impact Concomitant use of a CYP3A inhibitor increases the C max and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology (12.3) ] , which may increase the risk of toxicity of Effexor XR. Intervention Consider reducing the dose of Effexor XR. CYP2D6 Substrates Clinical Impact Concomitant use of Effexor XR increases C max and AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology (12.3) ] . Intervention Consider reduction in dose of concomitant CYP2D6 substrates. 7.2 Other Drug Interactions with Effexor XR Central Nervous System (CNS)-Active Drugs The risk of using venlafaxine concomitantly with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised when Effexor XR is taken concomitantly in combination with other CNS-active drugs. Weight Loss Agents Concomitant use of Effexor XR and weight loss agents is not recommended. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Effexor XR is not indicated for weight loss alone or in combination with other products. Laboratory Test Interference False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine 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 mechanism of action of venlafaxine in the treatment of MDD, GAD, SAD, and PD is unclear, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. 12.2 Pharmacodynamics In vitro studies have demonstrated that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H 1 -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 at 450 mg (2 times the maximum recommended dosage) was detected. 12.3 Pharmacokinetics Venlafaxine and ODV steady-state concentrations are reached within 3 days. Venlafaxine and ODV exhibited linear kinetics over the dosage range of 75 to 450 mg per day (0.33 to 2 times the maximum recommended dosage). Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Absorption Venlafaxine is well absorbed. 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 Effexor XR (150 mg once daily) generally resulted in lower C max and later T max values than for Effexor administered twice daily (Table 17). 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 Effexor XR capsule. Therefore, Effexor XR provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 17: Comparison of C max and T max Values for Venlafaxine and ODV Following Oral Administration of Effexor XR and Effexor (Immediate-Release) Venlafaxine ODV C max (ng/mL) T max (h) C max (ng/mL) T max (h) Effexor XR (150 mg once daily) 150 5.5 260 9 Effexor (75 mg twice daily) 225 2 290 3 Effect of Food Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Distribution Venlafaxine is 27% and ODV is 30% bound to plasma proteins. The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. Elimination Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. Metabolism 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 Figure 1). Excretion 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%). Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of venlafaxine and its active metabolite ODV is presented in Figure 1. Figure 1: Pharmacokinetics of Venlafaxine and Active Metabolite O-desmethylvenlafaxine (ODV) in Special Populations ODV=O-desmethylvenlafaxine; AUC=area under the curve; C max =peak plasma concentrations. * Similar effect is expected with strong CYP2D6 inhibitors. Figure 1: Pharmacokinetics of Venlafaxine and Active Metabolite O-desmethylvenlafaxine (ODV) in Special Populations Drug Interaction Studies Clinical Studies Effect of Other Drugs on Effexor XR and Active Metabolite ODV The effects of other drugs on the exposure of venlafaxine and ODV are summarized in Figure 2. Figure 2: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O‑desmethylvenlafaxine (ODV) ODV=O-desmethylvenlafaxine; AUC=area under the curve; C max =peak plasma concentrations; EM’s=extensive metabolizers; PM’s=poor metabolizers. Effect of Effexor XR on Other Drugs The effects of Effexor XR on the exposure of other drugs are summarized in Figure 3. Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites AUC=area under the curve; C max =peak plasma concentrations; OH=hydroxyl. * Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C max 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: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O desmethylvenlafaxine (ODV) Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites

12.1 Mechanism of Action The mechanism of action of venlafaxine in the treatment of MDD, GAD, SAD, and PD is unclear, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake.

12.2 Pharmacodynamics In vitro studies have demonstrated that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H 1 -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 at 450 mg (2 times the maximum recommended dosage) was detected.

