ADVERSE REACTIONS SECTION.

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 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)] Abnormal 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)] 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)] Abnormal 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)] 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 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 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 exposureDesvenlafaxine 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 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 treatmentIn 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 rate greater than placebo of the desvenlafaxine treated patients in the short-term studies, up to weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In longer-term study, up to 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 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 pooled 8-week, placebo-controlled, fixed dose clinical studiesTable 2: Common Adverse Reactions (>= 2% in any Fixed-Dose Groupand Twice the Rate of Placebo) in Pre-marketing Pooled MDD 8-Week Placebo-Controlled StudiesPercentage of Patients Reporting ReactionDesvenlafaxineSystem Organ Class Preferred TermPlacebo(n=636)50 mg(n=317)100 mg(n=424)200 mg(n=307)400 mg(n=317)Cardiac disordersBlood pressure increased 1 2 Gastrointestinal disordersNausea 10 22 26 36 41 Dry mouth 11 17 21 25 Constipation 9 10 14 Vomiting 3 6 General disorders and administration site conditionsFatigue 7 10 11 Chills 1 <1 4 Feeling jittery 1 3 Metabolism and nutrition disordersDecreased appetite 5 10 10 Nervous system disordersDizziness 13 10 15 16 Somnolence 4 12 12 Tremor 2 9 Disturbance in attention <1 <1 2 Psychiatric disordersInsomnia 9 12 14 15 Anxiety 3 4 Nervousness <1 2 Abnormal dreams 2 2 Renal and urinary disordersUrinary hesitation <1 2 Respiratory, thoracic and mediastinal disordersYawning <1 1 3 Skin and subcutaneous tissue disordersHyperhidrosis 10 11 18 21 Special SensesVision blurred 3 4 Mydriasis <1 2 6 Vertigo 2 5 Tinnitus 2 1 Dysgeusia 1 1 Vascular disordersHot flush <1 1 2 Sexual function adverse reactionsTable shows the incidence of sexual function adverse reactions that occurred in >= 2% of desvenlafaxine treated MDD patients in any fixed-dose group (pre-marketingpooled 8-week, placebo-controlled, fixed -dose, clinical studies). Table 3: Sexual Function Adverse Reactions (>=2% in Menor Womenin any Desvenlafaxine Group) During the On-Therapy PeriodDesvenlafaxine Placebo(n=239)50 mg(n=108)100 mg(n=157)200 mg(n=131)400 mg(n=154)Men onlyAnorgasmia 0 5 Libido decreased 4 6 Orgasm abnormal 0 2 Ejaculation delayed <1 5 6 Erectile dysfunction 3 8 11 Ejaculation disorder 0 2 Ejaculation failure 1 2 Sexual dysfunction 1 0 Placebo(n=397)Desvenlafaxine 50 mg(n=209) 100 mg(n=267) 200 mg(n=176) 400 mg(n=163) Women onlyAnorgasmia 1 0 Other adverse reactions observed in premarketing and postmarketing clinical studiesOther infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of 2% in MDD patients treated with desvenlafaxine were: Cardiac disorders tachycardia.General disorders and administration site conditions Asthenia. Investigations Weight increased, liver function test abnormal, blood prolactin increased.Musculoskeletal and connective tissue disorders Musculoskeletal stiffness. Nervous system disorders -Syncope, convulsion, dystonia. Psychiatric disorders Depersonalization, bruxism.Renal and urinary disorders Urinary retention.Skin and subcutaneous tissue disorders Rash, alopecia, photosensitivity reaction, angioedema.In clinical studies, there were uncommon reports of ischemic cardiac adverse reactions, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo.Laboratory, ECG and vital sign changes observed in MDD clinical studiesThe following changes were observed in pre-marketing placebo-controlled, short-term MDD studies with desvenlafaxine. LipidsElevations in fasting serum total cholesterol, LDL (low density lipoproteins) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant. The percentage of patients who exceeded predetermined threshold value is shown in Table 4. Table 4: Incidence (%) of Patients With Lipid Abnormalities of Potential Clinical Significance Desvenlafaxine Placebo50 mg100 mg200 mg400 mgTotal Cholesterol 3 4 10 (Increase of >= 50 mg/dl and an absolute value of >= 261 mg/dl) LDL Cholesterol 1 1 (Increase >= 50 mg/dl and an absolute value of >= 190 mg/dl) Triglycerides, fasting 2 4 (Fasting: >= 327 mg/dl) ProteinuriaProteinuria, greater than or equal to trace, was observed in the pre-marketingfixed-dose controlled studies (see Table 5). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.Table 5: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical StudiesDesvenlafaxine Placebo50 mg100 mg200 mg400 mgProteinuria 6 5 Vital sign changesTable summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine in patients with MDD (doses 50 to 400 mg). Table 6: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled StudiesDesvenlafaxine Placebo50 mg100 mg200 mg400 mgBlood pressure Supine systolicbp (mm Hg) -1.4 1.2 2.5 2.1 Supine diastolicbp (mm Hg) -0.6 0.7 0.8 1.8 2.3 Pulse rate Supine pulse(bpm) -0.3 1.3 1.3 0.9 4.1 Weight (kg)0 -0.4 -0.6 -0.9 -1.1 Treatment with desvenlafaxine at all doses from 50 mg per day to 400 mg per day in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) >=90 mm Hg and >=10 mm Hg above baseline for consecutive on-therapy visits (see Table 7). Analyses of patients in desvenlafaxine pre-marketing short-term controlled studies who met criteria for sustained hypertension