Desvenlafaxine

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

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 PRISTIQ is 50 mg once daily, with or without food. The 50 mg dose is both a starting dose and the therapeutic dose. PRISTIQ 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 PRISTIQ (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 PRISTIQ Adverse reactions may occur upon discontinuation of PRISTIQ [see Warnings and Precautions (5.7) ]. Gradually reduce the dosage rather than stopping PRISTIQ abruptly when discontinuing therapy with PRISTIQ. In some patients, discontinuation may need to occur over a period of several months. 2.6 Switching Patients From Other Antidepressants to PRISTIQ Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to PRISTIQ. 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 PRISTIQ. Conversely, at least 7 days should be allowed after stopping PRISTIQ before starting an MAOI intended to treat psychiatric disorders [see Contraindicat

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 Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc., at 1-800-438-1985 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 PRISTIQ 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 PRISTIQ; 2,116 were exposed to PRISTIQ 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 PRISTIQ (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 PRISTIQ (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of PRISTIQ 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 PRISTIQ 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 PRISTIQ 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 PRISTIQ 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 PRISTIQ System Organ Class Preferred Term Placebo (n=636) 50 mg (n=317) 100 mg (n=424) 200 mg (n=30

5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue PRISTIQ and serotonergic agents and initiate supportive treatment ( 5.2 ). • 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 this risk ( 5.4 ). • Angle Closure Glaucoma: Avoid use of antidepressants, including PRISTIQ, in patients with untreated anatomically narrow angles treated ( 5.5 ). • Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder. Caution patients about risk of activation of mania/hypomania ( 5.6 ). • Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms ( 5.7 ). • Seizure: Can occur. Use cautiously in patients with seizure disorder ( 5.8 ). • Hyponatremia: Can occur in association with SIADH ( 5.9 ). • Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.10 ). • Sexual Dysfunction: PRISTIQ may cause symptoms of sexual dysfunction ( 5.11 ). 5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown w

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

10 OVERDOSAGE 10.1 Human Experience with Overdosage There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine (PRISTIQ) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of PRISTIQ) 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 PRISTIQ) 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 PRISTIQ 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.