12.3 Pharmacokinetics Venlafaxine and ODV steady-state concentrations are reached within 3 days. Venlafaxine and ODV exhibited linear kinetics over the dosage range of 75 to 450 mg per day (0.33 to 2 times the maximum recommended dosage). Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Absorption Venlafaxine is well absorbed. 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 Effexor XR (150 mg once daily) generally resulted in lower C max and later T max values than for Effexor administered twice daily (Table 17). 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 Effexor XR capsule. Therefore, Effexor XR provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 17: Comparison of C max and T max Values for Venlafaxine and ODV Following Oral Administration of Effexor XR and Effexor (Immediate-Release) Venlafaxine ODV C max (ng/mL) T max (h) C max (ng/mL) T max (h) Effexor XR (150 mg once daily) 150 5.5 260 9 Effexor (75 mg twice daily) 225 2 290 3 Effect of Food Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Distribution Venlafaxine is 27% and ODV is 30% bound to plasma proteins. The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. Elimination Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. Metabolism 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 Figure 1). Excretion 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%). Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of venlafaxine and its active metabolite ODV is presented in Figure 1. Figure 1: Pharmacokinetics of Venlafaxine and Active Metabolite O-desmethylvenlafaxine (ODV) in Special Populations ODV=O-desmethylvenlafaxine; AUC=area under the curve; C max =peak plasma concentrations. * Similar effect is expected with strong CYP2D6 inhibitors. Figure 1: Pharmacokinetics of Venlafaxine and Active Metabolite O-desmethylvenlafaxine (ODV) in Special Populations Drug Interaction Studies Clinical Studies Effect of Other Drugs on Effexor XR and Active Metabolite ODV The effects of other drugs on the exposure of venlafaxine and ODV are summarized in Figure 2. Figure 2: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O‑desmethylvenlafaxine (ODV) ODV=O-desmethylvenlafaxine; AUC=area under the curve; C max =peak plasma concentrations; EM’s=extensive metabolizers; PM’s=poor metabolizers. Effect of Effexor XR on Other Drugs The effects of Effexor XR on the exposure of other drugs are summarized in Figure 3. Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites AUC=area under the curve; C max =peak plasma concentrations; OH=hydroxyl. * Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C max 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: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O desmethylvenlafaxine (ODV) Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites

20230815

2

3 DOSAGE FORMS AND STRENGTHS Effexor XR ® is available in the following strengths: • 37.5 mg extended-release capsule: grey cap and peach body with “W” and “Effexor XR” on the cap and “37.5” on the body • 75 mg extended-release capsule: peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body • 150 mg extended-release capsule: dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body • Extended-release capsules: 37.5 mg, 75 mg, and 150 mg ( 3 ).

Effexor XR VENLAFAXINE HYDROCHLORIDE VENLAFAXINE HYDROCHLORIDE VENLAFAXINE POWDERED CELLULOSE GELATIN, UNSPECIFIED FERRIC OXIDE RED TITANIUM DIOXIDE ETHYLCELLULOSE (100 MPA.S) HYPROMELLOSE, UNSPECIFIED HYPROMELLOSE 2910 (6 MPA.S) PEACH GRAY CAPSULE W;EffexorXR;375 Effexor XR VENLAFAXINE HYDROCHLORIDE VENLAFAXINE HYDROCHLORIDE VENLAFAXINE POWDERED CELLULOSE GELATIN, UNSPECIFIED FERRIC OXIDE RED TITANIUM DIOXIDE ETHYLCELLULOSE (100 MPA.S) HYPROMELLOSE, UNSPECIFIED HYPROMELLOSE 2910 (6 MPA.S) PEACH CAPSULE W;EffexorXR;75 Effexor XR VENLAFAXINE HYDROCHLORIDE VENLAFAXINE HYDROCHLORIDE VENLAFAXINE POWDERED CELLULOSE GELATIN, UNSPECIFIED FERRIC OXIDE RED TITANIUM DIOXIDE ETHYLCELLULOSE (100 MPA.S) HYPROMELLOSE, UNSPECIFIED HYPROMELLOSE 2910 (6 MPA.S) DARK ORANGE CAPSULE W;EffexorXR;150

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 ODV were lower in rats than in patients receiving the maximum recommended dose. 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, when desvenlafaxine succinate, the major human metabolite of venlafaxine, was administered orally to male and female rats, fertility was reduced at the high dose of 300 mg/kg/day, which is 10 (males) and 19 (females) times the AUC exposure at an adult human dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day, which is 3 (males) or 5 (females) times the AUC exposure at an adult human dose of 100 mg per day. These studies did not address reversibility of the effect on fertility. The relevance of these findings to humans is not known.