revealed consistent increase in the proportion of patients who developed sustained hypertension. This was seen at all doses with suggestion of higher rate at 400 mg per day. Table 7: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood PressureTreatment GroupProportion of Patients with Sustained HypertensionPlacebo 0.5% Desvenlafaxine 50 mg per day 1.3% Desvenlafaxine 100 mg per day 0.7% Desvenlafaxine 200 mg per day 1.1% Desvenlafaxine 400 mg per day 2.3% Orthostatic hypotensionIn the pre-marketingshort-term, placebo-controlled clinical studies with doses of 50 to 400 mg, systolic orthostatic hypotension (decrease >=30 mm Hg from supine to standing position) occurred more frequently in patients >=65 years of age receiving desvenlafaxine (8%, 7/87) versus placebo (2.5%, 1/40), compared to patients <65 years of age receiving desvenlafaxine (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218). 6.2 Postmarketing Experience. The following adverse reaction has been identified during post-approval use of desvenlafaxine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:Skin and subcutaneous tissue disorders -Stevens-Johnson syndrome. Gastrointestinal system Acute pancreatitis. Cardiovascular system Takotsubo cardiomyopathy.

CLINICAL PHARMACOLOGY SECTION.

12 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 potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).. 12.2 Pharmacodynamics. Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1-histaminergic, or 1-adrenergic receptors in vitro. Desvenlafaxine also lacked monoamine oxidase (MAO) inhibitory activity. ECG changesElectrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In 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 dose range of 50 to 600 mg per day. With once-daily dosing, steady-state plasma concentrations are achieved within approximately to days. At steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile. Absorption and distributionThe absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. food-effect study involving administration of desvenlafaxine extended-release tablets to healthy subjects under fasting and fed conditions (high-fat meal, 800 to 1000 calories) indicated that desvenlafaxine Cmax was increased about 16% in the fed state, while the AUCs were similar. This difference is not expected to be clinically significant; therefore, desvenlafaxine extended-release tablets can be taken without regard to meals [see Dosage and Administration (2.1)]. The plasma protein binding of desvenlafaxine is low (30%) and is independent of drug concentration. The desvenlafaxine volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.Metabolism and eliminationDesvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after administration of 100 mg, the pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. 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.Drug interaction studiesInhibitors of CYP3A4 (ketoconazole)CYP3A4 is minor pathway for the metabolism of desvenlafaxine. In clinical study, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve (AUC) of desvenlafaxine (400 mg single dose) by about 43% and Cmax by about 8%. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher concentrations of desvenlafaxine. Inhibitors of other CYP enzymesBased 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. Drugs metabolized by CYP2D6 (e.g. desipramine, dextromethorphan, metoprolol, atomoxetine) In vitro studies showed minimal inhibitory effect of desvenlafaxine on CYP2D6. Clinical studies have shown that desvenlafaxine does not have clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. When desvenlafaxine succinate was administered at dose of 100 mg daily in conjunction with single 50 mg dose of desipramine, CYP2D6 substrate, the Cmax and AUC of desipramine increased approximately 25% and 17%, respectively. When 400 mg (8 times the recommended 50 mg dose) was administered, the Cmax and AUC of desipramine increased approximately 50% and 90%, respectively. Concomitant use of desvenlafaxine with drug metabolized by CYP2D6 can result in higher concentrations of that drug [see Drug Interactions (7.5)]. Drugs metabolized by CYP3A4 (midazolam) In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. In clinical study, desvenlafaxine 400 mg daily (8 times the recommended 50 mg dose) was co-administered with single mg dose of midazolam (a CYP3A4 substrate). The AUC and Cmax of midazolam decreased by approximately 31% and 16%, respectively. Concomitant use of desvenlafaxine with drug metabolized by CYP3A4 can result in lower exposures to that drug. Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19 In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes. In vitro, desvenlafaxine is not substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of desvenlafaxine are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter, and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter. Special populationsAgeIn study of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in Cmax and 55% increase in AUC in subjects older than 75 years of age (n 17), compared with subjects 18 to 45 years of age (n 16). Subjects 65 to 75 years of age (n 15) had no change in Cmax, but an approximately 32% increase in AUC, compared to subjects 18 to 45 years of age [see Dosage and Administration (2.2)]. GenderIn study of healthy subjects administered doses of up to 300 mg, women had an approximately 25% higher Cmax and an approximately 10% higher AUC than age-matched men. No adjustment of dosage on the basis of gender is needed. RacePharmacokinetic analysis showed that race (White, = 466; Black, = 