Milnacipran

{{Short description|SNRI medication}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Watchedfields = changed | class = Serotonin–norepinephrine reuptake inhibitor (SNRI) | verifiedrevid = 408610912 | IUPAC_name = (±)-(1''R'',2''S'')-''rel''-2-(Aminomethyl)-''N'',''N''-diethyl-1- phenylcyclopropane-1-carboxamide | image = Milnacipran structure.svg | image_class = skin-invert-image | image2 = Milnacipran racemate ball-and-stick models.png | image_class2 = bg-transparent | width = 250 | caption = Top: (1''S'',2''R'')-milnacipran (L-milnacipran) Bottom: (1''R'',2''S'')-milnacipran (D-milnacipran) | chirality = Racemic mixture

| pronounce = | tradename = Savella, others | Drugs.com = {{drugs.com|monograph|milnacipran-hydrochloride}} | MedlinePlus = a609016 | pregnancy_AU = B3 | pregnancy_US = C | legal_AU = S4 | legal_BR = C1 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}</ref> | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = By mouth

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 92623-85-3 | ATC_prefix = N06 | ATC_suffix = AX17 | PubChem = 65833 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB04896 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 59245 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = G56VK1HF36 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08222 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 252923

| C = 15 | H = 22 | N = 2 | O = 1 | smiles = O=C(N(CC)CC)[C@@]2(c1ccccc1)[C@@H](CN)C2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3/t13-,15+/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = GJJFMKBJSRMPLA-HIFRSBDPSA-N }}

'''Milnacipran''', sold under the brand name '''Savella''' among others, is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia, major depressive disorder, and neuropathic pain. In the US, it is solely approved for the treatment of fibromyalgia, even though it is also approved for the treatment of major depressive disorder (but not fibromyalgia) in other countries (e.g., France).

==Medical uses==

===Depression=== In a pooled analysis of 7 comparative trials with imipramine,<ref name="kasper">{{cite journal | vauthors = Kasper S, Pletan Y, Solles A, Tournoux A | title = Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results | journal = International Clinical Psychopharmacology | volume = 11 | issue = Suppl 4 | pages = 35–9 | date = September 1996 | pmid = 8923125 | doi = 10.1097/00004850-199609004-00005 | s2cid = 27199308 }}</ref> milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and selective serotonin reuptake inhibitors (SSRIs)<ref name="Lopez-Ibor">{{cite journal | vauthors = Lopez-Ibor J, Guelfi JD, Pletan Y, Tournoux A, Prost JF | title = Milnacipran and selective serotonin reuptake inhibitors in major depression | journal = International Clinical Psychopharmacology | volume = 11 | issue = Suppl 4 | pages = 41–6 | date = September 1996 | pmid = 8923126 | doi = 10.1097/00004850-199609004-00006 | s2cid = 31546691 }}</ref> 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.<ref name="Papakostas">{{cite journal | vauthors = Papakostas GI, Fava M | title = 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 | journal = European Neuropsychopharmacology | volume = 17 | issue = 1 | pages = 32–6 | date = January 2007 | pmid = 16762534 | doi = 10.1016/j.euroneuro.2006.05.001 | s2cid = 27679241 }}</ref> A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients<ref name="nakagawa">{{cite journal | vauthors = Nakagawa A, Watanabe N, Omori IM, Barbui C, Cipriani A, McGuire H, Churchill R, Furukawa TA | title = Milnacipran versus other antidepressive agents for depression | journal = The Cochrane Database of Systematic Reviews | volume = 8 | issue = 3 | article-number = CD006529 | date = July 2009 | pmid = 19588396 | pmc = 4164845 | doi = 10.1002/14651858.CD006529.pub2 | veditors = Nakagawa A }}</ref> concluded that there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressant agents. However, compared with tricyclic antidepressants (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.{{Citation needed|date=April 2026}}

