MILNACIPRAN

Details

Stereochemistry	RACEMIC
Molecular Formula	C15H22N2O
Molecular Weight	246.348
Optical Activity	( + / - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCN(CC)C(=O)[C@@]1(C[C@@H]1CN)C2=CC=CC=C2

InChI

InChIKey=GJJFMKBJSRMPLA-HIFRSBDPSA-N

InChI=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

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664
Curator's Comment: Description was created based on several sources, including https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022256s013lbl.pdf

Milnacipran is the only marketed serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) reported to have greater relative potency at NET than SERT in vitro and is the first SNRI to report equal occupancy of both transporters at clinical doses. Milnacipran is a racemic mixture of the 1S, 2R (F2695/levomilnacipran) and 1R, 2S (F2696/dextromilnacipran) enantiomers. Savella® (Milnacipran) is indicated for the management of fibromyalgia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin transporter 172 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8146	290.0 nM [Ki]
Serotonin transporter 172 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8146	16.9 nM [Ki]
Norepinephrine transporter 183 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8146	139.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Fibromyalgia 89 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022256s013lbl.pdf	Primary		Approved 8307	SAVELLA Approved Use Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients [see Use in Specific Populations (8.4) Launch Date 1.2318912E12
Unknown 2554

C_max

Value	Dose	Co-administered	Analyte	Population
132 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26663198/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
150 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8923123/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1316.9 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26663198/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26663198/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8923123/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022256s023lbl.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MILNACIPRAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
87% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8923123/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
87% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022256s023lbl.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		MILNACIPRAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
100 mg 2 times / day multiple, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: multiple Dose: 100 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24188161 Page: p.593	unhealthy, 48.6 n = 181 Health Status: unhealthy Condition: Fibromyalgia Age Group: 48.6 Sex: M+F Population Size: 181 Sources: https://pubmed.ncbi.nlm.nih.gov/24188161 Page: p.593	Disc. AE: Nausea, Blood pressure increased... AEs leading to discontinuation/dose reduction: Nausea (2.4%) Blood pressure increased (1.4%) Heart rate increased (1%) Sources: https://pubmed.ncbi.nlm.nih.gov/24188161 Page: p.593
100 mg 2 times / day multiple, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: multiple Dose: 100 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Fibromyalgia Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.1	Disc. AE: Suicidal ideation, Serotonin syndrome... AEs leading to discontinuation/dose reduction: Suicidal ideation Serotonin syndrome Neuroleptic malignant syndrome Blood pressure increased Heart rate increased Seizures Hepatotoxicity ALT increased (mild) Aspartate aminotransferase increase (mild) Hepatitis fulminant (rare) Bleeding Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.1
100 mg 2 times / day multiple, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: multiple Dose: 100 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: Fibromyalgia Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.11	Disc. AE: Nausea, Palpitations... AEs leading to discontinuation/dose reduction: Nausea (6%) Palpitations (3%) Headache (2%) Constipation (1%) Heart rate increased (1%) Hyperhidrosis (1%) Vomiting (1%) Dizziness (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.11
100 mg 2 times / day multiple, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: multiple Dose: 100 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.5	unhealthy Health Status: unhealthy Condition: Fibromyalgia Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.5	Disc. AE: Suicidal ideation... AEs leading to discontinuation/dose reduction: Suicidal ideation (1.3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf Page: p.5

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1532 substrate 1670	inhibitor 1695 inducer 372	inhibitor 1789 substrate 1168	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1463 CYP2A6 670 CYP2C19 1410 CYP2E1 846	P-gp 1491 CYP2C19 955 CYP1A2 1013	CYP1A2 671 CYP2B6 521 CYP2C8 163 CYP2C19 283 CYP3A4/5 112