97; Hispanic, = 39; Other, = 33) had no apparent effect on the pharmacokinetics of desvenlafaxine. No adjustment of dosage on the basis of race is needed. Hepatic insufficiencyThe disposition of desvenlafaxine succinate after administration of 100 mg was studied in subjects with mild (Child-Pugh A, = 8), moderate (Child-Pugh B, = 8), and severe (Child-Pugh C, = 8) hepatic impairment and to healthy subjects (n 12). Average AUC was increased by approximately 31% and 35% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. Average AUC values were similar in subjects with mild hepatic impairment and healthy subjects (< 5% difference). Systemic clearance (CL/F) was decreased by approximately 20% and 36% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. CL/F values were comparable in mild hepatic impairment and healthy subjects (< 5% difference).The mean t1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Use in Specific Populations (8.6)]. Renal insufficiencyThe disposition of desvenlafaxine after administration of 100 mg was studied in subjects with mild (n 9), moderate (n 8), severe (n 7) and end-stage renal disease (ESRD) (n 9) requiring dialysis and in healthy, age-matched control subjects (n 8). Elimination was significantly correlated with creatinine clearance. Increases in AUCs of about 42% in mild renal impairment (24-hr CrCl 50 to 80 mL/min, Cockcroft-Gault [C-G]), about 56% in moderate renal impairment (24-hr CrCl 30 to 50 mL/min, C-G), about 108% in severe renal impairment (24-hr CrCl <=30 mL/min, C-G), and about 116% in ESRD subjects were observed, compared with healthy, age-matched control subjects.The mean terminal half-life (t1/2) was prolonged from 11.1 hours in the control subjects to approximately 13.5, 15.5, 17.6, and 22.8 hours in mild, moderate, severe renal impairment and ESRD subjects, respectively. Less than 5% of the drug in the body was cleared during standard 4-hour hemodialysis procedure.The maximum recommended dose in patients with moderate renal impairment is 50 mg per day. Dosage adjustment of 50 mg every other day is recommended in patients with severe renal impairment or ESRD [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

DOSAGE & ADMINISTRATION SECTION.

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).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 50 mg every other day (2.2). Moderate to severe hepatic impairment: Maximum dose 100 mg per day (2.2).. 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).. 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 50 mg every other day (2.2). Moderate to severe hepatic impairment: Maximum dose 100 mg per day (2.2).. 2.1 General Instruction for Use. The recommended dose for desvenlafaxine is 50 mg once daily, with or without food. The 50 mg dose is both 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.When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize discontinuation symptoms [see Dosage and Administration (2.4) and Warnings and Precautions (5.9)]. 2.2 Special Populations. Patients with renal impairment The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance [CrCl] 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose in patients with severe renal impairment (24-hr CrCl less than 30 mL/min, C-G) or end-stage renal disease (ESRD) is 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)]. Patients with hepatic impairment The recommended dose in patients with moderate to severe hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Clinical Pharmacology (12.3)]. 2.3 Maintenance/Continuation/Extended Treatment. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Patients should be periodically reassessed to determine the need for continued treatment.. 2.4 Discontinuing Desvenlafaxine. Symptoms associated with discontinuation of desvenlafaxine, other SNRIs and SSRIs have been reported [see Warnings and Precautions (5.9)]. Patients should be monitored for these symptoms when discontinuing treatment. gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at more gradual rate. 2.5 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. 2.6 Switching Patients To or From Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disordersand initiation of therapy with desvenlafaxine. Conversely, at least days should be allowed after stopping desvenlafaxine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)]. Use of Desvenlafaxine with other MAOIs such as Linezolid or Methylene BlueDo not start desvenlafaxine in patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In patient who requires more urgent treatment of psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, patient already receiving desvenlafaxine 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 particular patient, desvenlafaxine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with desvenlafaxine 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 mg/kg with desvenlafaxine 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)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Monoamine Oxidase Inhibitors (MAOI). Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 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 patient who is being treated with linezolid or intravenous methylene blue[see Dosage and Administration (2.6 ), Contraindications (4) and Warnings and Precautions (5.2)]. 7.2 Serotonergic Drugs. Based on the mechanism of action of desvenlafaxine and the potential for serotonin syndrome, caution is advised when desvenlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems[see Dosage and Administration (2.6), Contraindications (4) and Warnings and Precautions (5.2)]. 