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 ODV were lower in rats than in patients receiving the maximum recommended dose. 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, when desvenlafaxine succinate, the major human metabolite of venlafaxine, was administered orally to male and female rats, fertility was reduced at the high dose of 300 mg/kg/day, which is 10 (males) and 19 (females) times the AUC exposure at an adult human dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day, which is 3 (males) or 5 (females) times the AUC exposure at an adult human dose of 100 mg per day. These studies did not address reversibility of the effect on fertility. The relevance of these findings to humans is not known.

NDA020699

Effexor XR

VENLAFAXINE HYDROCHLORIDE

58151-127

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL – 37.5 mg ALWAYS DISPENSE WITH MEDICATION GUIDE NDC 58151-125-93 Effexor XR ® (venlafaxine HCl) Extended-Release Capsules 37.5 mg* 30 Capsules Rx only Store at controlled room temperature 20° to 25°C (68° to 77°F). USUAL DOSAGE See accompanying prescribing information. Package intended to be dispensed as a unit. *Each capsule contains venlafaxine HCI equivalent to 37.5 mg venlafaxine. Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. Made in Ireland © 2023 Viatris Inc. RUPJ125H Effexor XR Extended-Release Capsules 37.5 mg Bottle Label

Warnings and Precautions ( 5.2 , 5.4 ) 8/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1) ] . Concomitant Medication Instruct patients not to take Effexor XR with an MAOI or within 14 days of stopping an MAOI [see Contraindications (4) ] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of Effexor XR with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [ s ee Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . Elevated Blood Pressure Advise patients that they should have regular monitoring of blood pressure when taking Effexor XR [see Warnings and Precautions (5.3) ] . Increased Risk of Bleeding Inform patients about the concomitant use of Effexor XR with NSAIDs, aspirin, other antiplatelet drugs, warfarin, or other drugs that affect coagulation because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.4) ] . Activation of Mania/Hypomania Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.6) ] . Cardiovascular/Cerebrovascular Disease Caution is advised in administering Effexor XR 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 Adverse Reactions (6.1) ] . Discontinuation Syndrome Advise patients not to abruptly stop taking Effexor XR without talking first with their healthcare provider. Patients should be aware that discontinuation effects may occur when stopping Effexor XR and they should monitor for discontinuation symptoms [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ] . Sexual Dysfunction Advise patients that use of Effexor XR may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.13) ]. Interference with Cognitive and Motor Performance Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor XR therapy does not adversely affect their ability to engage in such activities. Alcohol Advise patients to avoid alcohol while taking Effexor XR [see Drug Interactions (7.2) ] . Allergic Reactions Advise patients to notify their healthcare provider if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing [see Contraindications (4) and Adverse Reactions (6.2) ] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Effexor XR. Advise patients that Effexor XR use during mid to late pregnancy may lead to an increased risk for preeclampsia and may increase the risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Effexor XR during pregnancy [see Use in Specific Populations (8.1) ] . Residual Spheroids Effexor XR 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. Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. Made in Ireland © 2023 Viatris Inc. EFFEXOR XR is a registered trademark of Viatris Specialty LLC, a Viatris Company. UPJ:EFFXRXR:RX2

