venlafaxine

1 INDICATIONS AND USAGE Venlafaxine Extended-Release Tablets are indicated in adults for the treatment of: Major depressive disorder (MDD) Generalized Anxiety Disorder (GAD) Venlafaxine Extended-Release Tablets are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated in adults for the treatment of: Major Depressive Disorder (MDD) ( 1 ) Generalized Anxiety Disorder (GAD) ( 1 )

2 DOSAGE AND ADMINISTRATION Do not initiate treatment with Venlafaxine Extended-Release Tablets. Use another venlafaxine extended-release product for initial dosage, titration, and dosages below 112.5 mg once daily ( 2.1 ). Take once daily with food. Swallow tablets whole with fluid. Do not divide, crush, chew, or place in water ( 2.1 ). Venlafaxine Extended-Release Tablets can be initiated at 112.5 mg once daily in patients who have received at least 75 mg of another venlafaxine extended-release product for at least 4 days ( 2.2 , 2.3 ). Maximum recommended dosage is 225 mg once daily ( 2.2 , 2.3 ). When discontinuing treatment, reduce the dose gradually. Gradual dosage reduction will require the use of another venlafaxine extended-release product ( 2.8 , 5.7 ). Hepatic and Renal impairment: Maximum recommended dosage of Venlafaxine Extended-Release Tablets is 112.5 mg once daily. Switch to another venlafaxine extended-release product if doses lower than 112.5 mg are needed ( 2.6 , 2.7 ). 2.1 Important Dosing and Administration Information Do not initiate venlafaxine treatment, titrate by doses less than 112.5 mg, or taper treatment with Venlafaxine Extended-Release Tablets, as dosing is not possible in these scenarios because Venlafaxine Extended-Release Tablets are only available in a 112.5 mg strength. Use another venlafaxine extended-release product for dosage initiation, titration, administration of dosages below 112.5 mg once daily, and to taper during discontinuation [see Dosage and Administration ( 2.6 , 2.7 , 2.8 )] . Refer to the Prescribing Information of other venlafaxine extended-release products for the recommended dosage of those products in these dosing scenarios. Venlafaxine Extended-Release Tablets can be initiated in patients who have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days [see Dosage and Administration ( 2.2 , 2.3 )] . Administer Venlafaxine Extended-Release Tablets as once daily with food, either in the morning or in the evening at approximately the same time each day [see Clinical Pharmacology ( 12.3 )] . Swallow tablets whole with fluid. Do not divide, crush, chew, or place in water. 2.2 Recommended Dosage for the Treatment of Major Depressive Disorder Initiate Venlafaxine Extended-Release Tablets at a dosage of 112.5 mg once daily in patients who have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days [see Dosage and Administration ( 2.1 )] . Patients not responding to their current venlafaxine dosage may benefit from dose increases to a maximum of 225 mg per day. Increase the dosage in increments of up to 75 mg per day, as needed, using another venlafaxine extended-release product at intervals of 4 days or more. 2.3 Recommended Dosage for the Treatment of Generalized Anxiety Disorder Initiate Venlafaxine Extended-Release Tablets at a dosage of 112.5 mg once daily in patients who have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days [see Dosage and Administration ( 2.1 )] . Patients not responding to their current venlafaxine dosage may benefit from dose increases to a maximum of 225 mg per day. Increase the dosage in increments of up to 75 mg per day, as needed, using another venlafaxine extended-release product at intervals of 4 days or more. 2.4 Screen for Bipolar Disorder Prior to Starting Venlafaxine Extended-Release Tablets Prior to initiating treatment with Venlafaxine Extended-Release Tablets, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.6 )] . 2.5 Switching Patients from Venlafaxine Tablets (Immediate-Release Formulation) Patients who are currently receiving venlafaxine tablets (immediate-release formulation) may be switched to Venlafaxine Extended-Release Tablets at the nearest equivalent dose (mg per day) if the total daily dosage is either 112.5 mg or 225…

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue Venlafaxine Extended-Release Tablets and serotonergic agents and initiate supportive treatment ( 4 , 5.2 , 7.1 ). Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3 ). Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk ( 5.4 ). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.5 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 2.4 , 5.6 ). Discontinuation Syndrome: Taper dose and monitor for discontinuation symptoms ( 5.7 ). Seizure: Can occur. Use with caution in patients with seizure disorder ( 5.8 ). Hyponatremia: Can occur in association with SIADH ( 5.9 ). Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.12 ). Sexual Dysfunction: Venlafaxine Extended-Release Tablets may cause symptoms of sexual dysfunction ( 5.13 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients *Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 years old 1 fewer patient ≥ 65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Venlafaxine Extended-Release Tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Venlafaxine Extended-Release Tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium…

4 CONTRAINDICATIONS Venlafaxine Extended-Release Tablets are contraindicated in patients: with known hypersensitivity to venlafaxine besylate, venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in Venlafaxine Extended-Release Tablets [see Adverse Reactions ( 6.2 )] . taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of increased risk of serotonin syndrome [see Dosage and Administration ( 2.9 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )] . Hypersensitivity to venlafaxine besylate, venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in Venlafaxine Extended-Release Tablets ( 4 ). Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI ( 4 , 5.2 , 7.1 ).