7.3 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin). Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when desvenlafaxine is initiated or discontinued [see Warnings and Precautions (5.4)]. 7.4 Potential for Desvenlafaxine to Affect Other Drugs. Based on in vitro data, no dose adjustment is required for desvenlafaxine when used concomitantly with inhibitors of CYP3A4 and CYP1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, 2E1, and the P-glycoprotein transporter. Clinical studies have demonstrated no clinically significant pharmacokinetic interaction between desvenlafaxine and strong CYP 3A4 inhibitors (Figure 1).. Figure 1. 7.5 Potential for Desvenlafaxine to Affect Other Drugs. Clinical studies have shown that desvenlafaxine does not have clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily (Figure 2). Substrates primarily metabolized by CYP2D6 (e.g., desipramine atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) should be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. Reduce the dose of these substrates by up to one-half if co-administered with 400 mg of desvenlafaxine. No additional dose adjustment is required for concomitant use of substrates of CYP3A4, 1A2, 2A6, 2C8, 2C9, and 2C19 isozymes, and P-glycoprotein transporter. Clinical studies have demonstrated no clinically significant pharmacokinetic interaction between desvenlafaxine and CYP3A4 substrates (Figure 2). Clinical studies have shown that desvenlafaxine (100 mg daily) does not have clinically relevant effect on tamoxifen and aripiprazole, compounds that are metabolized by combination of both CYP2D6 and CYP3A4 enzymes (Figure 2). In vitro studies showed minimal inhibitory effect of desvenlafaxine on the CYP2D6 isoenzyme. In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19, isozymes, and P-glycoprotein transporter and would not be expected to affect the pharmacokinetics of drugs that are substrates of these CYP isozymes and transporter.. Figure 2. 7.6 Other Drugs Containing Desvenlafaxine or Venlafaxine. Avoid use of desvenlafaxine with other desvenlafaxine-containing products or venlafaxine products. The concomitant use of desvenlafaxine with other desvenlafaxine-containing products or venlafaxine will increase desvenlafaxine blood levels and increase dose-related adverse reactions [see Adverse Reactions (6)]. 7.7 Ethanol. 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. 7.8 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Medication Guide).Advise patients, their families, and their caregivers about the benefits and risks associated with treatment with desvenlafaxine and counsel them in its appropriate use. Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document. Suicide Risk Advise patients, their families and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down [see Boxed Warning and Warnings and Precautions (5.1)].Concomitant Medication Advise patients taking desvenlafaxine extended-release tablets not to use concomitantly other products containing desvenlafaxine or venlafaxine. Healthcare professionals should instruct patients not to take desvenlafaxine with an MAOI or within 14 days of stopping an MAOI and to allow days after stopping desvenlafaxine before starting an MAOI [see Contraindications (4)].Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of desvenlafaxine with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort supplements) [see Warnings and Precautions (5.2)]. Elevated Blood Pressure Advise patients that they should have regular monitoring of blood pressure when taking desvenlafaxine [see Warnings and Precautions (5.3)]. Abnormal Bleeding Patients should be cautioned about the concomitant use of desvenlafaxine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions (5.4)].Angle Closure Glaucoma Patients should be advised that taking desvenlafaxine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.5)].Activation of Mania/Hypomania Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.6)].Discontinuation Advise patients not to stop taking desvenlafaxine without talking first with their healthcare professional. Patients should be aware that discontinuation effects may occur when stopping desvenlafaxine [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].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.Interference with Cognitive and Motor Performance Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that desvenlafaxine therapy does not adversely affect their ability to engage in such activities.Alcohol Advise patients to avoid alcohol while taking desvenlafaxine [see Drug Interactions (7.7)].Allergic Reactions Advise patients to notify their physician if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing.Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].Nursing Advise patients to notify their physician if they are breastfeeding an infant [see Use in Specific Populations (8.3)].Residual Inert Matrix Tablet Patients receiving desvenlafaxine may notice an inert matrix tablet passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional in dose range of 50 to 600 mg per day. With once-daily dosing, steady-state plasma concentrations are achieved within approximately to days. At steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile. Absorption and distributionThe absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. food-effect study involving administration of desvenlafaxine extended-release tablets to healthy subjects under fasting and fed conditions (high-fat meal, 800 to 1000 calories) indicated that desvenlafaxine Cmax was increased about 16% in the fed state, while the AUCs were similar. This difference is not expected to be clinically significant; therefore, desvenlafaxine extended-release tablets can be taken without regard to meals [see Dosage and Administration (2.1)]. The plasma protein binding of desvenlafaxine is low (30%) and is independent of drug concentration. The desvenlafaxine volume of distribution at steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.Metabolism and eliminationDesvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after administration of 100 mg, the pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. 