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STEPS New Drug Reviews

Milnacipran (Savella) for REMIGIUS OKEA, MD, MPH Science Medicine Research Institute and American Academy of Primary Care Research, Dallas, Texas

STEPS new drug reviews Milnacipran (Savella) is a - inhibitor labeled for the treat- cover Safety, Tolerability, ment of fibromyalgia. It is the third marketed for this use.1 Effectiveness, Price, and Simplicity. Each indepen- dent review is provided by authors who have no Recommended Approximate financial association with Drug dosage Starting dosage Dose form monthly cost* the drug manufacturer. Milnacipran 50 mg twice Day 1: 12.5 mg once 12.5-, 25-, 50-, and $126 (50 mg The series coordinator for (Savella) daily Days 2 and 3: 12.5 mg 100-mg tablets twice daily) AFP is Allen F. Shaugh- twice daily nessy, PharmD, Tufts University Family Medicine Days 4 through 7: 25 mg Residency Program at twice daily Cambridge Health Alli- After day 7: 50 mg twice ance, Malden, Mass. daily A collection of STEPS pub- lished in AFP is available *—Estimated retail price of one month’s treatment based on information obtained at http://www.drugstore.com at http://www.aafp.org/ (accessed August 16, 2010). afp/steps.

SAFETY hypertension, a typical dose will increase sys- Because milnacipran is a serotonin-norepi- tolic blood pressure by more than 15 mm Hg nephrine , it can cause in 7 percent of patients and diastolic blood .2 The manufacturer rec- pressure by more than 10 mm Hg in 8 per- ommends not using milnacipran with mono- cent of patients. It increases the heart rate amine oxidase inhibitors or within 14 days of by more than 20 beats per minute in about discontinuing them. Also, monoamine oxi- 8 percent of patients. A similar proportion dase inhibitors should not be started within of patients will report palpitations. Patients five days of discontinuing milnacipran. In who experience a sustained increase in blood patients with narrow-angle glaucoma, use of pressure or heart rate should receive a lower milnacipran is contraindicated. dose or discontinue treatment. Use of mil- Milnacipran carries the same warnings nacipran has not been evaluated in patients of increased suicidality as . with cardiac rhythm disorders.3 It may increase the risk of convulsions in Abrupt discontinuation of milnacipran can patients with seizure disorders. Hypona- induce withdrawal symptoms, including dys- tremia, sexual dysfunction, dysuria, and phoria and agitation. Patients should receive urinary retention, especially in men with tapered doses when discontinuing treatment. preexisting prostatic hypertrophy or prosta- Milnacipran is U.S. Food and Drug titis, may occur with milnacipran. Bleeding Administration pregnancy category C. It is disorders are possible in patients using mil- not approved for use in children. nacipran, especially in those taking aspirin.3 About one in five patients without hyper- TOLERABILITY tension will have a sustained increase More patients will discontinue a typical dose in blood pressure (140/90 mm Hg or of milnacipran than will discontinue pla- greater). Among patients with preexisting cebo (27 versus 10 percent; number needed ▲

Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2010 American Academy of Family Physicians. For the private, noncommercial use of October 15, 2010one ◆individual Volume user 82, of Number the Web site. 8 All other rights reserved.www.aafp.org/afp Contact [email protected] for copyright questions and/orAmerican permission Family requests. Physician 901 STEPS to harm = 6). Gastrointestinal symptoms, 4 through 7; and 50 mg twice daily after that. including nausea (35 percent) and consti- In patients who do not respond to this main- pation (16 percent), are the most common tenance dosage, the dosage may need to be adverse effects of milnacipran. About 18 increased to 100 mg twice daily.3 percent of patients will report headache.3,4 Milnacipran has a similar adverse effect pro- Bottom Line file to other in its class.1,4-6 Milnacipran can decrease the overall pain scores and improve symptoms of fibromy- EFFECTIVENESS algia. Safety in patients with severe comor- Milnacipran has been studied in four ran- bid medical and psychiatric conditions is domized placebo-controlled trials of patients unknown because these groups of patients with fibromyalgia, which is defined as were excluded from the study.1 Milnacipran chronic, widespread pain and pain at 11 or can be useful in select patients with fibromy- more tender points. At three months, about algia in whom first- and second-line treat- twice as many patients on a typical dose ments have failed. will report overall improvement compared Address correspondence to Remigius Okea, MD, MPH, with those receiving placebo (32.8 versus at [email protected]. Reprints are not available 17.3 percent; P = .003; number needed to from the author. treat = 6). Patients who respond continue Author disclosure: Nothing to disclose. to experience benefit at six months. Mental health scores and levels of bodily pain and REFERENCES fatigue also improve with treatment. How- 1. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy ever, measures of impact on daily life (e.g., and safety of milnacipran for treatment of fibromyal- physical function, work absence, job ability) gia: a randomized, double-blind, placebo-controlled 6 trial [published correction appears in J Rheumatol. are not improved. Milnacipran has not been 2009;36(3):661]. J Rheumatol. 2009;36(2):398-409. studied over the long term. Recent review of 2. Yacoub HA, Johnson WG, Souayah N. Serotonin syn- published and unpublished data indicated drome after administration of milnacipran for fibromy- that milnacipran, (Lyrica), and algia. Neurology. 2010;74(8):699-700. 3. RxList. Savella (milnacipran HCl tablets). Drug infor- (Cymbalta) have different effects mation. http://www.rxlist.com/savella-drug.htm. on the key symptoms of fibromyalgia syn- Accessed February 22, 2010. drome and differences in adverse effects and 4. Clauw DJ, Mease P, Plamer RH, Gendreau RM, Wang contraindications.7 Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double- blind, placebo-controlled, multiple-dose clini- PRICE cal trial [published corrections appear in Clin Ther. A one-month supply of milnacipran (50 mg 2009;31(7):1617, and Clin Ther. 2009;31(2):446]. Clin Ther. 2008;30(11):1988-2004. twice daily) costs $126. In comparison, a one- 5. Branco JC, Zachrisson O, Perrot S, Mainguy Y; Multi- month supply of pregabalin (150 mg twice national Coordinator Study Group. A European mul- daily) costs $176, and a one-month supply of ticenter randomized double-blind placebo-controlled duloxetine (60 mg daily) costs $154. monotherapy of milnacipran in treatment of fibromyalgia. J Rheumatol. 2010;37(4):851-859. SIMPLICITY 6. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran The recommended dosage of milnacipran is 50 in the treatment of fibromyalgia. Hum Psychopharma- mg twice daily. Patients should be started at a col. 2004;19(suppl 1):S27-S35. 7. Häuser W, Petzke F, Sommer C. Comparative efficacy single dose of 12.5 mg on day 1; 12.5 mg twice and harms of duloxetine, milnacipran, and pregabalin in daily on days 2 and 3; 25 mg twice daily on days fibromyalgia syndrome. J Pain. 2010;11(6):505-521. ■

904 American Family Physician www.aafp.org/afp Volume 82, Number 8 ◆ October 15, 2010