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1620	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP1A2 1620	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2A6 702	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2B6 946	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C19 1484	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C19 1484	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2C8 923	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C9 1747	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C9 1747	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2D6 1826	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2E1 929	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP3A4 1857	inhibitor 3185 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP3A4/5 314	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1491	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=7 Page: 7.0	no
CYP2C19 955	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	no (co-administration study) Comment: no changes in PK of warfarin or milnacipran were observed Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0
CYP1A2 1013	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	unlikely (co-administration study) Comment: when coadministered with carbamazepine, exposure (Cmax and AUC) to milnacipran decreased by 18% and 19%, respectively; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0
CYP2D6 1168	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	unlikely (co-administration study) Comment: At steady state, Cmax and AUC for milnacipran increased by only 10% and 20% when coadministered with levomepromazine; no changes in PK of warfarin or milnacipran were observed Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0
CYP3A4 1670	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0	no	unlikely (co-administration study) Comment: when coadministered with carbamazepine, exposure (Cmax and AUC) to milnacipran decreased by 18% and 19%, respectively; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=55 Page: 55.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1603	inhibitor 1584 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_PharmR_P2.pdf#page=59 Page: 59.0

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B2-6287	http://www.3bsc.com/index/pro_info.php?id=116365
AK Scientific, Inc. (AKSCI)	R211	http://www.aksci.com/item_detail.php?cat=R211
Acorn PharmaTech	ACN-035533	http://www.acornpharmatech.com/
Ambinter	Amb22801750	http://www.ambinter.com/reference/22801750
BLD Pharm	BD631023	http://www.bldpharm.com/products/92623-85-3.html
BLD Pharm	BD00756442	http://www.bldpharm.com/products/96847-55-1.html
BioCrick	BCC4194	http://www.biocrick.com/Milnacipran-BCC4194.html
CSNpharm	CSN18592	https://www.csnpharm.com/products/milnacipran.html
Chem Scene	CS-2009	http://www.chemscene.com/92623-85-3.html
ChemMol	99177637	http://www.chemmol.com/chemmol/99177637.html
ChemMol	99185159	http://www.chemmol.com/chemmol/99185159.html
Clearsynth	CS-P-00447	http://www.clearsynth.com/en/CSP00447.html
Hairui	HR143593	http://www.hairuichem.com/en/product/92623-85-3.html
Lab Network	LN01343162	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01343162
MedChem Express	HY-B0168	https://www.medchemexpress.com/milnacipran.html
MuseChem	I012513	https://www.musechem.com/product/I012513.html
OChem	10310	http://www.ocheminc.com/index.php?act=psearch&pid=623M853
Sigma-Aldrich	CDS022174_ALDRICH	https://www.sigmaaldrich.com/catalog/product/aldrich/cds022174?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Smolecule	S006221	http://www.smolecule.com/products/s006221
Smolecule	S535456	http://www.smolecule.com/products/s535456
THE BioTek	bt-255210	https://www.thebiotek.com/product/inhibitors/bt-255210
THE BioTek	bt-276385	https://www.thebiotek.com/product/inhibitors/bt-276385
iChemical	EBD2321826	http://www.ichemical.com/products/92623-85-3.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs

