desvenlafaxine succinate

Warnings and Precautions ( 5.2 , 5.4 ) 8/2023

1 INDICATIONS AND USAGE Desvenlafaxine is indicated for the treatment of adults with major depressive disorder (MDD) [see Clinical Studies ( 14 )]. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of adults with major depressive disorder (MDD) ( 1 ).

2 DOSAGE AND ADMINISTRATION • Recommended dose: 50 mg once daily with or without food ( 2.1 ). • There was no evidence that doses greater than 50 mg per day confer any additional benefit ( 2.1 ). • The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment or dosing in severe renal and end-stage renal disease patients ( 2.1 ). • Discontinuation: Reduce dose gradually whenever possible ( 2.1 ). • Take tablets whole; do not divide, crush, chew, or dissolve ( 2.1 ). • Moderate renal impairment: Maximum dose 50 mg per day ( 2.2 ). • Severe renal impairment and end-stage renal disease: Maximum dose 25 mg per day or 50 mg every other day ( 2.2 ). • Moderate to severe hepatic impairment: Maximum dose 100 mg per day ( 2.3 ). 2.1 General Instructions for Use The recommended dose for desvenlafaxine is 50 mg once daily, with or without food. The 50 mg dose is both a starting dose and the therapeutic dose. Desvenlafaxine should be taken at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved. In clinical studies, doses of 10 mg to 400 mg per day were studied. In clinical studies, doses of 50 mg to 400 mg per day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg per day and adverse reactions and discontinuations were more frequent at higher doses. The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment. When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize discontinuation symptoms [see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.7 )]. 2.2 Dosage Recommendations for Patients with Renal Impairment The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance [Cl Cr ] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose in patients with severe renal impairment (Cl Cr 15 to 29 mL/min, C-G) or end-stage renal disease (ESRD, Cl Cr < 15 mL/min, C-G) is 25 mg every day or 50 mg every other day. Supplemental doses should not be given to patients after dialysis [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 2.3 Dosage Recommendations for Patients with Hepatic Impairment The recommended dose in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]. 2.4 Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Longer-term efficacy of desvenlafaxine (50-400 mg) was established in two maintenance trials [see Clinical Studies ( 14 )]. Patients should be periodically reassessed to determine the need for continued treatment. 2.5 Discontinuing Desvenlafaxine Adverse reactions may occur upon discontinuation of desvenlafaxine [see Warnings and Precautions ( 5.7 )]. Gradually reduce the dosage rather than stopping desvenlafaxine abruptly when discontinuing therapy with desvenlafaxine. In some patients, discontinuation may need to occur over a period of several months. 2.6 Switching Patients From Other Antidepressants to Desvenlafaxine Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine. Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms. 2.7 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with desvenlafaxine. Conversely, at least 7 days should be allowed after stopping desvenlafaxin …

3 DOSAGE FORMS AND STRENGTHS • 50 mg Tablet: Pink color, circular shaped, biconvex, coated tablets debossed with M41 on one side and plain on the other side. • 100 mg Tablet: Reddish orange color, circular shaped, biconvex, coated tablets debossed with M42 on one side and plain on the other side. • Desvenlafaxine extended-release tablets: 50 mg and 100 mg ( 3 ). • Each tablet contains 76mg or 152mg of desvenlafaxine succinate equivalent to 50 mg or 100 mg of desvenlafaxine, respectively ( 3 ).

4 CONTRAINDICATIONS • Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine formulation. Angioedema has been reported in patients treated with desvenlafaxine [see Adverse Reactions ( 6.1 )]. • The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine is contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.2 )]. • Starting desvenlafaxine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration ( 2.8 ) and Warnings and Precautions ( 5.2 )]. • Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or any excipients in the desvenlafaxine formulation ( 4 ). • Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine. Do not use desvenlafaxine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start desvenlafaxine in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ).

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. • Hypersensitivity [see Contraindications ( 4 )] • Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [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 )] • Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions ( 5.10 )] • Sexual Dysfunction [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (incidence ≥5% and twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 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. Patient Exposure Desvenlafaxine was evaluated for safety in 8,394 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 2,784 patient-years of exposure. Of the total 8,394 patients exposed to at least one dose of desvenlafaxine; 2,116 were exposed to desvenlafaxine for 6 months, representing 1,658 patient-years of exposure, and 421 were exposed for one year, representing 416 patient-years of exposure. Adverse Reactions Reported as Reasons for Discontinuation of Treatment In the pre-marketing pooled 8-week placebo-controlled studies in patients with MDD, 1,834 patients were exposed to desvenlafaxine (50 to 400 mg). Of the 1,834 patients, 12% discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of desvenlafaxine the discontinuation rate due to an adverse reaction was 8.7%. The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than placebo of the desvenlafaxine treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-term study, up to 9 months, the most common was vomiting (2%). Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in desvenlafaxine treated MDD patients in pre-marketing pooled 8-week, placebo-controlled, fixed-dose studies (incidence ≥ 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders. Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of desvenlafaxine treated MDD patients and twice the rate of placebo at any dose in the pre-marketing pooled 8-week, placebo-controlled, fixed dose clinical studies . Table 2: Common Adverse Reactions (≥ 2% in any Fixed-Dose Group and Twice the Rate of Placebo) in Pre-marketing Pooled MDD 8-Week Placebo-Controlled Studies Percentage of Patients Reporting Reaction System Organ Class Preferred Term D …

