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			{{Short description|Antidepressant}}
			{{cs1 config|name-list-style=vanc|display-authors=6}}
	{{Drugbox		{{Drugbox
			| Watchedfields = changed
	| drug_name = Milnacipran
	| verifiedrevid = 408609174		| verifiedrevid = 408610912
	| IUPAC_name = (1''R''*,2''S''*)-2-(aminomethyl)-''N'',''N''-diethyl-1-phenylcyclopropanecarboxamide		| IUPAC_name = (±)-(1''R'',2''S'')-''rel''-2-(Aminomethyl)-''N'',''N''-diethyl-1- phenylcyclopropane-1-carboxamide
	| image = Milnacipran Enantiomers Structural Formulae.png		| image = Milnacipran structure.svg
			| image2 = Milnacipran3Dan.gif
	| imagename = 1 : 1 mixture (racemate)
	| width = 200		| width = 250
			| caption = Top: (1''S'',2''R'')-milnacipran (])<br />Bottom: (1''R'',2''S'')-milnacipran (<small>D</small>-milnacipran)
	| CASNo_Ref = {{cascite|correct|CAS}}
			| chirality = ]
			<!--Clinical data-->
			| pronounce =
			| tradename = Ixel, Joncia, Savella
			| 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=] |language=pt-BR |publication-date=2023-04-04}}</ref>
			| legal_CA = Rx-only
			| legal_UK = POM
			| legal_US = Rx-only
			| routes_of_administration = ] (]), ])
			<!--Pharmacokinetic data-->
			| bioavailability = 85%
			| protein_bound = 13%
			| metabolism = ]
			| elimination_half-life = 8 hours
			| excretion = ]
			<!--Identifiers-->
			| 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_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 59245		| ChemSpiderID = 59245
	| UNII_Ref = {{fdacite|correct|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = G56VK1HF36		| UNII = G56VK1HF36
			| KEGG_Ref = {{keggcite|correct|kegg}}
	| InChI = 1/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
			| KEGG = D08222
	| InChIKey = GJJFMKBJSRMPLA-HIFRSBDPBS
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 252923		| ChEMBL = 252923
			<!--Chemical data-->
			| C=15 | H=22 | N=2 | O=1
			| smiles = O=C(N(CC)CC)2(c1ccccc1)(CN)C2
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| 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		| 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_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = GJJFMKBJSRMPLA-HIFRSBDPSA-N		| StdInChIKey = GJJFMKBJSRMPLA-HIFRSBDPSA-N
	| CAS_number = 92623-85-3
	| ATC_prefix = N06
	| ATC_suffix = AX17
	| PubChem = 65833
	| DrugBank = DB04896
	| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = D08222
	| C = 15 | H = 22 | N = 2 | O = 1
	| molecular_weight = 246.348 g/mol
	| smiles = O=C(N(CC)CC)2(c1ccccc1)(CN)C2
	| bioavailability = 85%
	| protein_bound = 13%
	| metabolism = ]
	| elimination_half-life = 8 hours
	| excretion = ]
	| pregnancy_US = X
	| legal_US = Rx-only
	| routes_of_administration = ]
	}}		}}
	'''Milnacipran''' ('''Ixel''', '''Savella''', '''Dalcipran''', '''Toledomin''') is a ] (SNRI) used in the clinical treatment of ] and ].		'''Milnacipran''' (trade names '''Ixel''', '''Savella''', '''Dalcipran''', '''Toledomin''') is a ] (SNRI) used in the clinical treatment of ]. It is not approved for the clinical treatment of ] in the US, but it is in other countries.
	==History==		==Medical uses==
	Milnacipran was first approved for the treatment of major depressive episodes in ] in December 1996. It is currently marketed (as '''Ixel''') for this indication in over 45 countries worldwide including several ]an countries such as ], ], ], ], ], and ]. It is also available in ] (as '''Toledomin''') and ] (as '''Dalcipran'''). ] bought the exclusive rights for approval and marketing of the drug for any purpose in the ] and ] in 2003 from the manufacturer ].
			===Depression===
	In January 2009 the ] (FDA) approved milnacipran (under the brand name '''Savella''') for the treatment of ], making it the third medication approved for this purpose in the United States.
			In a pooled analysis of 7 comparative trials with ],<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 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 | pages = 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 ], 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.
