Milnacipran was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed (as Ixel) for this indication in over 45 countries worldwide including several European countries such as Austria, Bulgaria, Finland, France, Portugal, and Russia. It is also available in Japan (as Toledomin) and Mexico (as Dalcipran). Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the United States and Canada in 2003 from the manufacturer Laboratoires Pierre Fabre.
In January 2009 the U.S. Food and Drug Administration (FDA) approved milnacipran (under the brand name Savella) only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States.
In a pooled analysis of 7 comparative trials with imipramine,[4] milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs [5] concluded a superior efficacy for milnacipran with similar tolerability for milnacipran and SSRIs. A more recent meta-analysis of 6 studies involving more than 1,000 patients showed no distinction between milnacipran and SSRIs in efficacy or discontinuation rates, including discontinuation for side effects or lack of efficacy.[6] A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients [7] concluded that there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressant agents. However, compared with TCAs, significantly fewer patients taking milnacipran dropped out due to adverse events. As with other antidepressants, 1 to 3 weeks may elapse before significant antidepressant action becomes clinically evident.
Clinical results in fibromyalgia
During its development for fibromyalgia, milnacipran was evaluated utilizing a composite responder approach. To be considered as a responder for the composite ‘treatment of fibromyalgia’ endpoint, each patient had to show concurrent and clinically meaningful improvements in pain, physical function and global impression of disease status. Using these criteria placebo-controlled trials [8][9] involving a total of over 2000 patients have shown milnacipran, at both 100 and 200 mg/day, to be significantly more effective than placebo in treating both pain and the broader syndrome of fibromyalgia. Response rates with milnacipran were similar in patients with and without co-morbid depression.
Pharmacokinetics
Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%. Meals do not have an influence on the rapidity and extent of absorption. Peak plasma concentrations are reached 2 hours after oral dosing. The elimination half-life of 8 hours is not increased by liver impairment and old age, but by significant renal disease. Milnacipran is conjugated to the inactive glucuronide and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found.
Indications and dosage
Milnacipran is indicated for:
treatment of major depressive disorder (not in USA)
management of fibromyalgia (USA and Russia)
The recommended dose for depression is 100 mg/day (given as 50 mg 2 times daily), with a starting period of 4 days on 25 mg/day. The dose should be decreased in patients with renal disease.
The recommended dose for fibromyalgia is 100 mg/day (after an uptitration period ) which may be increased to 200 mg/day based on individual patient response.
After successful treatment of the acute depressive episode, patients should be maintained on milnacipran for several months (normally 9 months) in order to prevent relapse of depression.
In America, Savella® is supplied by Forest Pharmaceuticals in a 2-week, professional sample titration pack to be provided directly by the doctor to the patient initiating milnacipran therapy. This pack contains five 12.5 mg tablets (one on day one, one tablet twice a day on days 2-3), eight 25 mg tablets (one tablet twice a day on days 4-7), and fourteen 50 mg tablets (one tablet twice a day on days 8-14). Therapy is then continued with one 50 mg tablet twice a day, or adjusted as needed by the physician.
Side effects
The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension [FDA Savella prescribing information]. Milnacipran can have a significant impact on sexual functions, including both a decrease in sexual desire and ability. Milnacipran can cause pain and swelling of the testicles in men as well as blood in the urine and stools. The incidence of cardiovascular and anticholinergic side effects was significantly lower compared to TCAs as a controlled study with over 3,300 patients revealed. Elevation of liver enzymes without signs of symptomatic liver disease has been infrequent. Mood swing to mania has also been seen and dictates termination of treatment. In psychotic patients emergence of delirium has been noticed. Milnacipran has a low incidence of sedation but improves sleep (both duration and quality) in depressed patients. In agitated patients or those with suicidal thoughts additive sedative/anxiolytic treatment is usually indicated.
Alcohol - no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended; the FDA advises against the concomitant use of alcohol and milnacipran
Contraindications
Administration of milnacipran should be avoided in individuals with the following:
Known hypersensitivity to milnacipran (absolute contraindication)
Patients under 15 years of age (no sufficient clinical data)
Hypertrophy of the prostate gland (possibly urination hesitancy induced), with hypertension and heart disease (tachycardia may be a problem) as well as with open angle glaucoma
Milnacipran should not be used during pregnancy because it may cross the placenta barrier and no clinical data exists on harmful effects in humans and animal studies. Milnacipran is contraindicated during lactation because it is excreted in the milk, and it is not known if it is harmful to the newborn.
References
^Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M (1985). "Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug". Neuropharmacology. 24 (12): 1211–9. doi:10.1016/0028-3908(85)90157-1. PMID3005901.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Briley M, Prost JF, Moret C (1996). "Preclinical pharmacology of milnacipran". International clinical psychopharmacology. 11 Suppl 4: 9–14. PMID8923122.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Puozzo C, Panconi E, Deprez D (2002). "Pharmacology and pharmacokinetics of milnacipran". International clinical psychopharmacology. 17 Suppl 1: S25–35. PMID12369608.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Kasper S, Pletan Y, Solles A, Tournoux A (1996). "Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results". International Clinical Psychopharmacolgy. 11 (Suppl 4): 35–39. doi:10.1097/00004850-199609004-00005. PMID8923125.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Lopez-Ibor J, Guelfi JD, Pletan Y, Tournoux A, Prost JF (1996). "Milnacipran and selective serotonin reuptake inhibitors in major depression". International Clinical Psychopharmacology. 11 (Suppl 4): 41–46. doi:10.1097/00004850-199609004-00006. PMID8923126.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Papakostas GI, Fava M (2007). "A meta-analysis of clinical trials comparing milnacipran, a serotonin--norepinephrine reuptake inhibitor, with a selective serotonin reuptake inhibitor for the treatment of major depressive disorder". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 17 (1): 32–6. doi:10.1016/j.euroneuro.2006.05.001. PMID16762534.
^Nakagawa A, Watanabe N, Omori IM, Barbui C, Cipriani A, McGuire H, Churchill R, Furukawa TA (2009). Nakagawa, Atsuo (ed.). "Milnacipran versus other antidepressive agents for depression". Cochrane Database of Systematic Reviews. 8 (3): CD006529. doi:10.1002/14651858.CD006529.pub2. PMID19588396.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y (2008). "Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial". Clinical Therapeutics. 30 (11): 1988–2004. doi:10.1016/j.clinthera.2008.11.009. PMID19108787.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH (2009). "The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial". Journal Rheumatology. 36 (2): 398–409. doi:10.3899/jrheum.080734. PMID19132781.{{cite journal}}: CS1 maint: multiple names: authors list (link)
