In a pooled analysis of 7 comparative trials withimipramine,[2] milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs[3] 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.[4] A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients[5] concluded that there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressant agents. However, compared withTCAs, 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.
During its development forfibromyalgia, 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. A systematic review in 2015 showed moderate relief for a minority of people with fibromyalgia. Milnacipran was associated with increased adverse events when discontinuing use of the drug.[6]
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.
The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhydrosis, 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[citation needed]. Milnacipran can cause pain of the testicles in men. The incidence of cardiovascular andanticholinergic side effects was significantly lower compared toTCAs as a controlled study with over 3,300 patients revealed. Elevation ofliver enzymes without signs of symptomatic liver disease has been infrequent. Mood swing tomania has also been seen and dictates termination of treatment. Inpsychotic patients emergence ofdelirium has been noticed. Milnacipran has a low incidence ofsedation but improvessleep (both duration and quality) in depressed patients. Inagitated patients or those withsuicidal thoughts additive sedative/anxiolytic treatment is usually indicated.[8] However, several studies found that there seems to be no "activation syndrome" and no increased risk of suicidality in milnacipran therapy; instead it is said to reduce suicidality along with depressive symptoms.[9][10][11]
Triptans — there have been rare postmarketing reports of hyperserotonergia (serotonin syndrome). If concomitant treatment of milnacipran with a triptan is clinically warranted, careful observation of patient is advised when starting or increasing dosages.[12]
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
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.[16]
Milnacipran was first approved for the treatment of major depressive episodes inFrance in December 1996. It is currently marketed (asIxel) for this indication in over 45 countries worldwide including severalEuropean countries such asAustria,Bulgaria,Finland,France,Portugal, andRussia. It is also available inJapan (asToledomin) andMexico (asDalcipran).Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in theUnited States andCanada in 2003 from the manufacturerLaboratoires Pierre Fabre.
In January 2009 theU.S. Food and Drug Administration (FDA) approved milnacipran (under the brand nameSavella) only for the treatment offibromyalgia, making it the third medication approved for this purpose in the United States. In July and November 2009, theEuropean Medicines Agency refused marketing authorization for a milnacipran product (under the brand nameImpulsor) for the treatment of fibromyalgia.[19]
^Kasper S, Pletan Y, Solles A, Tournoux A (September 1996). "Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results".International Clinical Psychopharmacology.11 (Suppl 4):35–9.doi:10.1097/00004850-199609004-00005.PMID8923125.S2CID27199308.
^Lopez-Ibor J, Guelfi JD, Pletan Y, Tournoux A, Prost JF (September 1996). "Milnacipran and selective serotonin reuptake inhibitors in major depression".International Clinical Psychopharmacology.11 (Suppl 4):41–6.doi:10.1097/00004850-199609004-00006.PMID8923126.S2CID31546691.
^Papakostas GI, Fava M (January 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.17 (1):32–6.doi:10.1016/j.euroneuro.2006.05.001.PMID16762534.S2CID27679241.
^Montgomery SA, Prost JF, Solles A, Briley M (September 1996). "Efficacy and tolerability of milnacipran: an overview".International Clinical Psychopharmacology.11 (Suppl 4):47–51.doi:10.1097/00004850-199609004-00007.PMID8923127.S2CID173746.
^Takano A, Halldin C, Farde L (March 2013). "SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study".Psychopharmacology.226 (1):147–153.doi:10.1007/s00213-012-2901-z.PMID23090625.
^Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M (December 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.S2CID46629043.
^Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S (2014). "Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1".CNS & Neurological Disorders Drug Targets.13 (8):1427–31.doi:10.2174/1871527313666141023145703.PMID25345508.