MEDICATION GUIDE EFFEXOR XR (e-fex-or XR) (venlafaxine extended-release) capsules What is the most important information I should know about EFFEXOR XR? EFFEXOR XR may cause serious side effects, including: • Increased risk of suicidal thoughts and actions. EFFEXOR XR and other antidepressant medicines may increase suicidal thoughts and actions in some children, adolescents, and young adults, especially within the first few months of treatment or when the dose is changed. EFFEXOR XR is not for use in children. o Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? o Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency help right away if you or a family member have any of the following symptoms, especially if they are new, worse, or worry you: • attempts to commit suicide • acting aggressive, being angry, or violent • new or worse depression • panic attacks • new or worse irritability • an extreme increase in activity or talking (mania) • thoughts about suicide or dying • acting on dangerous impulses • new or worse anxiety • feeling very agitated or restless • trouble sleeping • other unusual changes in behavior or mood What is EFFEXOR XR? EFFEXOR XR is a prescription medicine used to treat adults with: • a certain type of depression called Major Depressive Disorder (MDD) • Generalized Anxiety Disorder (GAD) • Social Anxiety Disorder (SAD) • Panic Disorder (PD) It is not known if EFFEXOR XR is safe and effective for use in children. Do not take EFFEXOR XR if you: • are allergic to venlafaxine hydrochloride, desvenlafaxine succinate, or any of the ingredients in EFFEXOR XR. See the end of this Medication Guide for a complete list of ingredients in EFFEXOR XR. • take a Monoamine Oxidase Inhibitor (MAOI) • have stopped taking an MAOI in the last 14 days • are being treated with the antibiotic linezolid or intravenous methylene blue Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including MAOIs such as linezolid or intravenous methylene blue. Do not start taking an MAOI for at least 7 days after you stop treatment with EFFEXOR XR. Before taking EFFEXOR XR tell your healthcare provider about all your medical conditions, including if you: • have, or have a family history of suicide, bipolar disorder, depression, mania or hypomania • have high blood pressure • have heart problems • have cerebrovascular problems or had a stroke • have or have had bleeding problems • have high pressure in the eye (glaucoma) • have high cholesterol or high triglycerides • have kidney or liver problems • have or had seizures or convulsions • have low sodium levels in your blood • have lung problems • drink alcohol • are pregnant or plan to become pregnant. EFFEXOR XR may harm your unborn baby. Talk to your healthcare provider about the risk to you and your unborn baby if you take EFFEXOR XR during pregnancy. o Tell your healthcare provider if you become pregnant or think you are pregnant during treatment with EFFEXOR XR. o Pregnancy Exposure Registry. There is a pregnancy registry for women who are exposed to EFFEXOR XR during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with EFFEXOR XR, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or by visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. • are breastfeeding or plan to breastfeed. EFFEXOR XR passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with EFFEXOR XR. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. EFFEXOR XR and other medicines may affect each other causing possible serious side effects. EFFEXOR XR may affect the way other medicines work and other medicines may affect the way EFFEXOR XR works. Especially tell your healthcare provider if you take: • medicines to treat migraine headaches known as triptans • tricyclic antidepressants • lithium • tramadol, fentanyl, meperidine, methadone, or other opioids • tryptophan • buspirone • amphetamines • St. John’s Wort • phentermine • other medicines containing desvenlafaxine or venlafaxine • medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take EFFEXOR XR with your other medicines. Do not start or stop any other medicines during treatment with EFFEXOR XR without first talking to your healthcare provider. Stopping EFFEXOR XR suddenly may cause you to have serious side effects. See “What are the possible side effects of EFFEXOR XR?” Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I take EFFEXOR XR? • Take EFFEXOR XR exactly as your healthcare provider tells you to. Do not change your dose or stop taking EFFEXOR XR without first talking to your healthcare provider. • Your healthcare provider may need to change the dose of EFFEXOR XR until it is the right dose for you. • Take EFFEXOR XR 1 time each day with food. • EFFEXOR may be taken either in the morning or in the evening, but take it the same way each time. • Swallow EFFEXOR XR whole with fluid. Do not divide, crush, chew, or dissolve EFFEXOR XR. • If you cannot swallow EFFEXOR XR capsules whole, the EFFEXOR XR capsules may be opened and the entire contents sprinkled on a spoonful of applesauce. o Swallow the EFFEXOR XR and applesauce mixture right away without chewing. o Follow with a glass of water to make sure you have swallowed all of the EFFEXOR XR pellets. • If you take too much EFFEXOR XR, call your healthcare provider or poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should I avoid while taking EFFEXOR XR? • Do