FDA Approves Milnacipran for Fibromyalgia

Susan Jeffrey

January 15, 2009

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January 15, 2009 — Forest Laboratories and Cypress Bioscience announced January 14 that the Food and Drug Administration (FDA) has approved milnacipran (Savella), a dual serotonin- and norepinephrine-reuptake inhibitor (SNRI), for the management of fibromyalgia.

Efficacy of the drug was established in two pivotal US phase 3 trials, the companies note in a press statement. Treatment with 100-mg/day and 200-mg/day doses demonstrated "statistically significant and clinically meaningful" concurrent improvements in pain, patient global assessment, and physical function, the statement adds.

The companies expect the drug to be available in pharmacies by March 2009.

Fibromyalgia, characterized by widespread pain and decreased physical function, affects as many as 6 million people in the United States, according to estimates from the American College of Rheumatology, the statement notes.

Although the exact mechanism of the benefit of milnacipran in this setting is not known, "some researchers believe that abnormalities in certain brain neurotransmitters may be central to fibromyalgia," the release states. Milnacipran blocks reuptake of serotonin and norepinephrine, with greater selectivity for norepinephrine in vitro. "This may be the mechanism by which [milnacipran] acts to improve the symptoms of fibromyalgia."

Phase 3 Trials

Data to support this indication were taken from 2 phase 3 trials that used a "composite responder analysis," the statement states. "This end point required individual patients to demonstrate concurrent improvement to multiple validated measures, including pain (visual analog scale), patient global assessment (patient global impression of change), and physical function (Short Form-36 Physical Component Summary)," the companies note.

The phase 3 trials, 6 months and 3 months in duration respectively, included 2084 patients, 1460 treated with milnacipran and 624 with placebo. In both studies, a greater proportion of patients treated with 100 or 200 mg/day of milnacipran had at least a 30% reduction in pain from baseline and rated themselves as "very much improved" or "much improved" on the patient global assessment. More treated patients also met criteria for treatment response by concurrent improvements in pain, physical function, and patient global assessment.

The treatment was safe and generally well tolerated. The most frequently occurring adverse reaction was nausea; other common reactions included constipation, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension. The majority of these reactions were mild to moderate in nature, the statement adds.

Cautions

As an SNRI, milnacipran is similar to other drugs used for the treatment of depression and other psychiatric disorders, the statement points out. Antidepressants cause increased thoughts of suicidality in children, adolescents, and young adults compared with placebo. Although it is not approved for major depressive disorder or in pediatric patients, "patients of all ages who are started on [milnacipran] should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior," the press release states. "Families and caregivers should be advised of the need for close observation and communication with the prescriber."

A variety of other contraindications are noted in the release. The drug should not be taken concomitantly with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI. Development of potentially life-threatening serotonin syndrome can occur with drugs that, like milnacipran, inhibit serotonin reuptake, particularly with concomitant use ofserotonergic drugs such as triptans or tramadol or with drugs that impair metabolism of serotonin such as MAOIs. Concomitant use with serotonin precursors is also not recommended.

Blood pressure and heart rate should be monitored prior to initiating treatment and periodically during treatment, as SNRIs, including milnacipran, have been shown to increase blood pressure and heart rate. Preexisting hypertension, tachyarrhythmias, and other cardiac diseases should be treated before use of the drug, the release notes, and it should be used with caution in patients with significant hypertension or cardiac disease. For those who experience a sustained increase in blood pressure or heart rate on treatment, either dose reduction or discontinuation should be considered, the release states. Gradual reductions in dose are recommended, as withdrawal symptoms have been observed following discontinuation of milnacipran.

Mild elevations in liver enzymes have also been observed with treatment and, rarely, fulminant hepatitis, the statement adds. It also increases bleeding risk, and patients should be cautioned about concomitant use of milnacipran and nonsteroidal anti-inflammatory drugs, aspirin, warfarin, or other drugs that affect coagulation.

Milnacipran should be prescribed "with caution" in patients with a history of seizure disorder, mania, or controlled narrow-angle glaucoma and should "ordinarily not be prescribed" in patients with substantial alcohol use or evidence of chronic liver disease, the statement adds.

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