Desvenlafaxine Drug Information

Desvenlafaxine extended-release tablets are indicated for the treatment of adults with major depressive disorder (MDD).

Dosage Recommendations for Patients with Renal Impairment

The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance = 30 to 50 mL/min, Cockcroft-Gault ) is 50 mg per day. Supplemental doses should not be given to patients after dialysis.

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.

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. Patients should be periodically reassessed to determine the need for continued treatment.

Discontinuing Desvenlafaxine Extended-Release Tablets

Adverse reactions may occur upon discontinuation of desvenlafaxine extended-release tablets. 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.

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.

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.

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. 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.

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.

The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients Serotonin Syndrome Elevated Blood Pressure Increased Risk of Bleeding Angle Closure Glaucoma Activation of Mania/Hypomania Discontinuation Syndrome Seizure Hyponatremia Interstitial Lung Disease and Eosinophilic Pneumonia Sexual Dysfunction 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.

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). 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%). 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 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 Libido decreased Orgasm abnormal Ejaculation delayed Erectile dysfunction Ejaculation disorder Ejaculation failure Sexual dysfunction 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 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 mg Total Cholesterol (Increase of ≥ 50 mg/dl and an absolute value of ≥ 261 mg/dl) LDL Cholesterol (Increase ≥ 50 mg/dl and an absolute value of ≥ 190 mg/dl) Triglycerides, fasting (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).

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 Studies Desvenlafaxine extended-release tablets Placebo mg Proteinuria Vital Sign Changes Table 6 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine extended-release tablets 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 Studies Desvenlafaxine Extended-Release Tablets Placebo mg Blood pressureSupine systolic bp (mm Hg) Supine diastolic bp (mm Hg) Pulse rate Supine pulse (bpm) Weight (kg) Treatment with desvenlafaxine extended-release tablets 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 3 consecutive on- therapy visits (see Table 7).

Analyses of patients in desvenlafaxine extended-release tablets pre-marketing short-term controlled studies who met criteria for sustained hypertension revealed a consistent increase in the proportion of patients who developed sustained hypertension. This was seen at all doses with a suggestion of a higher rate at 400 mg per day. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Skin and subcutaneous tissue disorders– Stevens-Johnson syndrome Gastrointestinal disorders– Pancreatitis acute Cardiovascular system– Takotsubo cardiomyopathy Respiratory, thoracic and mediastinal disorders– Anosmia, hyposmia

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.

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.

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.

Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablets formulation. Angioedema has been reported in patients treated with desvenlafaxine extended-release tablets. The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine extended-release tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets is contraindicated because of an increased risk of serotonin syndrome.

The use of desvenlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting desvenlafaxine extended-release tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

Management of Overdosage

No specific antidotes for desvenlafaxine extended-release tablets are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.