Milnacipran: Wikis


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Systematic (IUPAC) name
(1R*,2S*)-2-(aminomethyl)- N,N-diethyl-1-phenylcyclopropanecarboxamide
CAS number 92623-85-3
ATC code N06AX17
PubChem 65833
Chemical data
Formula C 15H22N2O 
Mol. mass 246.348
Pharmacokinetic data
Bioavailability 85%
Protein binding 13%
Metabolism Hepatic
Half life 8 hours
Excretion Renal
Therapeutic considerations
Licence data

US FDA:link

Pregnancy cat. X(US)
Legal status -only (US)
Routes Oral
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Milnacipran (Ixel, Savella) is a psychoactive drug which functions as a serotonin-norepinephrine reuptake inhibitor (SNRI). It is used for the treatment of clinical depression and fibromyalgia.



Milnacipran was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed for this indication (as Ixel) in over 45 countries worldwide including several European countries including Austria, Finland France, Portugal , Russia … (as Ixel) and Japan (as Toledomin). It is also available in Mexico (as Dalcipran). Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the US and Canada in 2003 from the manufacturer Pierre Fabre.

In January 2009 the U.S. Food and Drug Administration (FDA) approved milnacipran (under the brand name Savella) for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States.[1]


Milnacipran inhibits serotonin and norepinephrinere uptake in a 3:1 ratio, in practical use this means a balanced (equal) action upon both transmitters. The serotonin reuptake inhibition is likely to improve depression, while the norepinephrine reuptake inihibition probably improves chronic pain. Milnacipran exerts no significant actions on postsynaptic H1, alpha-1, D1, D2, and muscarinic receptors, as well as on benzodiazepine/opiate binding sites.[2][3][4].

Clinical results in depression

In a pooled analysis of 7 comparative trials with imipramine [5] milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs [6] 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.[7] A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients [8] 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 [9][10] 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. Furthermore, data from an extension study showed that the therapeutic effects of milnacipran were sustained for at least 1 year of therapy. Response rates with milnacipran were similar in patients with and without co-morbid depression.


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. Enzymes of the CYP class do not play a role in the metabolism of Milnacipran so that the risk of interactions with drugs metabolized by CYP enzymes is minimal.

Indications & dosage

Milnacipran is indicated for:

  • treatment of major depressive disorder (not in USA)
  • management of fibromyalgia (USA only)

The recommended dose for depression is 50 mg/day (given as 25 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.

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 increased, dry mouth, and hypertension [FDA Savella prescribing information]. Milnacipran does not seem to have a negative impact on sexual functions. 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.


  • MAOIs, lithium - hyperserotonergia (serotonin syndrome), potentially lethal hypertensive crisis
  • 5-HT1 receptor agonists - coronary vasoconstriction with risk of angina pectoris and myocardial infarction
  • Epinephrine, Norepinephrine (also in local anesthesia) - hypertensive crisis and/or possible cardiac arrhythmia
  • MDA, MDMA or other serotonergic amphetamines - hyperserotonergia, hyperthermia and potentially lethal hypertensive crisis
  • Clonidine - antihypertensive action of clonidine may be antagonized
  • Digitalis - hemodynamic actions increased
  • Alcohol - no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended


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)
  • Concomitant treatment with irreversible MAO-Inhibitors (e.g. tranylcypromine (Parnate), phenelzine (Nardil), (l)-deprenyl (Selegiline)), digitalis glycosides or 5-HT1D-Agonists (e.g. sumatriptan) is an absolute contraindication.

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

  • Concomitant treatment with parenteral epinephrine, norepinephrine, with clonidine and reversible MAO-A Inhibitors (moclobemide, toloxatone).
  • Advanced renal disease (decreased dosage required)
  • 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.


Ph 420 200 10K 120 7 10K
3-Cl-Ph 170 38 10K 86 33 9K
4-Cl-Ph 190 140 3700 790 44 10K
3,4-di-Cl-Ph 84 10 540 440 26 1700
4-F-Ph 320 500 10K 210 63 10K
4-MeO-Ph 230 140 10K 510 35 10K
1-Naphthyl 1200 200 5300 7100 370 10K
2-Naphthyl 18 5 140 130 29 1400
2-Thiophene 520 1500 970 250 65 10K
3-Thiophene 250 410 10K 190 19 10K


  1. ^
  2. ^ 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.  
  3. ^ Briley M, Prost JF, Moret C (1996). "Preclinical pharmacology of milnacipran". International clinical psychopharmacology 11 Suppl 4: 9–14. PMID 8923122.  
  4. ^ Puozzo C, Panconi E, Deprez D (2002). "Pharmacology and pharmacokinetics of milnacipran". International clinical psychopharmacology 17 Suppl 1: S25–35. PMID 12369608.  
  5. ^ 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. PMID 8923125.  
  6. ^ 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. PMID 8923126.  
  7. ^ 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.  
  8. ^ Nakagawa A, Watanabe N, Omori IM, Barbui C, Cipriani A, McGuire H, Churchill R, Furukawa TA (2009). "Milnacipran versus other antidepressive agents for depression". Cochrane Database Systematic Review 8 (3): CD006529. PMID 19588396.  
  9. ^ 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. PMID 19108787.  
  10. ^ 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. PMID 19132781.  

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