			=== Impulse Control ===
	==Pharmacology==
			Milnacipran was found to improve impulse control in rats, which has been linked to its activation of D<sub>1</sub>-like receptors in the infralimbic cortex.<ref>{{cite journal | vauthors = Tsutsui-Kimura I, Ohmura Y, Izumi T, Kumamoto H, Yamaguchi T, Yoshida T, Yoshioka M | title = Milnacipran enhances the control of impulsive action by activating D₁-like receptors in the infralimbic cortex | journal = Psychopharmacology | volume = 225 | issue = 2 | pages = 495–504 | date = January 2013 | pmid = 22892727 | doi = 10.1007/s00213-012-2835-5 | hdl-access = free | s2cid = 12806222 | hdl = 2115/54108 }}</ref> However, high doses of milnacipran did not show this effect, likely because of increased dopamine in the nucleus accumbens.<ref>{{cite journal | vauthors = Tsutsui-Kimura I, Ohmura Y, Yoshida T, Yoshioka M | title = Milnacipran affects mouse impulsive, aggressive, and depressive-like behaviors in a distinct dose-dependent manner | journal = Journal of Pharmacological Sciences | volume = 134 | issue = 3 | pages = 181–189 | date = July 2017 | pmid = 28694090 | doi = 10.1016/j.jphs.2017.06.004 | hdl = 2115/67315 | hdl-access = free }}</ref> Depression has been associated with increased impulsivity.
	Milnacipran ]s the ] of ] and ] in an approximately 1:3 ratio, respectively; in practical use this means a relatively balanced action upon both ]s. Inhibition of both neurotransmitters simultaneously works synergistically to treat both depression and fibromyalgia. Milnacipran exerts no significant actions on ], ], ], ], and ] ]s, as well as on ] and ] ]s.<ref name="Moret">{{cite journal
	|author=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
	|year=1985
	|pmid=3005901
	|doi=10.1016/0028-3908(85)90157-1
	}}</ref><ref name="Briley">{{cite journal
	|author=Briley M, Prost JF, Moret C
	|title=Preclinical pharmacology of milnacipran
	|journal=International clinical psychopharmacology
	|volume=11 Suppl 4
	|issue=
	|pages=9–14
	|year=1996
	|pmid=8923122
	|doi=
	}}</ref><ref name="Puozzo">{{cite journal
	|author=Puozzo C, Panconi E, Deprez D
	|title=Pharmacology and pharmacokinetics of milnacipran
	|journal=International clinical psychopharmacology
	|volume=17 Suppl 1
	|issue=
	|pages=S25–35
	|year=2002
	|pmid=12369608
	}}</ref>
			===Fibromyalgia===
	==Clinical results in depression==
			During its development for ], 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 | pages = CD008244 | date = October 2015 | volume = 2019 | pmid = 26482422 | pmc = 6481368 | doi = 10.1002/14651858.CD008244.pub3 }}</ref>
	In a pooled analysis of 7 comparative trials with ],<ref name="kasper">{{cite journal
	|author=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 Psychopharmacolgy
	|volume=11
	|issue=Suppl 4
	|pages=35–39
	|year=1996
	|pmid=8923125
	|doi=10.1097/00004850-199609004-00005
	}}</ref> milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs <ref name="Lopez-Ibor">{{cite journal
	|author=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=41–46
	|year=1996
	|pmid=8923126
	|doi=10.1097/00004850-199609004-00006
	}}</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
	|author=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 : the journal of the European College of Neuropsychopharmacology
	|volume=17
	|issue=1
	|pages=32–6
	|year=2007
	|pmid=16762534
	|doi=10.1016/j.euroneuro.2006.05.001
	}}</ref> A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients <ref name="nakagawa">{{cite journal
	|author=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=Cochrane Database Systematic Review
	|volume=8
	|issue=3
	|pages=CD006529
	|year=2009
	|pmid=19588396
	|doi=10.1002/14651858.CD006529.pub2
	}}</ref> 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.
			===Social anxiety===
	==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 <ref name="clauw">{{cite journal
	|author=Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y
	|title=Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial
	|journal=Clinical Therapeutics
	|volume=30
	|issue=11
	|pages=1988–2004
	|year=2008
	|pmid=19108787
	|doi=10.1016/j.clinthera.2008.11.009
	}}</ref><ref name="mease">{{cite journal
	|author=Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH
	|title=The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial
	|journal=Journal Rheumatology
	|volume=36
	|issue=2
	|pages=398–409
	|year=2009
	|pmid=19132781
	|doi=10.3899/jrheum.080734
	}}</ref> involving a total of over 2000 patients have shown milnacipran, at both 100 and 200&nbsp;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.
			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>
	==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. 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.
			==Contraindications==
	==Indications and dosage==
			Administration of milnacipran should be avoided in individuals with the following:
	Milnacipran is indicated for:
	* treatment of major depressive disorder (not in USA)
	* management of fibromyalgia (USA only)
			* Known hypersensitivity to milnacipran (absolute contraindication)
	The recommended dose for depression is 100&nbsp;mg/day (given as 50&nbsp;mg 2 times daily), with a starting period of 4 days on 25&nbsp;mg/day. The dose should be decreased in patients with renal disease.
