Effexor

Warnings and Precautions ( 5.2 , 5.4 ) 8/2023

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 impairme …

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 ).

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 ).

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 patien …

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.

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, …

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.

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

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.

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).