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.Drug interaction studiesInhibitors of CYP3A4 (ketoconazole)CYP3A4 is minor pathway for the metabolism of desvenlafaxine. In clinical study, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve (AUC) of desvenlafaxine (400 mg single dose) by about 43% and Cmax by about 8%. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher concentrations of desvenlafaxine. Inhibitors of other CYP enzymesBased 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. Drugs metabolized by CYP2D6 (e.g. desipramine, dextromethorphan, metoprolol, atomoxetine) In vitro studies showed minimal inhibitory effect of desvenlafaxine on CYP2D6. Clinical studies have shown that desvenlafaxine does not have clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. When desvenlafaxine succinate was administered at dose of 100 mg daily in conjunction with single 50 mg dose of desipramine, CYP2D6 substrate, the Cmax and AUC of desipramine increased approximately 25% and 17%, respectively. When 400 mg (8 times the recommended 50 mg dose) was administered, the Cmax and AUC of desipramine increased approximately 50% and 90%, respectively. Concomitant use of desvenlafaxine with drug metabolized by CYP2D6 can result in higher concentrations of that drug [see Drug Interactions (7.5)]. Drugs metabolized by CYP3A4 (midazolam) In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme. In clinical study, desvenlafaxine 400 mg daily (8 times the recommended 50 mg dose) was co-administered with single mg dose of midazolam (a CYP3A4 substrate). The AUC and Cmax of midazolam decreased by approximately 31% and 16%, respectively. Concomitant use of desvenlafaxine with drug metabolized by CYP3A4 can result in lower exposures to that drug. Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19 In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes. In vitro, desvenlafaxine is not substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of desvenlafaxine are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter, and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter. Special populationsAgeIn study of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in Cmax and 55% increase in AUC in subjects older than 75 years of age (n 17), compared with subjects 18 to 45 years of age (n 16). Subjects 65 to 75 years of age (n 15) had no change in Cmax, but an approximately 32% increase in AUC, compared to subjects 18 to 45 years of age [see Dosage and Administration (2.2)]. GenderIn study of healthy subjects administered doses of up to 300 mg, women had an approximately 25% higher Cmax and an approximately 10% higher AUC than age-matched men. No adjustment of dosage on the basis of gender is needed. RacePharmacokinetic analysis showed that race (White, = 466; Black, = 97; Hispanic, = 39; Other, = 33) had no apparent effect on the pharmacokinetics of desvenlafaxine. No adjustment of dosage on the basis of race is needed. Hepatic insufficiencyThe disposition of desvenlafaxine succinate after administration of 100 mg was studied in subjects with mild (Child-Pugh A, = 8), moderate (Child-Pugh B, = 8), and severe (Child-Pugh C, = 8) hepatic impairment and to healthy subjects (n 12). Average AUC was increased by approximately 31% and 35% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. Average AUC values were similar in subjects with mild hepatic impairment and healthy subjects (< 5% difference). Systemic clearance (CL/F) was decreased by approximately 20% and 36% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. CL/F values were comparable in mild hepatic impairment and healthy subjects (< 5% difference).The mean t1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Use in Specific Populations (8.6)]. Renal insufficiencyThe disposition of desvenlafaxine after administration of 100 mg was studied in subjects with mild (n 9), moderate (n 8), severe (n 7) and end-stage renal disease (ESRD) (n 9) requiring dialysis and in healthy, age-matched control subjects (n 8). Elimination was significantly correlated with creatinine clearance. Increases in AUCs of about 42% in mild renal impairment (24-hr CrCl 50 to 80 mL/min, Cockcroft-Gault [C-G]), about 56% in moderate renal impairment (24-hr CrCl 30 to 50 mL/min, C-G), about 108% in severe renal impairment (24-hr CrCl <=30 mL/min, C-G), and about 116% in ESRD subjects were observed, compared with healthy, age-matched control subjects.The mean terminal half-life (t1/2) was prolonged from 11.1 hours in the control subjects to approximately 13.5, 15.5, 17.6, and 22.8 hours in mild, moderate, severe renal impairment and ESRD subjects, respectively. Less than 5% of the drug in the body was cleared during standard 4-hour hemodialysis procedure.The maximum recommended dose in patients with moderate renal impairment is 50 mg per day. Dosage adjustment of 50 mg every other day is recommended in patients with severe renal impairment or ESRD [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

SPL MEDGUIDE SECTION.

