Pharmacy & Therapeutics - April 2008 - (Page 234) Pharmaceutical Approval Update Blood pressure elevations. Because sustained increases in blood pressure (BP) were noted in clinical studies, patients receiving desvenlafaxine should have regular BP monitoring. Pre-existing hypertension should be controlled before treatment with desvenlafaxine begins. Caution should be exercised in treating patients with pre-existing hypertension or other underlying conditions that might be compromised by increases in BP. Cases of elevated BP requiring immediate treatment have been reported with desvenlafaxine. Sustained increases in BP can have adverse consequences. For patients who experience a sustained increase in BP while receiving desvenlafaxine, either the dose should be reduced or the drug should be discontinued. Treatment with desvenlafaxine at all doses, from 50 mg/day to 400 mg/day, was associated with sustained hypertension (supine diastolic BP of 90 mm Hg and 10 mm Hg or more above the baseline BP) for three consecutive on-therapy visits. Studies showed a consistent increase in the proportion of those subjects who developed sustained hypertension at all doses with a suggestion of a higher rate at 400 mg/day. Abnormal bleeding. SSRIs and SNRIs, including desvenlafaxine, may increase the risk of bleeding. The concomitant use of aspirin, nonsteroidal anti-inflammator y drugs (NSAIDs), warfarin (Coumadin, Bristol-Myers Squibb), and other anticoagulants may add to this risk. Case reports and epidemiological studies have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of GI 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. Glaucoma. Mydriasis has been reported in association with desvenlafaxine; therefore, patients with elevated intraocular pressure or those at risk of acute narrow-angle (angleclosure) glaucoma should be monitored. Mania or hypomania. During all phase 2 and 3 studies of MDD and vasomotor symptoms, mania was reported for approximately 0.1% of patients receiving desvenlafaxine. Activation of mania or hypomania has also been reported in some patients with major affective disorder who used other marketed antidepressants. As with all antidepressants, des venlafaxine should be used cautiously in patients with a history or family history of mania or hypomania. Heart disease. Caution is advised for patients with cardiovascular, cerebrovascular, or lipid metabolism disorders. Increases in BP and small increases in heart rates were observed in studies with desvenlafaxine. Desvenlafaxine has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical studies. Cholesterol and triglycerides. Dose-related elevations in fasting serum total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglycerides were observed in controlled studies. Serum lipids should be monitored during treatment with desvenlafaxine. Discontinuation of treatment. Abruptly discontinuing or reducing the dose of desvenlafaxine has been associated with new symptoms, including dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with a longer duration of therapy. During marketing of SNRIs and SSRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs (particularly with abrupt cessation), including dysphoric mood, irritability, agitation, dizziness, sensor y disturbances (paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events have generally been self-limiting, serious discontinuation symptoms have been reported. Renal impairment. In patients with moderate or severe renal impairment or end-stage renal disease (ESRD), the clearance of desvenlafaxine was decreased, thus prolonging the elimination half-life of the drug. As a result, there were potentially clinically significant increases in exposures to desvenlafaxine. A dosage adjustment (50 mg every other day) is necessary in patients with severe renal impairment or ESRD. The doses should not be escalated in patients with moderate or severe renal impairment or ESRD. Seizures. Seizures have been reported in premarketing clinical studies with desvenlafaxine even though patients with a history of seizures were excluded from premarketing clinical studies. This drug has not been systematically evaluated in patients with seizure disorders; therefore, desvenlafaxine should be prescribed with caution in these patients. Hyponatremia. Low sodium levels may occur after 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 of serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk for hyponatremia with SSRIs and SNRIs, and patients who are taking diuretics or who are volume-depleted can be at greater risk. 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 or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Coadministration with venlafaxine. Desvenlafaxine is the major active metabolite of venlafaxine. Products containing desvenlafaxine and products containing venlafaxine should not be used with each other. Lung disease and pneumonia. In rare instances, interstitial lung disease and eosinophilic pneumonia associated with venlafaxine have been reported. The possibility of these adverse events should be considered in patients receiving desvenlafaxine who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of desvenlafaxine should be considered. Dosage and Administration: The recommended dose of 234 P&T® • April 2008 • Vol. 33 No. 4
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