7 DRUG INTERACTIONS Alcohol: Increases the release rate of Venlafaxine Extended-Release Tablets. Avoid concomitant use ( 7.1 ). 7.1 Drugs Having Clinically Important Interactions with Venlafaxine Extended-Release Tablets Table 13: Clinically Significant Drug Interactions with Venlafaxine Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of SNRIs, including Venlafaxine Extended-Release Tablets, with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of Venlafaxine Extended-Release Tablets is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.9 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] . Other Serotonergic Drugs Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets 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 Venlafaxine Extended-Release Tablets is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Venlafaxine Extended-Release Tablets and/or concomitant serotonergic drugs [see Dosage and Administration ( 2.8 ), Warnings and Precautions ( 5.2 )] . Alcohol Clinical Impact Based on an in vitro study, alcohol increases the release rate of Venlafaxine Extended-Release Tablets [see Clinical Pharmacology ( 12.3 )] . Intervention Avoid concomitant use of alcohol during treatment with Venlafaxine Extended-Release Tablets. Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. Intervention Closely monitor patients receiving an antiplatelet or anticoagulant drug for bleeding when Venlafaxine Extended-Release Tablets is initiated or discontinued [see Warnings and Precautions ( 5.4 )] . CYP3A Inhibitors Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets with 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 venlafaxine. Intervention Consider reducing the dose of Venlafaxine Extended-Release Tablets. CYP2D6 Substrates Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets with a CYP2D6 substrate increases C max and AUC of the 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 Venlafaxine Extended-Release Tablets Weight Loss Agents The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of Venlafaxine Extended-Release Tablets and weight loss agents is not recommended. Venlafaxine Extended-Release Tablets are 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. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including Venlafaxine Extended-Release Tablets, 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/research/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 exposure to SNRIs, including Venlafaxine Extended-Release Tablets, 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 of 201 women with a history of major depression who were euthymic 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 Venlafaxine Extended-Release Tablets in mid to late pregnancy may increase the risk for preeclampsia, and exposure to Venlafaxine Extended-Release Tablets in the month before near delivery may be associated with an increased the risk for 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 Venlafaxine Extended-Release Tablets in the third trimester of p…

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 )] Seizures [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 Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of Venlafaxine Extended-Release Tablets for the treatment of MDD and GAD is based on adequate and well controlled studies of venlafaxine extended-release capsules. Below is a display of adverse reactions of venlafaxine extended-release capsules from those adequate and well-controlled studies in MDD, GAD, and other indications. Most Common Adverse Reactions The most commonly observed adverse reactions in the clinical study database in venlafaxine extended-release capsules treated patients in MDD, GAD, and other indications (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 MDD, GAD, and other indications, 12% of the 3,558 patients who received venlafaxine extended-release capsules within a dosage range of 37.5 mg to 225 mg discontinued treatment due to an adverse reaction, compared with 4% of the 2,197 placebo-treated patients in those studies [Venlafaxine Extended-Release Tablets are only available as 112.5 mg dosage strength]. The most common adverse reactions leading to discontinuation in ≥ 1% of the venlafaxine extended-release capsules treated patients in the short-term studies (up to 12 weeks) in MDD, GAD, and other indications are shown in Table 7. Table 7: Adverse Reactions Leading to Discontinuation in Venlafaxine Extended-Release Capsule Placebo-controlled Clinical Studies (up to 12 Weeks Duration) Body System Adverse Reaction Venlafaxine Extended-Release Capsules n = 3,558 Placebo n = 2,197 Body as a whole Asthenia 1.7 0.5 Headache 1.5 0.8 Digestive system Nausea 4.3 0.4 Nervous system Dizziness 2.2 0.8 Insomnia 2.1 0.6 Somnolence 1.7 0.3 Skin and appendages 1.5 0.6 Sweating 1.0 0.2 Common Adverse Reactions in Placebo-controlled Studies Common adverse reactions (those that occurred in ≥ 2% of venlafaxine extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, and 1,820 patients for other indications] and more frequently than placebo) in venlafaxine extended-re…