not drive, or operate heavy machinery, or do other dangerous activities until you know how EFFEXOR XR affects you. EFFEXOR XR can make you drowsy. • You should not drink alcohol during treatment with EFFEXOR XR. Drinking alcohol during treatment with EFFEXOR XR can increase your risk of having serious side effects. What are the possible side effects of EFFEXOR XR? EFFEXOR XR may cause serious side effects, including: • See “What is the most important information I should know about EFFEXOR XR?” • Serotonin syndrome. Taking EFFEXOR XR can cause a potentially life-threatening problem called serotonin syndrome. The risk of developing serotonin syndrome is increased when EFFEXOR XR is taken with certain other medicines. See “Do not take EFFEXOR XR if you:” Stop taking EFFEXOR XR and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: o agitation o confusion o fast heartbeat o dizziness o flushing o tremors, stiff muscles, or muscle twitching o seizures o seeing or hearing things that are not real (hallucinations) o coma o changes in blood pressure o sweating o high body temperature (hyperthermia) o loss of coordination o nausea, vomiting, diarrhea • Increases in blood pressure. Your healthcare provider should check your blood pressure before starting treatment and regularly during treatment with EFFEXOR XR. If you have high blood pressure, it should be controlled before you start treatment with EFFEXOR XR. • Increased risk of bleeding. Taking EFFEXOR XR with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or blood thinners may add to this risk. Tell your healthcare provider right away about any unusual bleeding or bruising. • Eye problems (angle-closure glaucoma). EFFEXOR XR may cause a certain type of eye problem called angle‑closure glaucoma. 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 if you have eye pain, changes in your vision, or swelling or redness in or around the eye . • Manic episodes. Manic episodes may happen in people with bipolar disorder who take EFFEXOR XR. Symptoms may include: o greatly increased energy o racing thoughts o unusually grand ideas o talking more or faster than usual o severe trouble sleeping o reckless behavior o excessive happiness or irritability • Discontinuation syndrome. Suddenly stopping EFFEXOR XR may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: o dizziness o irritability and agitation o anxiety o sweating o seizures o ringing in your ears (tinnitus) o nausea o problems sleeping o tiredness o confusion o electric shock sensation (paresthesia) o headache o diarrhea o abnormal dreams o changes in your mood o hypomania • Seizures (convulsions). • Low sodium levels in your blood (hyponatremia). Low sodium levels can happen during treatment with EFFEXOR XR. Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and symptoms of low sodium levels in your blood may include: o headache o difficuty concentrating o memory changes o confusion o weakness and unsteadiness on your feet which can lead to falls In severe or more sudden cases, signs and symptoms include: o hallucinations (seeing or hearing things that are not real) o fainting o seizures o coma o respiratory arrest • Lung problems. Some people who have taken the medicine venlafaxine, which is the same kind of medicine as the medicine in EFFEXOR XR, have had lung problems. Symptoms of lung problems include difficulty breathing, cough, or chest discomfort. Tell your healthcare provider right away if you have any of these symptoms. • Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SNRIs), including EFFEXOR XR, may cause sexual problems. Symptoms in males may include: o delayed ejaculation or inability to have an ejaculation o decreased sex drive o problems getting or keeping an erection Symptoms in females may include: o decreased sex drive o delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with EFFEXOR XR. There may be treatments your healthcare provider can suggest. Your healthcare provider may tell you to stop taking EFFEXOR XR if you develop serious side effects during treatment with EFFEXOR XR. The most common side effects of EFFEXOR XR include: • nausea • dry mouth • male and female sexual problems • loss of appetite (anorexia) • sleepiness • sweating • constipation These are not all the possible side effects of EFFEXOR XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store EFFEXOR XR? • Store EFFEXOR XR at room temperature between 68°F to 77°F (20°C to 25°C). • Keep EFFEXOR XR in a dry place. Keep EFFEXOR XR and all medicines out of the reach of children. General information about the safe and effective use of EFFEXOR XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EFFEXOR XR for a condition for which it was not prescribed. Do not give EFFEXOR XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about EFFEXOR XR that is written for healthcare professionals. What are the ingredients in EFFEXOR XR? Active ingredient: venlafaxine Inactive ingredients: cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide. Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. Made in Ireland © 2023 Viatris Inc. EFFEXOR XR is a registered trademark of Viatris Specialty LLC, a Viatris Company. UPJ:MG:EFFXRXR:RX2 For more information about EFFEXOR XR, call Viatris at 1-877-446-3679 (1-877-4-INFO-RX). This Medication was approved by the U.S. Food and Drug Administration. Revised: 8/2023