			* Patients under 15 years of age (no sufficient clinical data)
	The recommended dose for fibromyalgia is 100&nbsp;mg/day (after an uptitration period ) which may be increased to 200&nbsp;mg/day based on individual patient response.
			* Concomitant treatment with irreversible ]s (e.g. ] (Parnate), ] (Nardil), >10&nbsp;mg ]) or ] ]s is an absolute contraindication.
			Administration of milnacipran should be done with caution in individuals with the following:
	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.
			* Concomitant treatment with parenteral ], ], with ], ] (such as ], ]) or 5-HT<sub>1D</sub>-agonists (e.g. ] 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==		==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 . 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 ] side effects was significantly lower compared to ]s as a controlled study with over 3,300 patients revealed. Elevation of ] without signs of symptomatic liver disease has been infrequent. Mood swing to ] has also been seen and dictates termination of treatment. In ] patients emergence of ] has been noticed. Milnacipran has a low incidence of ] but improves ] (both duration and quality) in depressed patients. In ] patients or those with ] thoughts additive sedative/anxiolytic treatment is usually indicated.		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 . 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 ] side effects was significantly lower compared to ]s as a controlled study with over 3,300 patients revealed. Elevation of ] without signs of symptomatic liver disease has been infrequent. Mood swing to ] has also been seen and dictates termination of treatment. In ] patients emergence of ] has been noticed. Milnacipran has a low incidence of ] but improves ] (both duration and quality) in depressed patients. In ] patients or those with ] thoughts additive sedative/anxiolytic treatment is usually indicated.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022256s014s015lbl.pdf |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==		== Interactions ==
	*]s - hyperserotonergia (serotonin syndrome), potentially lethal hypertensive crisis
	*5-HT1 receptor agonists - coronary vasoconstriction with risk of ] and ]
	*], ] (also in local anesthesia) - hypertensive crisis and/or possible cardiac arrhythmia
	*] - antihypertensive action of clonidine may be antagonized
	*] - hemodynamic actions increased
	*] - no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended
			* ]s — hyperserotonergia (]), potentially lethal hypertensive crisis
	==Contraindications==
			* 5-HT<sub>1</sub> receptor agonists — coronary vasoconstriction with risk of ] and ]
	Administration of milnacipran should be avoided in individuals with the following:
			* ], ] (also in local anesthesia) — hypertensive crisis and/or possible cardiac arrhythmia
	*Known hypersensitivity to milnacipran (absolute contraindication)
			* ] — antihypertensive action of clonidine may be antagonized
	*Patients under 15 years of age (no sufficient clinical data)
			* ] — hemodynamic actions increased
	*Concomitant treatment with irreversible ]s (e.g. ] (Parnate), ] (Nardil), ] (Selegiline)), ] ]s or 5-HT<sub>1D</sub>-agonists (e.g. ] migraine drugs) is an absolute contraindication.
			* ] — 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.<ref>{{cite web | publisher = National Institute of Health | work = DailyMed | title = SAVELLA - milnacipran hydrochloride tablet, film coated | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08214b30-3dab-4621-a6c0-6bb68529dee3 }}</ref>
			* ] — 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
			==Pharmacology==
	Administration of milnacipran should be done with caution in individuals with the following:
	*Concomitant treatment with parenteral ], ], with ] and reversible MAO-A Inhibitors (], ]).
	*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
			===Pharmacodynamics===
	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 ]s the ] of ] and ] 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 ], ], ], ], and ] ]s, nor on ] and ] ]s.<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, ], the ] ] of milnacipran, has been found to act as an ] of ] (BACE-1), which is responsible for ] plaque formation, and hence may be a potentially useful drug in the treatment of ].<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 ] (ASP1720), ], and ] were in ]s 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 | pages = 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.
	==References==
	{{Reflist}}
			===Pharmacokinetics===
	==External links==
			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/>
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	* License Agreement Cypress - Pierre Fabre.
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			==History==
			Milnacipran was first approved for the treatment of major depressive episodes in ] in December 1996. It is currently marketed (as '''Ixel''') for this indication in over 45 countries worldwide including several ]an countries such as ], ], ], ], ], and ]. It is also available in ] (as '''Toledomin''') and ] (as '''Dalcipran'''). ] bought the exclusive rights for approval and marketing of the drug for any purpose in the ] and ] in 2003 from the manufacturer ].
			In January 2009 the ] (FDA) approved milnacipran (under the brand name '''Savella''') only for the treatment of ], making it the third medication approved for this purpose in the United States. In July and November 2009, the ] 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|url-status=dead}}</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 }}
			* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/milnacipran%20hydrochloride | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Milnacipran hydrochloride }}
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