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Milnacipran HCl Tablets (Savella™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
The FDA has approved another selective serotonin and norepinephrine reuptake inhibitor for the management of fibromyalgia (FM). Milnacipran is more selective for norepinephrine than serotonin. This is in contrast to venlafaxine, which is more selective for serotonin and duloxetine, which is balanced in inhibition. Milnacipran is licensed from Pierre Fabre Medicament and Cypress Biosciences, Inc., and marketed by Forest Pharmaceutical, Inc., as Savellaä.
Milnacipran is indicated for the management of fibromyalgia.1
The recommended dose is 100 mg daily (50 mg twice daily). Dose escalation should be over 7 days using the following schedule: 12.5 mg (day 1), 12.5 mg twice daily (days 2-3), 25 mg twice daily (days 4-7), and 50 mg twice daily (after day 7). It may be increased to 200 mg daily based on response and tolerability.1 Maintenance dose should be reduced to 25 mg twice daily for patients with severe renal impairment. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment or mild renal impairment. The drug should be used with caution in patients with moderate renal impairment and severe hepatic impairment.
Milnacipran is available as 12.5 mg, 25 mg, 50 mg, and 100 mg tablets.
Milnacipran-treated patients showed improvement in pain and overall improvement in FM compared to placebo.1-3 The drug does not appear to have any clinically significant pharmacokinetic drug-drug interactions.1
Milnacipran does not appear to improve quality or quantity of sleep. The most common adverse effects of milnacipran compared to placebo were nausea (37% vs 20%), headache (18% vs 14%), constipation (16% vs 4%), hot flush (12% vs 2%), insomnia (12% vs 10%), dizziness (10% vs 6%), hyperhidrosis (9% vs 2%), and vomiting (7% vs 2%). Milnacipran shares the same class warning for suicidality as other selective serotonin and norepinephrine reuptake inhibitor antidepressants. Overall improvement seems to lessen with longer duration of therapy (i.e., 15 vs 27 weeks).
The approval of milnacipran was based on two pivotal U.S. Phase III clinical trials involving predominately female patients (~95%) with a mean age of 50 years.2-4 One study (study 1) was 27 weeks in duration (n = 888) and the other (study 2) was a 15 weeks (n = 1196). Patients met American College of Rheumatology criteria for fibromyalgia. These included a history of widespread pain for 3 months and pain present at 11 or more of the 18 tender point sites. The minimum mean baseline pain score was ≥ 50 mm on a 100 visual analog scale (VAS) compared to ≥ 40 for study 2. Subjects were randomized to milnacipran 100 mg, 200 mg, or placebo at a 1:1:2 ratio in study 1 and 1:1:1 in study 2. Each study included a 3-week dose-escalation period and 12 weeks or 24 weeks of a stable dose. The primary efficacy outcome for FM was a composite criterion involving pain, patient global impression of change, and physical function. Patients were categorized as responders to therapy if they had a ≥ 30 improvement from baseline on VAS score, a rating of much improved or very much improved on Patient Global Impression of Change (PGIC), and a ≥ 6 point improvement in the SF-36 Physical Component Summary from baseline. FM pain outcomes included the first 2 criteria. Analysis of the results were based on baseline observation carried forward (BOCF) for the 15-week study and a modified BOCF for the 27-week study. Based on this approach, all subjects who missed the last assessment (week 15) were considered non-responders. For the 27-week study, BOCF was applied to subjects who dropped out of the study before week 15 and last observation carried forward (LOCF) for subjects completing week 15. At 15 weeks, composite response rates were 19.6% for 100 mg, 19.3% for 200 mg, and 12.1% for placebo in study 1, and 15.4%, 14.6%, and 9.2%, respectively, for study 2. These all reached statistical significance. At 27 weeks the FM composite responder rates were not statistically significant. The FM pain composite responder rates were statistically significant for both doses of milnacipran at 15 weeks. The rates were 27.2%, 26.8%, and 19.3% for study 1, and 23.8%, 26.2%, and 16.9% for study 2. At 27 weeks only the 200 mg dose reached statistical significance, likely due to a larger sample size and statistical power. Pain relief was detected after week 1 and maximal relief after week 9. Subjects reported greater overall improvement in terms of FM based on patient global assessment at week 15 for both doses but only for the 200 mg dose at week 27. In the two clinical trials, approximately one-quarter of subjects discontinued participation due to adverse events.
Milnacipran is the most recent drug approved for FM. Pregabalin and duloxetine also have FDA approval, while tricyclic antidepressants, SSRIs, and gabapentin have been both studied and used in clinical practice. Without comparative studies, the relative effectiveness of milnacipran vs other agents is not known. Recently published systematic reviews make a strong case for TCAs such as amitriptyline.4,5 The magnitude of effect for pain reduction was considered large for TCAs and small for SNRIs (duloxetine and milnacipran).4 In addition, TCAs reduced fatigue and sleep disturbance, while milnacipran improved fatigue but not sleep quality or quantity.
1. Savella Product Information. Forest Pharmaceuticals, Inc. New York, NY; 2009.
2. Mease PJ, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol 2008 Dec 15; Epub ahead of print.
3. Clauw DJ, et al. Milnacipran for the treatment of fibromyalgia in adults: A 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther 2008;30:1988-2004.
4. Hauser W, et al. Treatment of fibromyalgia syndrome with antidepressants: A meta-analysis. JAMA 2009; 301:198-209.
5. Uceyler N, et al. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum 2008;59:1279-1298.