Clinical Studies Effect of Other Drugs on Effexor XR and Active Metabolite ODV The effects of other drugs on the exposure of venlafaxine and ODV are summarized in Figure 2. Figure 2: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O‑desmethylvenlafaxine (ODV) ODV=O-desmethylvenlafaxine; AUC=area under the curve; C max =peak plasma concentrations; EM’s=extensive metabolizers; PM’s=poor metabolizers. Effect of Effexor XR on Other Drugs The effects of Effexor XR on the exposure of other drugs are summarized in Figure 3. Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites AUC=area under the curve; C max =peak plasma concentrations; OH=hydroxyl. * Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C max 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: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O desmethylvenlafaxine (ODV) Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites

8.5 Geriatric Use The percentage of patients in clinical studies for Effexor XR for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 16. Table 16: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indication In addition, in the premarketing assessment of Effexor (immediate-release), 12% (357/2,897) of patients were ≥ 65 years of age. Indication Effexor XR 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 Effexor XR, 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 1). 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 (2.8 , 2.9) ] .

8.4 Pediatric Use Safety and effectiveness of Effexor XR in pediatric patients have not been established. 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 Effexor XR, and the data were not sufficient to support use in pediatric patients. In the studies conducted in pediatric patients ages 6 to 17 years, the occurrence of blood pressure and cholesterol increases was considered to be clinically relevant in pediatric patients and was similar to that observed in adult patients [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) ] . The following adverse reactions were also observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height [see Warnings and Precautions (5.10 , 5.11) ]. Decreased appetite and weight loss were observed in placebo-controlled studies of pediatric patients 6 to 17 years. In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning , Warnings and Precautions (5.1) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including Effexor XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ . Risk Summary Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.4) and Clinical Considerations ] . Available data from published epidemiologic studies on venlafaxine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes (see Data ) . Available data from observational studies with venlafaxine have identified a potential increased risk for preeclampsia when used during mid to late pregnancy; exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage (see Clinical Considerations ) . There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including Effexor XR, during pregnancy (see Clinical Considerations ) . In animal studies, there was no evidence of malformations or fetotoxicity following administration of venlafaxine during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m 2 basis. Postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m 2 ) the maximum human daily dose. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depression who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Exposure to Effexor XR in mid to late pregnancy may increase the risk for preeclampsia, and exposure to Effexor XR in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.4) ] Fetal/Neonatal Adverse Reactions Neonates exposed to SNRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of 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) ]. Monitor neonates who were exposed to Effexor XR in the third trimester of pregnancy for drug discontinuation syndrome (see Data ). Data Human Data Published epidemiological studies of pregnant women exposed to venlafaxine have not established an increased risk of major birth defects, miscarriage or other adverse developmental outcomes. Methodological limitations may both fail to identify true findings and also identify findings that are not true. Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted [adj] RR 1.57, 95% confidence interval [CI] 1.29-1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg per day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10-20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg per day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders. Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24 [95% CI 1.69-2.97]). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64-1.76). The results of this study may be confounded by the effects of depression. Animal Data 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/m 2 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/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m 2 basis. When desvenlafaxine succinate, the major metabolite of venlafaxine, was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no fetal malformations were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Third trimester use may increase risk for symptoms of poor neonatal adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including Effexor XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ . Risk Summary Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.4) and Clinical Considerations ] . Available data from published epidemiologic studies on venlafaxine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes (see Data ) . Available data from observational studies with venlafaxine have identified a potential increased risk for preeclampsia when used during mid to late pregnancy; exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage (see Clinical Considerations ) . There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including Effexor XR, during pregnancy (see Clinical Considerations ) . In animal studies, there was no evidence of malformations or fetotoxicity following administration of venlafaxine during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m 2 basis. Postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m 2 ) the maximum human daily dose. