Desvenlafaxine Er for Depression

Desvenlafaxine extended-release tablets are indicated for the treatment of adults with major depressive disorder (MDD) [see CLINICAL STUDIES (14)].

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 [ClCr] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose in patients with severe renal impairment (ClCr 15 to 29 mL/min, C-G) or end- stage renal disease (ESRD, ClCr < 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 (50-400 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)] .

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 desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, 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)] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of desvenlafaxine extended-release tablets with MAOIs is contraindicated. In addition, do not initiate desvenlafaxine extended-release tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking desvenlafaxine extended-release tablets, discontinue desvenlafaxine extended-release tablets before initiating treatment with the MAOI [see CONTRAINDICATIONS (4), DRUG INTERACTIONS (7.1

Drugs Having Clinically Important Interactions with Desvenlafaxine Extended-Release Tablets Table 8: Clinically Important Drug Interactions with Desvenlafaxine Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SSRIs and SNRIs including desvenlafaxine extended-release tablets with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of desvenlafaxine extended-release tablets is contraindicated: With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with desvenlafaxine extended-release tablets. Within 14 days of stopping an MAOI intended to treat psychiatric disorders. In a patient who is being treated with linezolid or intravenous methylene blue. [see DOSAGE AND ADMINISTRATION (2.7), CONTRAINDICATIONS (4)and WARNINGS AND PRECAUTIONS (5.2)]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of desvenlafaxine extended-release tablets with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when desvenlafaxine extended-release tablets are used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of desvenlafaxine extended-release tablets and/or concomitant serotonergic drugs [see WARNINGS AND PRECAUTIONS (5.2)]. Examples other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of desvenlafaxine extended-release tablets with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of desvenlafaxine extended-release tablets on the release of serotonin by platelets. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when desvenlafaxine extended-release tablets are initiated or discontinued [see WARNINGS AND PRECAUTIONS (5.4)] . Examples NSAIDs, aspirin, and warfarin Drugs that are Primarily Metabolized by CYP2D6 Clinical Impact Concomitant use of desvenlafaxine extended-release tablets increases Cmax and AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug [see CLINICAL PHARMACOLOGY (12.3)] . Intervention Original dose should be taken when co-administered with desvenlafaxine extended-release tablets 100 mg or lower. Reduce the dose of these drugs by up to one-half if co-administered with 400 mg of desvenlafaxine extended-release tablets. Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine 7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Extended-Release Tablets Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine extended-release tablets [see CLINICAL PHARMACOLOGY (12.3)]. 7.3 Alcohol A clinical study has shown that desvenlafaxine extended-release tablets 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 extended-release tablets. 7.4 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.