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Desvenlafaxine Table 8: Clinically Important Drug Interactions with desvenlafaxine Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SSRIs and SNRIs including desvenlafaxine with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of desvenlafaxine is contraindicated: • With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with desvenlafaxine. • Within 14 days of stopping an MAOI intended to treat psychiatric disorders. • In a patient who is being treated with linezolid or intravenous methylene blue. [see Dosage and Administration ( 2.7 ), Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of desvenlafaxine with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when desvenlafaxine is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of desvenlafaxine and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )]. Examples other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of desvenlafaxine with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of desvenlafaxine on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when desvenlafaxine is initiated or discontinued [see Warnings and Precautions ( 5.4 )] . Examples NSAIDs, aspirin, and warfarin Drugs that are Primarily Metabolized by CYP2D6 Clinical Impact Concomitant use of desvenlafaxine increases Cmax and AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug [see Clinical Pharmacology ( 12.3 )] . Intervention Original dose should be taken when co-administered with desvenlafaxine 100 mg or lower. Reduce the dose of these drugs by up to one-half if co-administered with 400 mg of desvenlafaxine. Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine 7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine [see Clinical Pharmacology ( 12.3 )]. 7.3 Alcohol A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine. 7.4 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Third trimester use may result in neonatal discontinuation syndrome ( 8.1 ). • Geriatric Use: There is an increased incidence of orthostatic hypotension in desvenlafaxine treated patients ≥ 65 years ( 6.1 and 8.5 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185. 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]. There are no published studies on desvenlafaxine in pregnant women; however published epidemiologic studies of pregnant women exposed to venlafaxine, the parent compound, have not reported a clear association with adverse developmental outcomes (see Data). There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including desvenlafaxine, during pregnancy (see Clinical Considerations). In reproductive developmental studies in rats and rabbits treated with desvenlafaxine succinate, there was no evidence of teratogenicity at a plasma exposure (AUC) that is up to 19-times (rats) and 0.5-times (rabbits) the exposure at an adult human dose of 100 mg per day. However, fetotoxicity and pup deaths were observed in rats at 4.5-times the AUC exposure observed with an adult human dose of 100 mg per day. The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Maternal Adverse Reactions Exposure to desvenlafaxine in mid to late pregnancy may increase the risk for preeclampsia, and exposure to desvenlafaxine 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 Exposure to SNRIs or SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Monitor neonates who were exposed to desvenlafaxine in the third trimester of pregnancy for drug discontinuation syndrome (see Data). Data Human Data Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage. Methodological limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies cannot establish or exclude any drug-associated risk during pregnancy. 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% CI 1 …

12.1 Mechanism of Action The exact mechanism of the antidepressant action of desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that desvenlafaxine is a potent and selective SNRI.

11 DESCRIPTION Desvenlafaxine is an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder. Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C 16 H 25 NO 2 (free base) and C 16 H 25 NO 2 •C 4 H 6 O 4 •H 2 O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below. Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21. Desvenlafaxine is formulated as an extended-release tablet for once-a-day oral administration. Each tablet contains 76 mg or 152 mg of desvenlafaxine succinate equivalent to 50 mg or 100 mg of desvenlafaxine, respectively. Inactive ingredients for the 50 mg tablet consist of microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, isopropyl alcohol, talc, magnesium stearate and film coating, which consists of Hypromellose, Polyethylene Glycol 400, Polyethylene Glycol 6000, Talc, Titanium Dioxide, Red Iron Oxide and Yellow Iron Oxide. Inactive ingredients for the 100 mg tablet consist of microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, isopropyl alcohol, talc, magnesium stearate and film coating, which consists of Hypromellose, Polyethylene Glycol 400, Polyethylene Glycol 6000, Talc, Titanium Dioxide, Red Iron Oxide, Yellow Iron Oxide and FD&C Yellow No. 6 Al. Lake str

10 OVERDOSAGE 10.1 Human Experience with Overdosage There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine (desvenlafaxine) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert. In postmarketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine) 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), sinus and 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 pre-existing 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. 10.2 Management of Overdosage No specific antidotes for desvenlafaxine are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Desvenlafaxine Extended-Release Tablets are available as follows: 50 mg, pink color, circular shaped, biconvex, coated tablets debossed with M41 on one side and plain on the other side. NDC 33342-388-07, bottle of 30 tablets in unit-of-use package NDC 33342-388-10, bottle of 90 tablets in unit-of-use package NDC 33342-388-12, One carton of 100 (10 x 10 unit dose) tablets. 100 mg, reddish orange color, circular shaped, biconvex, coated tablets debossed with M42 on one side and plain on the other side. NDC 33342-389-07, bottle of 30 tablets in unit-of-use package NDC 33342-389-10, bottle of 90 tablets in unit-of-use package NDC 33342-389-12, One carton of 100 (10 x 10 unit dose) tablets. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Each tablet contains 76 mg or 152 mg of desvenlafaxine succinate equivalent to 50 mg or 100 mg of desvenlafaxine, respectively.