Effexor XR

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 58151-125

Application: NDA020699

Effective: 20230815

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 )

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) ] .

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 ).

Not available.

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) ]