DESVENLAFAXINE extended-release tablets

DESVENLAFAXINE extended-release tablets

DESVENLAFAXINE extended-release tablets

Desvenlafaxine extended-release tablets for oral administration contains desvenlafaxine, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder.

Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C16H25NO2. Desvenlafaxine has a molecular weight of 263.38.

Inactive ingredients for the 50 mg tablet consist of 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.

Inactive ingredients for the 100 mg tablet consist of 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.

Indications and usage

Desvenlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder (MDD)

Mechanism of Action

The exact mechanism of the antidepressant action of desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).

Dosage and administration

The recommended dose for desvenlafaxine is 50 mg once daily, with or without food. The 50 mg dose is both a 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.

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 or 50 mg every other day. Supplemental doses should not be given to patients after dialysis

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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

Discontinuing Desvenlafaxine

Symptoms associated with discontinuation of desvenlafaxine, other SNRIs and SSRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a 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 a more gradual rate.

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.

Contraindications

  • Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablets formulation. Angioedema has been reported in patients treated with desvenlafaxine
  • The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine is contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
  • Starting desvenlafaxine 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.

Warnings and precautions

Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants. Monitor for worsening and emergence of suicidal thoughts and behaviors.

Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with desvenlafaxine, 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. John’s 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 a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment.

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.

Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder. Caution patients about risk of activation of mania/hypomania.

Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms.

Seizure: Can occur. Use cautiously in patients with seizure disorder.

Hyponatremia: Can occur in association with SIADH.

Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur

Adverse reactions

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

Drug interactions

Monoamine Oxidase Inhibitors (MAOI): Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 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 a patient who is being treated with linezolid or intravenous methylene blue.

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.

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.

Ethanol: A 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.

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.

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Use in specific populations

Pregnancy Category C: There are no adequate and well-controlled studies of desvenlafaxine in pregnant women. A 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 a relapse of major depression than women who continued antidepressant medication.

Nursing Mothers: Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from desvenlafaxine, a 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.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Anyone considering the use of desvenlafaxine in a child or adolescent must balance the potential risks with the clinical need.

Overdosage

In postmarketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine) has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.

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