===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. 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.<ref>{{cite journal | vauthors = Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ | title = Milnacipran for pain in fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | issue = 10 | article-number = CD008244 | date = October 2015 | volume = 2019 | pmid = 26482422 | pmc = 6481368 | doi = 10.1002/14651858.CD008244.pub3 }}</ref>

===Social anxiety===

There is some evidence that milnacipran may be effective for social anxiety.<ref>{{cite journal | vauthors = Higuchi T, Briley M | title = Japanese experience with milnacipran, the first serotonin and norepinephrine reuptake inhibitor in Japan | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 1 | pages = 41–58 | date = February 2007 | pmid = 19300537 | pmc = 2654524 | doi = 10.2147/nedt.2007.3.1.41 | doi-access = free }}</ref>

==Contraindications== {{Unreferenced section|date=April 2026}} 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, phenelzine, >10 mg selegiline) or digitalis glycosides 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, reversible MAO-A Inhibitors (such as moclobemide, toloxatone) or 5-HT1D-agonists (e.g. triptan migraine drugs) * 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.

==Side effects== 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|reason=This claim needs a reliable source; most papers indicate the opposite.|date=March 2015}} 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.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022256s014s015lbl.pdf |archive-url=https://web.archive.org/web/20140504172000/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022256s014s015lbl.pdf |archive-date=May 4, 2014 |title=www.accessdata.fda.gov }}</ref> 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.<ref>{{cite journal | vauthors = Kirino E, Gitoh M | title = Rapid improvement of depressive symptoms in suicide attempters following treatment with milnacipran and tricyclic antidepressants - a case series | journal = Neuropsychiatric Disease and Treatment | volume = 7 | pages = 723–728 | date = 2011 | pmid = 22247614 | pmc = 3255999 | doi = 10.2147/NDT.S27718 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Avedisova A, Borodin V, Zakharova K, Aldushin A | title = Effect of milnacipran on suicidality in patients with mild to moderate depressive disorder | journal = Neuropsychiatric Disease and Treatment | volume = 5 | pages = 415–420 | date = 2009 | pmid = 19721721 | pmc = 2732008 | doi = 10.2147/ndt.s5467 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Montgomery SA, Prost JF, Solles A, Briley M | title = Efficacy and tolerability of milnacipran: an overview | journal = International Clinical Psychopharmacology | volume = 11 | issue = Suppl 4 | pages = 47–51 | date = September 1996 | pmid = 8923127 | doi = 10.1097/00004850-199609004-00007 | s2cid = 173746 }}</ref>

== Interactions ==

* MAOIs – serotonin syndrome, potentially lethal hypertensive crisis{{Citation needed|date=April 2026}} * 5-HT1 receptor agonists – coronary vasoconstriction with risk of angina pectoris and myocardial infarction{{Citation needed|date=April 2026}} * Epinephrine, norepinephrine (also in local anesthesia) – hypertensive crisis or possible cardiac arrhythmia{{Citation needed|date=April 2026}} * Clonidine – antihypertensive action of clonidine may be antagonized{{Citation needed|date=April 2026}} * Digitalis – hemodynamic actions increased{{Citation needed|date=April 2026}} * Triptans – there have been rare postmarketing reports of serotonin syndrome. If concomitant treatment of milnacipran with a triptan is clinically warranted, careful observation of patient is advised when starting or increasing dosages.<ref>{{cite web | publisher = National Institute of Health | work = DailyMed | title = SAVELLA - milnacipran hydrochloride tablet, film coated | url = https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08214b30-3dab-4621-a6c0-6bb68529dee3 }}</ref> * 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{{Citation needed|date=April 2026}}

