desvenlafaxine 100 MG Oral Tablet

INDICATIONS AND USAGE Desvenlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder (MDD) [see Clinical Studies (14) and Dosage and Administration (2.1)] . The efficacy of desvenlafaxine has been established in four short-term (8-week, placebo-controlled studies) of outpatients who met DSM-IV criteria for major depressive disorder. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of major depressive disorder (MDD) (1).

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 extended-release tablets is 50 mg once daily, with or without food. The 50 mg dose is both a starting dose and the therapeutic dose. Desvenlafaxine extended-release tablets 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 extended-release tablets (50 to 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 Extended-Release Tablets Adverse reactions may occur upon discontinuation of desvenlafaxine extended-release tablets [see Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping desvenlafaxine extended-release tablets abruptly when discontinuing therapy with desvenlafaxine extended-release tablets. In some patients, discontinuation may need to occur over a period of several months. 2.6 Switching Patients from Other Antidepressants to Desvenlafaxine Extended-Release Tablets Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine extended-release tablets. 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 extended-release tablets. Conversely, at least 7 days should be allowed after stopping desvenlafaxine extended-release tablets before starting an MAOI intended to treat psychiatric disorders [ see Contraindications ( 4 ) ] . 2.8 Use of Desvenlafaxine Extended-Release Tablets with other MAOIs such as Linezolid or Methylene Blue Do not start desvenlafaxine extended-release tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4 )] . In some cases, a patient already receiving desvenlafaxine extended-release tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, desvenlafaxine extended-release tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with desvenlafaxine extended-release tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions ( 5.2 )] . The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with desvenlafaxine extended-release tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.2 )] .

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 whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) ] . Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PRISTIQ should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that PRISTIQ is not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including PRISTIQ, 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, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7.1) ] . Serotoni

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

CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro . Desvenlafaxine also lacked monoamine oxidase (MAO) inhibitory activity. ECG changes Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval. 12.3 Pharmacokinetics The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional in a dose range of 50 to 600 mg (1 to 12 times the recommended approved dosage) per day. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4 to 5 days. At steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile. Absorption The absolute oral bioavailability of desvenlafaxine extended-release tablets after oral administration is about 80%. Effect of Food Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine Cmax about 16% and had no effect on AUC. Distribution Steady-state volume of distribution of desvenlafaxine is 3.4 L/kg. Plasma protein binding of desvenlafaxine is 30% and is independent of drug concentration. Elimination Metabolism Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. Excretion Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine. Specific Populations No clinically significant differences in the exposures of desvenlafaxine were observed based on ethnicity (White, Black, Hispanic). The effect of intrinsic patient factors on the pharmacokinetics of desvenlafaxine is presented in Figure 1. Figure 1 Impact of Intrinsic Factors (Renal, Hepatic Impairment and Population Description) on Desvenlafaxine Pharmacokinetics Drug Interaction Studies Clinical Studies Other Drugs on desvenlafaxine extended-release tablets The effect of ketoconazole on the exposures of desvenlafaxine is summarized in Figure 2. Figure 2. Effect of Other Drugs on Desvenlafaxine Pharmacokinetics Desvenlafaxine extended-release tablets on Other Drugs The effects of desvenlafaxine extended-release tablets on the exposures of other drugs are summarized in Figure 3. Figure 3. Effects of desvenlafaxine extended-release tablets on Pharmacokinetics of Other Drugs In Vitro Studies Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of desvenlafaxine. Desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19 CYP2D6, or CYP3A4 isozymes. Desvenlafaxine does not induce CYP3A4 either. Desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein (P-gp) transporter. image description image description image description