Pharmacy & Therapeutics - March 2009 - (Page 158) Pharmaceutical Approval Update that impair metabolism of 5-HT, including monoamine oxidase (MAO) inhibitors. Symptoms may include changes in mental status (agitation, hallucinations, coma), autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (hyperreflexia, incoordination), and gastrointestinal (GI) symptoms (nausea, vomiting, diarrhea). The concomitant use of milnacipran with MAO inhibitors is contraindicated. Effects on blood pressure. Inhibition of the reuptake of NE and 5-HT can lead to cardiovascular effects. SNRIs, including milnacipran, have been associated with reports of increases in blood pressure (BP). In placebo-controlled trials, among fibromyalgia patients who did not have hypertension at baseline, approximately twice as many patients in the milnacipran arms became hypertensive at the end of the study (with a systolic BP of 140 mm Hg or higher or a diastolic BP of 90 mm Hg or higher) compared with placebo patients: 7.2% of patients receiving placebo versus 19.5% of patients receiving milnacipran 100 mg/day and 16.6% of patients receiving milnacipran 200 mg/day. Among patients who met systolic criteria for pre-hypertension at baseline (with a systolic BP of 120 to 139 mm Hg), more milnacipran patients became hypertensive at the end of the study compared with placebo patients: 9% with placebo versus 14% with milnacipran 100 mg/day and 200 mg/day. Among fibromyalgia patients who had hypertension at baseline, more patients in the milnacipran arms experienced an increase of more than15 mm Hg in systolic BP than placebo patients at the end of the study: 1% of placebo patients versus 7% of patients in the milnacipran 100-mg/day arm and 2% in the milnacipran 200-mg/day arm. Similarly, more patients who were hypertensive at baseline and who used milnacipran had diastolic BP increases above 10 mm Hg than placebo patients at the end of the study: 3% of placebo patients versus 8% of patients in the milnacipran 100-mg/day and 6% in the milnacipran 200-mg/day arms. Sustained increases in systolic BP of 15 mm Hg or more on three consecutive post-baseline visits occurred in 2% of placebo patients, in 9% of patients receiving milnacipran 100 mg/day, and in 6% of patients receiving milnacipran 200 mg/day. Sustained increases in diastolic BP (an increase of 10 mm Hg or more on three consecutive post-baseline visits) occurred in 4% of patients receiving placebo, in 13% of patients receiving milnacipran 100 mg/day, and in 10% of patients receiving milnacipran 200 mg/day. Effects on heart rate. SNRIs have been associated with reports of an increase in heart rate. The heart rate should be measured before patients begin treatment and periodically throughout treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before milnacipran therapy starts. For patients who experience a sustained increase in heart rate while receiving milnacipran, either a dose reduction or discontinuation should be considered. Seizures. Milnacipran should be prescribed with care in patients with a history of a seizure disorder. Hepatotoxicity. In placebo-controlled fibromyalgia trials, increases in the number of patients treated with milnacipran who had mild elevations of liver enzymes (ALT or AST (at one to three times the upper limit of normal [ULN]) were observed. Increases in ALT were more frequent in patients receiving 100 mg/day (6%) and 200 mg/day (7%), compared with patients who were treated with placebo (3%). In one patient receiving 100 mg/day (0.2%), the increase in ALT was more than five times the ULN but did not exceed 10 times the ULN. Increases in AST were more frequently observed with milnacipran 100 mg/day (in 3% of patients) and 200 mg/day (in 5% of patients) compared with placebo (in 2% of patients). Discontinuation of treatment. Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and selective serotonin reuptake inhibitors (SSRIs). During the marketing of milnacipran and other SNRIs and SSRIs, there were spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring when patients discontinued these drugs, particularly when discontinuation was abrupt. Adverse events included dysphoric mood, irritability, agitation, dizziness, sensory disturbances (paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been severe. Hyponatremia. Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including milnacipran. In many cases, hyponatremia appears to result from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Abnormal bleeding. SSRIs and SNRIs, including milnacipran, may increase the risk of bleeding events. The concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin (Coumadin, Bristol-Myers Squibb), and other anticoagulants may elevate this risk. Patients with a history of dysuria. Because of their noradrenergic effect, SNRIs (including milnacipran) can affect urethral resistance and micturition. In controlled trials of fibromyalgia, dysuria occurred more frequently in milnacipran patients (1%) than in placebo patients (0.5%). Narrow-angle glaucoma. Because mydriasis has been reported in association with SNRIs and milnacipran, milnacipran should be used cautiously in patients with controlled narrow-angle glaucoma. Use with alcohol. In clinical trials, elevated transaminase levels (ALT and AST) occurred in more milnacipran patients than in placebo-treated patients. Because milnacipran may exacerbate pre-existing liver disease, it should not be prescribed for patients with substantial alcohol use or evidence of chronic liver disease. Allergy to coloring agents. Milnacipran contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in susceptible persons such as those with aspirin hypersensitivity. Dosage and Administration: The recommended dose of milnacipran is 100 mg/day (50 mg twice daily). Doses should be titrated according to the following schedule: day 1, 12.5 mg once daily; days 2 to 3, 25 mg/day (12.5 mg twice daily); days 4 to 7, 50 mg/day (25 mg twice daily); and after day 7, 100 mg/day (50 mg twice daily). According to individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 158 P&T® • March 2009 • Vol. 34 No. 3
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