Top: (1S,2R)-milnacipran (L-milnacipran)
Bottom: (1R,2S)-milnacipran (D-milnacipran)
Clinical data
Pronunciation /milnæsipræn/
Trade names Ixel, Joncia, Savella
AHFS/ Consumer Drug Information
MedlinePlus a609016
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
By mouth (tablets), capsules)
ATC code N06AX17 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 85%
Protein binding 13%
Metabolism Hepatic
Biological half-life 8 hours
Excretion Renal
CAS Number 92623-85-3 YesY
PubChem (CID) 65833
DrugBank DB04896 YesY
ChemSpider 59245 YesY
KEGG D08222 YesY
Chemical and physical data
Formula C15H22N2O
Molar mass 246.348 g/mol
3D model (Jmol) Interactive image
Chirality Racemic mixture

Milnacipran (trade names Ixel, Savella, Dalcipran, Toledomin) is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the USA, but it is in other countries.

Medical uses


In a pooled analysis of 7 comparative trials with imipramine,[1] milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs [2] 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.[3] A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients [4] 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.


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. A systematic review in 2012 showed moderate relief for a minority of people with fibromyalgia. Milnacipran was associated with increased adverse events and discontinuing use of the drug.[5]

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 of the testicles in men. 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.[6]



Administration of milnacipran should be avoided in individuals with the following:

Administration of milnacipran should be done with caution in individuals with the following:

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.


Milnacipran inhibits the reuptake of serotonin and norepinephrine in an approximately 1:3 ratio, respectively; in practical use this means a relatively balanced action upon both neurotransmitters. Increasing both neurotransmitters concentration simultaneously works synergistically to treat both depression and fibromyalgia. Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors, as well as on benzodiazepine and opioid binding sites.[8][9][10]

Recently, levomilnacipran has been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment of Alzheimer's disease.[11] Other BACE-1 inhibitors, such as CTS-21166 (ASP1720), MK-8931, and AZD3293 are currently in clinical trials for the treatment of Alzheimer's disease.[12]


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.

Regulatory status

Milnacipran is indicated for:

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 the United States, 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.


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 July and November 2009, the European Medicines Agency refused marketing authorization for a milnacipran product (under the brand name Impulsor) for the treatment of fibromylagia.[13]

See also


  1. 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. PMID 8923125.
  2. 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. PMID 8923126.
  3. 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. PMID 16762534.
  4. Nakagawa A, Watanabe N, Omori IM, Barbui C, Cipriani A, McGuire H, Churchill R, Furukawa TA (2009). Nakagawa A, ed. "Milnacipran versus other antidepressive agents for depression". Cochrane Database of Systematic Reviews. 8 (3): CD006529. doi:10.1002/14651858.CD006529.pub2. PMID 19588396.
  5. Derry, S; Gill, D; Phillips, T; Moore, RA (Mar 14, 2012). "Milnacipran for neuropathic pain and fibromyalgia in adults.". Cochrane database of systematic reviews (Online). 3: CD008244. doi:10.1002/14651858.CD008244.pub2. PMID 22419330.
  6. "" (PDF).
  7. National Institute of Health. DailyMed.
  8. 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. PMID 3005901.
  9. Briley M, Prost JF, Moret C (1996). "Preclinical pharmacology of milnacipran". International clinical psychopharmacology. 11 Suppl 4: 9–14. doi:10.1097/00004850-199609004-00002. PMID 8923122.
  10. Puozzo C, Panconi E, Deprez D (2002). "Pharmacology and pharmacokinetics of milnacipran". International clinical psychopharmacology. 17 Suppl 1: S25–35. doi:10.1097/00004850-200206001-00004. PMID 12369608.
  11. 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 Neurol Disord Drug Targets. 13 (8): 1427–31. doi:10.2174/1871527313666141023145703. PMID 25345508.
  12. Menting KW, Claassen JA (2014). "β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease". Front Aging Neurosci. 6: 165. doi:10.3389/fnagi.2014.00165. PMC 4104928Freely accessible. PMID 25100992.
  13. European Medicines Agency. "Questions and answers on the recommendati on for the refusal of the marketing authorisation for Milnacipran Pierre Fabre Médicament/Impulsor" (PDF). European Medicines Agency. Retrieved 30 May 2013.
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