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depression who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Exposure to Effexor XR in mid to late pregnancy may increase the risk for preeclampsia, and exposure to Effexor XR in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.4) ] Fetal/Neonatal Adverse Reactions Neonates exposed to SNRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of 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) ]. Monitor neonates who were exposed to Effexor XR in the third trimester of pregnancy for drug discontinuation syndrome (see Data ). Data Human Data Published epidemiological studies of pregnant women exposed to venlafaxine have not established an increased risk of major birth defects, miscarriage or other adverse developmental outcomes. Methodological limitations may both fail to identify true findings and also identify findings that are not true. Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted [adj] RR 1.57, 95% confidence interval [CI] 1.29-1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg per day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10-20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg per day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders. Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24 [95% CI 1.69-2.97]). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64-1.76). The results of this study may be confounded by the effects of depression. Animal Data 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/m 2 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/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m 2 basis. When desvenlafaxine succinate, the major metabolite of venlafaxine, was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no fetal malformations were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day. 8.2 Lactation Risk Summary Data from published literature report the presence of venlafaxine and its active metabolite in human milk and have not shown adverse reactions in breastfed infants (see Data ) . There are no data on the effects of venlafaxine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Effexor XR and any potential adverse effects on the breastfed child from Effexor XR or from the underlying maternal condition. Data In a lactation study conducted in 11 breastfeeding women (at a mean of 20.1 months post-partum) who were taking a mean daily dose of 194.3 mg of venlafaxine and in a lactation study conducted in 6 breastfeeding women who were taking a daily dose of 225 mg to 300 mg of venlafaxine (at a mean of 7 months post-partum), the estimated mean relative infant dose was 8.1% and 6.4% based on the sum of venlafaxine and its major metabolite, desvenlafaxine. No adverse reactions were seen in the infants. 8.4 Pediatric Use Safety and effectiveness of Effexor XR in pediatric patients have not been established. 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 Effexor XR, and the data were not sufficient to support use in pediatric patients. In the studies conducted in pediatric patients ages 6 to 17 years, the occurrence of blood pressure and cholesterol increases was considered to be clinically relevant in pediatric patients and was similar to that observed in adult patients [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) ] . The following adverse reactions were also observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. Although no studies have been designed to primarily assess Effexor XR’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height [see Warnings and Precautions (5.10 , 5.11) ]. Decreased appetite and weight loss were observed in placebo-controlled studies of pediatric patients 6 to 17 years. In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning , Warnings and Precautions (5.1) ] . 8.5 Geriatric Use The percentage of patients in clinical studies for Effexor XR for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 16. Table 16: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indication In addition, in the premarketing assessment of Effexor (immediate-release), 12% (357/2,897) of patients were ≥ 65 years of age. Indication Effexor XR 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 Effexor XR, 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 1). 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 (2.8 , 2.9) ] . 8.6 Hepatic Impairment Dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment or hepatic cirrhosis [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment Dosage adjustment is recommended in patients with mild (CLcr = 60-89 mL/min), moderate (CLcr = 30-59 mL/min), or severe (CLcr <30 mL/min) renal impairment, and in patients undergoing hemodialysis [see Dosage and Administration (2.9) and Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Effexor XR ® is available as: • 37.5 mg, grey cap/peach body with “W” and “Effexor XR” on the cap and “37.5” on the body. NDC 58151-125-93, bottle of 30 capsules in unit-of-use package. NDC 58151-125-77, bottle of 90 capsules in unit-of-use package. • 75 mg, peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body. NDC 58151-126-93, bottle of 30 capsules in unit-of-use package. NDC 58151-126-77, bottle of 90 capsules in unit-of-use package. • 150 mg, dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body. NDC 58151-127-93, bottle of 30 capsules in unit-of-use package. NDC 58151-127-77, bottle of 90 capsules in unit-of-use package. Store at controlled room temperature, 20° to 25°C (68° to 77°F).

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1) ] . Effexor XR is not approved for use in pediatric patients [see Use in Specific Populations (8.4) ] . WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thoughts and behavior in pediatric patients and young adults taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ). • Effexor XR is not approved for use in pediatric patients ( 8.4 ).