Medication Guide. DESVENLAFAXINE extended-release tablets (des VEN la FAX een) Read this Medication Guide before you start taking desvenlafaxine and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions Talk to your healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have particularly high risk of having suicidal thoughts or actions. These include people who have (or have family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can watch for and try to prevent suicidal thoughts and actions Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying trouble sleeping (insomnia) attempts to commit suicide new or worse irritability new or worse depression acting aggressive, being angry, or violent new or worse anxiety acting on dangerous impulses feeling very agitated or restless an extreme increase in activity and talking (mania) panic attacks other unusual changes in behavior or mood What else do need to know about antidepressant medicines Never stop an antidepressant medicine without first talking to healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of this medicine. Antidepressant medicines can interact with other medicines. Know all of the medicines that you take. Keep list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your childs healthcare provider for more information. Important Information about desvenlafaxine extended-release tablets Read the patient information that comes with desvenlafaxine before you take desvenlafaxine and each time you refill your prescription. There may be new information. If you have questions, ask your healthcare provider. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. What is desvenlafaxine Desvenlafaxine is prescription medicine used to treat depression. Desvenlafaxine belongs to class of medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors). Who should not take desvenlafaxine Do not take desvenlafaxine if you: are allergic to desvenlafaxine, venlafaxine or any of the ingredients in desvenlafaxine extended-release tablets. See the end of this Medication Guide for complete list of ingredients in desvenlafaxine extended-release tablets. take monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid and the intravenous medicine methylene blue. have taken an MAOI within days of stopping desvenlafaxine unless directed by your healthcare provider. have started desvenlafaxine and if you stopped taking an MAOI in the last 14 days unless directed by your healthcare provider. What should tell my healthcare provider before taking desvenlafaxine Tell your healthcare provider about all your medical conditions, including if you: have high blood pressure have heart problems have high cholesterol or high triglycerides have history of stroke have or had depression, suicidal thoughts or behavior have kidney problems have liver problems have or had bleeding problems have or had seizures or convulsions have mania or bipolar disorder have low sodium levels in your blood are pregnant or plan to become pregnant. It is not known if desvenlafaxine will harm your unborn baby. are breastfeeding. Desvenlafaxine can pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take desvenlafaxine. Serotonin syndrome Rare, but potentially life-threatening conditions called serotonin syndrome can happen when medicines such as desvenlafaxine are taken with certain other medicines. Serotonin syndrome can cause serious changes in how your brain, muscles, heart and blood vessels, and digestive system work. Especially tell your healthcare provider if you take the following: amphetamines medicines to treat migraine headaches known as triptans medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), or other dopamine antagonists, such as metoclopramide silbutramine tramadol St. Johns Wort MAOIs (including linezolid, an antibiotic and intravenous methylene blue) tryptophan supplements Ask your healthcare provider if you are not sure if you are taking any of these medicines. Before you take desvenlafaxine with any of these medicines, talk to your healthcare provider about serotonin syndrome. See What are the possible side effects of desvenlafaxine Do not take desvenlafaxine extended-release tablets with other medicines containing venlafaxine or desvenlafaxine. How should take desvenlafaxine Take desvenlafaxine exactly as your healthcare provider has told you. Take desvenlafaxine at about the same time each day. Desvenlafaxine may be taken either with or without food. Swallow desvenlafaxine tablets whole, with fluid. Do not crush, cut, chew, or dissolve desvenlafaxine tablets because the tablets are time-released. When you take desvenlafaxine, you may see something in your stool that looks like tablet. This is the empty shell from the tablet after the medicine has been absorbed by your body. It is common for antidepressant medicines such as desvenlafaxine to take several weeks before you start to feel better. Do not stop taking desvenlafaxine if you do not feel results right away. Do not stop taking or change the dose of desvenlafaxine without talking with your healthcare provider, even if you feel better. Talk with your healthcare provider about how long you should use desvenlafaxine. Take desvenlafaxine for as long as your healthcare provider tells you to. If you miss dose of desvenlafaxine, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Do not try to make up for the missed dose by taking two doses at the same time. Do not take more desvenlafaxine than prescribed by your healthcare provider. If you take more desvenlafaxine than the amount prescribed, contact your healthcare provider right away. If you take too much desvenlafaxine, call the Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away. Switching from other antidepressants Side effects from discontinuing antidepressant medication have occurred when patients switched from other antidepressants, including venlafaxine, to desvenlafaxine. Your doctor may gradually reduce the dose of your initial antidepressant medication to help to reduce these side effects. What should avoid while taking desvenlafaxine Do not drive car or operate machinery until you know how desvenlafaxine affects you. Avoid drinking alcohol while taking desvenlafaxine. What are the possible side effects of desvenlafaxine Desvenlafaxine can cause serious side effects, including: See the beginning of this Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions. Serotonin syndrome. See What should tell my healthcare provider before taking desvenlafaxine Get medical help right away if you think that you have these syndromes. Signs and symptoms of these syndromes may include one or more of the following: restlessness increase in blood pressure hallucinations (seeing and hearing things that are not real) diarrhea loss of coordination coma fast heart beat nausea increased body temperature vomiting muscle stiffness confusion Desvenlafaxine may also cause other serious side effects, including: New or worsened high blood pressure (hypertension). Your healthcare provider should monitor your blood pressure before and while you are taking desvenlafaxine. If you have high blood pressure, it should be controlled before you start taking desvenlafaxine. Abnormal bleeding or bruising. Desvenlafaxine and other SNRIs/SSRIs may cause you to have an increased chance of