The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity [see CONTRAINDICATIONS (4)] Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [see WARNINGS AND PRECAUTIONS (5.1)] Serotonin Syndrome [see WARNINGS AND PRECAUTIONS (5.2)] Elevated Blood Pressure [see WARNINGS AND PRECAUTIONS (5.3)] Increased Risk of Bleeding [see WARNINGS AND PRECAUTIONS (5.4)] Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS (5.5)] Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS (5.6)] Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS (5.7)] Seizure [see WARNINGS AND PRECAUTIONS (5.8)] Hyponatremia [see WARNINGS AND PRECAUTIONS (5.9)] Interstitial Lung Disease and Eosinophilic Pneumonia [see WARNINGS AND PRECAUTIONS (5.10)] Sexual Dysfunction [see WARNINGS AND PRECAUTIONS (5.11)] 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient Exposure Desvenlafaxine extended-release tablets were 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 extended-release tablets; 2,116 were exposed to desvenlafaxine extended-release tablets for 6 months, representing 1,658 patient-years of exposure, and 421 were exposed for one year, representing 416 patient-years of exposure. Adverse Reactions Reported as Reasons for Discontinuation of Treatment In the pre-marketing pooled 8-week placebo-controlled studies in patients with MDD, 1,834 patients were exposed to desvenlafaxine extended-release tablets (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 extended-release tablets (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of desvenlafaxine extended-release tablets the discontinuation rate due to an adverse reaction was 8.7%. The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than placebo of the desvenlafaxine extended-release tablets treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-term study, up to 9 months, the most common was vomiting (2%). Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in desvenlafaxine extended-release tablets treated MDD patients in pre- marketing pooled 8-week, placebo-controlled, fixed-dose studies (incidence ≥ 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders. Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of desvenlafaxine extended-release tablets treated MDD patients and twice the rate of placebo at any dose in the pre-marketing pooled 8-week, placebo-controlled, fixed dose clinical studies. Table 2: Common Adverse Reactions (≥ 2% in any Fixed-Dose Group and Twice the Rate of Placebo) in Pre-marketing Pooled MDD 8-Week Placebo-Controlled Studies Percentage of Patients Reporting Reaction Desvenlafaxine Extended-Release Tablets System Organ Class Preferred Term Placebo (n=636) 50 mg (n=317) 100 mg (n=424) 200 mg (n=307) 400 mg (n=317) Cardiac disorders Blood pressure increased 1 1 1 2 2 Gastrointestinal disorders Nausea 10 22 26 36 41 Dry mouth 9 11 17 21 25 Constipation 4 9 9 10 14 Vomiting 3 3 4 6 9 General disorders and administration site conditions Fatigue 4 7 7 10 11 Chills 1 1 <1 3 4 Feeling jittery 1 1 2 3 3 Metabolism and nutrition disorders Decreased appetite 2 5 8 10 10 Nervous system disorders Dizziness 5 13 10 15 16 Somnolence 4 4 9 12 12 Tremor 2 2 3 9 9 Disturbance in attention <1 <1 1 2 1 Psychiatric disorders Insomnia 6 9 12 14 15 Anxiety 2 3 5 4 4 Nervousness 1 <1 1 2 2 Abnormal dreams 1 2 3 2 4 Renal and urinary disorders Urinary hesitation 0 <1 1 2 2 Respiratory, thoracic and mediastinal disorders Yawning <1 1 1 4 3 Skin and subcutaneous tissue disorders Hyperhidrosis 4 10 11 18 21 Special Senses Vision blurred 1 3 4 4 4 Mydriasis <1 2 2 6 6 Vertigo 1 2 1 5 3 Tinnitus 1 2 1 1 2 Dysgeusia 1 1 1 1 2 Vascular disorders Hot flush <1 1 1 2 2 Sexual Function Adverse Reactions Table 3 shows the incidence of sexual function adverse reactions that occurred in ≥ 2% of desvenlafaxine extended-release tablets treated MDD patients in any fixed-dose group (pre-marketing pooled 8-week, placebo- controlled, fixed -dose, clinical studies) [s ee WARNINGS AND PRECAUTIONS (5.11)] . Table 3: Sexual Function Adverse Reactions (≥ 2% in Men or Women in any Desvenlafaxine Extended-Release Tablets Group) During the On-Therapy Period Desvenlafaxine Extended-Release Tablets Placebo (n=239) 50 mg (n=108) 100 mg (n=157) 200 mg (n=131) 400 mg (n=154) Men only Anorgasmia 0 0 3 5 8 Libido decreased 1 4 5 6 3 Orgasm abnormal 0 0 1 2 3 Ejaculation delayed <1 1 5 7 6 Erectile dysfunction 1 3 6 8 11 Ejaculation disorder 0 0 1 2 5 Ejaculation failure 0 1 0 2 2 Sexual dysfunction 0 1 0 0 2 Desvenlafaxine Extended-Release Tablets Placebo (n=397) 50 mg (n=209) 100 mg (n=267) 200 mg (n=176) 400 mg (n=163) Women only Anorgasmia 0 1 1 0 3 Other Adverse Reactions Observed in Premarketing and Postmarketing Clinical Studies Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with desvenlafaxine extended-release tablets 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 extended-release tablets treatment as compared to placebo. Laboratory, ECG and Vital Sign Changes Observed in MDD Clinical Studies The following changes were observed in pre-marketing placebo-controlled, short-term MDD studies with desvenlafaxine extended-release tablets. Lipids Elevations 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 a predetermined threshold value is shown in Table 4. Table 4: Incidence (%) of Patients with Lipid Abnormalities of Potential Clinical Significance* Desvenlafaxine extended-release tablets Placebo 50 mg 100 mg 200 mg 400 mg Total Cholesterol 2 3 4 4 10 *(Increase of ≥ 50 mg/dl and an absolute value of ≥ 261 mg/dl) LDL Cholesterol 0 1 0 1 2 *(Increase ≥ 50 mg/dl and an absolute value of ≥ 190 mg/dl) Triglycerides, fasting 3 2 1 4 6 *(Fasting: ≥ 327 mg/dl) Proteinuria Proteinuria, greater than or equal to trace, was observed in the pre-marketing fixed-dose controlled studies (see Table 5).