==Pharmacology==

===Pharmacodynamics=== Milnacipran inhibits the reuptake of serotonin and norepinephrine in an approximately 2:1 ratio, respectively.<ref>{{cite journal | vauthors = Takano A, Halldin C, Farde L | title = SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study | journal = Psychopharmacology | volume = 226 | issue = 1 | pages = 147–153 | date = March 2013 | pmid = 23090625 | doi = 10.1007/s00213-012-2901-z }}</ref> Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors, nor on benzodiazepine and opioid binding sites.<ref name="Moret">{{cite journal | vauthors = Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M | title = Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug | journal = Neuropharmacology | volume = 24 | issue = 12 | pages = 1211–9 | date = December 1985 | pmid = 3005901 | doi = 10.1016/0028-3908(85)90157-1 | s2cid = 46629043 }}</ref><ref name="Briley">{{cite journal | vauthors = Briley M, Prost JF, Moret C | title = Preclinical pharmacology of milnacipran | journal = International Clinical Psychopharmacology | volume = 11 | pages = 9–14 | date = September 1996 | issue = Suppl 4 | pmid = 8923122 | doi = 10.1097/00004850-199609004-00002 | s2cid = 37407165 }}</ref><ref name="Puozzo">{{cite journal | vauthors = Puozzo C, Panconi E, Deprez D | title = Pharmacology and pharmacokinetics of milnacipran | journal = International Clinical Psychopharmacology | volume = 17 | pages = S25-35 | date = June 2002 | issue = Suppl 1 | pmid = 12369608 | doi = 10.1097/00004850-200206001-00004 | s2cid = 45279690 }}</ref>

Recently, levomilnacipran, the levorotatory enantiomer of milnacipran, 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.<ref name="pmid25345508">{{cite journal | vauthors = Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S | title = 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 | journal = CNS & Neurological Disorders Drug Targets | volume = 13 | issue = 8 | pages = 1427–31 | year = 2014 | pmid = 25345508 | doi = 10.2174/1871527313666141023145703 }}</ref> Other BACE-1 inhibitors, such as CTS-21166 (ASP1720), MK-8931, and AZD3293 were in clinical trials for the treatment of Alzheimer's disease,<ref name="pmid25100992">{{cite journal | vauthors = Menting KW, Claassen JA | title = β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease | journal = Frontiers in Aging Neuroscience | volume = 6 | page = 165 | year = 2014 | pmid = 25100992 | pmc = 4104928 | doi = 10.3389/fnagi.2014.00165 | doi-access = free }}</ref> but in both cases clinical trials were halted due to a lack of positive evidence of a favorable benefit to risk ratio and both were considered unlikely to return satisfactory results.

===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.<ref name=Puozzo/>

==History== 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.{{Citation needed|date=April 2026}}

In January 2009 the US 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. The manufacturer has not applied for FDA approval for usage of milnacipran for depression.<ref name="DOD">{{cite web |title=DOD PHARMACY AND THERAPEUTICS COMMITTEE RECOMMENDATIONS |url=https://www.health.mil/Reference-Center/Meeting-References/2010/01/14/BAP-Background-January-14-2010 |website=Health.mil |publisher=Military Health System |quote=Savella is approved for depression outside of the US, but the manufacturer will not seek FDA approval for depression.}}</ref> 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 fibromyalgia.<ref name="Doc. Ref.: EMA/814249/2009">{{cite web|author=European Medicines Agency|title=Questions and answers on the recommendati on for the refusal of the marketing authorisation for Milnacipran Pierre Fabre Médicament/Impulsor|url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/001034/WC500089875.pdf|publisher=European Medicines Agency|access-date=30 May 2013|archive-date=22 February 2014|archive-url=https://web.archive.org/web/20140222154105/http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/001034/WC500089875.pdf}}</ref>

== References == {{Reflist}}

== External links == * {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/rn/92623-85-3 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Milnacipran }}{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}} * {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/milnacipran%20hydrochloride | archive-url = https://web.archive.org/web/20201015072134/https://druginfo.nlm.nih.gov/drugportal/name/milnacipran%20hydrochloride | archive-date = October 15, 2020 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Milnacipran hydrochloride }}

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