bleeding. Taking aspirin, NSAIDs (non-steroidal anti-inflammatory drugs), or blood thinners may add to this risk. Tell your healthcare provider right away about any unusual bleeding or bruising. Visual problems oeye painchanges in visionswelling or redness in or around the eyeOnly some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Symptoms when stopping desvenlafaxine (discontinuation symptoms). Side effects may occur when stopping desvenlafaxine (discontinuation symptoms), especially when therapy is stopped suddenly. Your healthcare provider may want to decrease your dose slowly to help avoid side effects. Some of these side effects may include: dizziness anxiety nausea abnormal dreams headache tiredness irritability sweating sleeping problems (insomnia) diarrhea Seizures (convulsions) Low sodium levels in your blood. Symptoms of this may include: headache, difficulty concentrating, memory changes, confusion, weakness and unsteadiness on your feet. In severe or more sudden cases, symptoms can include: hallucinations (seeing or hearing things that are not real), fainting, seizures and coma. If not treated, severe low sodium levels could be fatal. Lung problems. Some people who have taken the medicine venlafaxine which is the same kind of medicine as the medicine in desvenlafaxine have had lung problems. Symptoms of lung problems include difficulty breathing, cough, or chest discomfort. Tell your healthcare provider right away if you have any of these symptoms. Common side effects with desvenlafaxine include: nausea dizziness insomnia sweating constipation sleepiness loss of appetite anxiety decreased sex drive delayed orgasm and ejaculationThese are not all the possible side effects of desvenlafaxine. Tell your healthcare provider about any side effect that bothers you or does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store desvenlafaxine Store desvenlafaxine at room temperature between 68F to 77F (20C to 25C). Do not use desvenlafaxine after the expiration date (EXP), which is on the container. The expiration date refers to the last day of that month. Keep desvenlafaxine and all medicines out of the reach of children. General Information about the safe and effective use of desvenlafaxine Medicines are sometimes used for conditions that are not mentioned in Medication Guides. Do not use desvenlafaxine for condition for which it was not prescribed. Do not give desvenlafaxine to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about desvenlafaxine. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about desvenlafaxine that is written for healthcare professionals. What are the ingredients in desvenlafaxine extended-release tablets Active ingredient: desvenlafaxine Inactive ingredients: For the 50 mg tablet, alginic acid, citric acid monohydrate powder, hypromellose, microcrystalline cellulose, povidone, talc, magnesium stearate and film coating, which consist of hypromellose, titanium dioxide, polyethylene glycol, talc, and iron oxide red. For the 100 mg tablet, alginic acid, citric acid monohydrate powder, hypromellose, microcrystalline cellulose, povidone, talc, magnesium stearate and film coating, which consist of hypromellose, titanium dioxide, polyethylene glycol, iron oxide red, and iron oxide black. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal, Gujarat, India. Revised: 09/2019. changes in vision. swelling or redness in or around the eye. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1).Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3).Geriatric Use: There is an increased incidence of orthostatic hypotension in desvenlafaxine treated patients >= 65 years (6.1 and 8.5). Pregnancy: Based on animal data, may cause fetal harm (8.1).. Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3).Geriatric Use: There is an increased incidence of orthostatic hypotension in desvenlafaxine treated patients >= 65 years (6.1 and 8.5). 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 Category CRisk summaryThere are no adequate and well-controlled studies of desvenlafaxine in pregnant women. In reproductive developmental studies in rats and rabbits with desvenlafaxine succinate, evidence of teratogenicity was not observed at doses up to 30 times human dose of 100 mg per day (on mg/m2 basis) in rats, and up to 15 times human dose of 100 mg per day (on mg/m2 basis) in rabbits. An increase in rat pup deaths was seen during the first days of lactation when dosing occurred during gestation and lactation, at doses greater than 10 times human dose of 100 mg per day (on mg/m2 basis). Desvenlafaxine should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.Clinical considerations prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience relapse of major depression than women who continued antidepressant medication.Human dataNeonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), 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, tremor, jitteriness, irritability, and constant crying. These features are consistent with either direct toxic effect of SSRIs and SNRIs or, possibly, 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)]. Animal dataWhen desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed. These doses are 30 times human dose of 100 mg per day (on mg/m2 basis) in rats and 15 times human dose of 100 mg per day (on mg/m2 basis) in rabbits. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with no-effect dose 10 times human dose of 100 mg per day (on mg/m2 basis).When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was decrease in pup weights and an increase in pup deaths during the first four days of lactation at the highest dose of 300 mg/kg/day. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 10 times human dose of 100 mg per day (on mg/m2 basis). Post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine succinate at dose 30 times human dose of 100 mg per day (on mg/m2 basis).. 8.3 Nursing Mothers. Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from desvenlafaxine, decision should be made whether or not to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established [see Boxed Warning and Warnings and Precautions (5.1)]. Anyone considering the use of desvenlafaxine in child or adolescent must balance the potential risks with the clinical need. 8.5 Geriatric Use. Of the 4,158 patients in clinical studies with desvenlafaxine, 6% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was higher incidence of systolic orthostatic hypotension in patients >=65 years of age compared to patients <65 years of age treated with desvenlafaxine [see Adverse Reactions (6)]. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. SSRIs and SNRIs, including desvenlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.9)]. 8.6 Other Patient Factors. The effect of intrinsic patient factors on the pharmacokinetics of desvenlafaxine is presented in Figure 3. Renal Impairment In subjects with renal impairment the clearance of desvenlafaxine was decreased. In subjects with severe renal impairment (24-hr CrCl <30 mL/min, Cockcroft-Gault) and end-stage renal disease, elimination half-lives were significantly prolonged, increasing exposures to desvenlafaxine; therefore, dosage adjustment is recommended in these patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment The mean terminal half life (t1/2) changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with moderate to severe hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Clinical Pharmacology (12.3)]. Figure 3.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Clinical Worsening/Suicide Risk:Monitor for clinical worsening and suicide risk (5.1). Serotonin Syndrome:Serotonin syndrome has been reported with SSRIs and SNRIs, including with desvenlafaxine extended-release tablets, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort). If such symptoms occur, discontinue desvenlafaxine and initiate supportive treatment. If concomitant use of desvenlafaxine with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). Elevated Blood Pressure:Controlhypertension before initiating treatment. Monitor blood pressure regularly during treatment (5.3). Abnormal Bleeding:Desvenlafaxine may increase risk of bleeding events. Caution patients about risk of bleeding associated with concomitant use of desvenlafaxine and NSAIDs, aspirin, or other drugs that affect coagulation (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: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). Clinical Worsening/Suicide Risk:Monitor for clinical worsening and suicide risk (5.1). Serotonin Syndrome:Serotonin syndrome has been reported with SSRIs and SNRIs, including with desvenlafaxine extended-release tablets, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort). If such symptoms occur, discontinue desvenlafaxine and initiate supportive treatment. If concomitant use of desvenlafaxine with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). Elevated Blood Pressure:Controlhypertension before initiating treatment. Monitor blood pressure regularly during treatment (5.3). Abnormal Bleeding:Desvenlafaxine may increase risk of bleeding events. Caution patients about risk of bleeding associated with concomitant use of desvenlafaxine and NSAIDs, aspirin, or other drugs that affect coagulation (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: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).. 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). 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults. Patients with major depressive disorder (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 known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been long-standing concern, however, that antidepressants may have 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 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 total of 24 short-term studies of antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included total of 295 short-term studies (median duration of months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but 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 1Age 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 additional cases Decreases Compared to Placebo 25 to 64 fewer case >=65 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 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 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 patients 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) and Warnings and Precautions (5.7) for description of the risks of discontinuation of desvenlafaxine].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 desvenlafaxine 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 disorderA 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 mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such 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 detailed psychiatric history, including family history of suicide, bipolar disorder, and depression. It should be noted that desvenlafaxine is not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome. The development of potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including desvenlafaxine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.The concomitant use of desvenlafaxine with MAOIs intended to treat psychiatric disorders is contraindicated. Desvenlafaxine should also not be started in patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of mg/kg to mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with MAOI such as linezolid or intravenous methylene blue in patient taking desvenlafaxine. Desvenlafaxine should be discontinued before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration (2.6)]. If concomitant use of desvenlafaxine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. Johns Wort is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with desvenlafaxine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.. 5.3 Elevated Blood Pressure. Patients receiving desvenlafaxine should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions (6.1)]. Pre-existing hypertension should be controlled before initiating treatment with desvenlafaxine. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine. Sustained blood pressure increases could have adverse consequences. For patients who experience sustained increase in blood pressure while receiving desvenlafaxine, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1)]. 5.4 Abnormal Bleeding. SSRIs and SNRIs, including desvenlafaxine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of desvenlafaxine and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. 5.5 Angle Closure Glaucoma. Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including desvenlafaxine may trigger an angle closure attack in patient with anatomically narrow angles who does not have patent iridectomy.. 5.6 Activation of Mania/Hypomania. During all MDD phase and phase studies, mania was reported for approximately 0.02% of patients treated with desvenlafaxine. Activation of mania/hypomania has also been reported in small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, desvenlafaxine should be used cautiously in patients with history or family history of mania or hypomania. 5.7 Discontinuation Syndrome. Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with desvenlafaxine during clinical studies in Major Depressive Disorder. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy. During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with desvenlafaxine. gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at more gradual rate [see Dosage and Administration (2.4) and Adverse Reactions (6.1)]. 5.8 Seizure. Cases of seizure have been reported in pre-marketing clinical studies with desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with seizure disorder. Patients with history of seizures were excluded from pre-marketing clinical studies. Desvenlafaxine should be prescribed with caution in patients with seizure disorder. 5.9 Hyponatremia. Hyponatremia may occur as result of treatment with SSRIs and SNRIs, including desvenlafaxine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.6)]. Discontinuation of desvenlafaxine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.10 Interstitial Lung Disease and Eosinophilic Pneumonia. Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of desvenlafaxine) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with desvenlafaxine who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo prompt medical evaluation, and discontinuation of desvenlafaxine should be considered.