PubMed

Title	Date	PubMed
Which bioequivalence study for a racemic drug? Application to milnacipran.	1998 Apr-Jun	9725476
Elevation of blood pressure induced by high-dose milnacipran.	2002 Dec	12457380
Conformational analysis of the NMDA receptor antagonist (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) designed by a novel conformational restriction method based on the structural feature of cyclopropane ring.	2002 Jul	12130856
Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats.	2002 Jul	12122491
Remarkable effect of milnacipran in the treatment of Japanese major depressive patients.	2002 Jun	12404688
Clinical utility of milnacipran in comparison with other antidepressants.	2002 Jun	12369610
Japanese experience with dual-action antidepressants.	2002 Jun	12369609
Pharmacology and pharmacokinetics of milnacipran.	2002 Jun	12369608
Optimizing antidepressant treatment: efficacy and tolerability.	2002 Jun	12369607
In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs.	2002 Nov 15	12429415
Silent thyroiditis associated with short-term lithium therapy.	2002 Nov-Dec	12490351
The role of noradrenaline and selective noradrenaline reuptake inhibition in depression.	2002 Oct	12208564
A randomised, double-blind comparison of milnacipran and imipramine in the treatment of depression.	2002 Oct	12204314
Effect of chronic treatment with milnacipran on sleep architecture in rats compared with paroxetine and imipramine.	2002 Oct	12151030
Partial response and nonresponse to antidepressant therapy: current approaches and treatment options.	2002 Sep	12363125
Repeated administration of milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors but not postsynaptic 5-HT1A receptors.	2002 Sep	12236634
Mechanism of action of antidepressants.	2002 Summer	12490828
[Pharmacokinetics and drug interaction of antidepressants and anti-manic drugs].	2003	12877004
[Adverse effects of antidepressants and antimanics].	2003	12877003
Dual action antidepressants and some important considerations.	2003 Apr	12656958
Therapeutic effects of milnacipran (serotonin noradrenalin reuptake inhibitor) on depression following mild and moderate traumatic brain injury.	2003 Aug	12928711
Parkinsonism associated with a serotonin and noradrenaline reuptake inhibitor, milnacipran.	2003 Jan	12486290
Functional expression of the norepinephrine transporter in cultured rat astrocytes.	2003 Jan	12485410
Milnacipran plasma levels and antidepressant response in Japanese major depressive patients.	2003 Jun	12766929
Modulation of the human glucocorticoid receptor function by antidepressive compounds.	2003 May 22	12757900
Addition of a dopamine agonist, cabergoline, to a serotonin-noradrenalin reuptake inhibitor, milnacipran as a therapeutic option in the treatment of refractory depression: two case reports.	2003 Sep-Oct	14520161
Favorable effect of milnacipran on depression induced by interferon-alpha.	2003 Spring	12724470
Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum disorders.	2004 Apr	15009832
Acute effect of milnacipran on the relationship between the locus coeruleus noradrenergic and dorsal raphe serotonergic neuronal transmitters.	2004 Dec	15589386
Post-treatment emergent adverse events in depressed patients following treatment with milnacipran and paroxetine.	2004 Dec	15570574
Associations between baseline plasma MHPG (3-methoxy-4-hydroxyphenylglycol) levels and clinical responses with respect to milnacipran versus paroxetine treatment.	2004 Feb	14709941
Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity.	2004 Feb 1	14744476
Reboxetine: a norepinephrine selective reuptake pump inhibitor.	2004 Jan	15334987
Determination of milnacipran, a serotonin and noradrenaline reuptake inhibitor, in human plasma using liquid chromatography with spectrofluorimetric detection.	2004 Jul 5	15171932
A comparative study of milnacipran and imipramine in the treatment of major depressive disorder.	2004 Jun	15200743
Augmentation of milnacipran by risperidone in treatment for major depression.	2004 Mar	14731310
Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha 1-adrenoceptors.	2004 Mar 4	15036582
The monoamine reuptake inhibitor milnacipran does not affect nociception to acute visceral distension in rats.	2004 May	15105216
Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.	2004 Nov	15254142
The effectiveness of lithium augmentation of milnacipran: preliminary data using the modified Japanese Psychopharmacology Algorithm.	2004 Oct	15658504
A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia.	2004 Oct	15378666
Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms.	2004 Sep	15337646
In vitro inhibition of recombinant ligand-gated ion channels by high concentrations of milnacipran.	2004 Sep	14997275
Remarkable effect of milnacipran, a serotonin-noradrenalin reuptake inhibitor (SNRI), on depressive symptoms in patients with Parkinson's disease who have insufficient response to selective serotonin reuptake inhibitors (SSRIs): two case reports.	2005 Feb	15694247
[Effects of milnacipran on neuronal excitability and synaptic transmission in neurons of the rat locus coeruleus].	2005 Jan	15675357
Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action.	2005 Jul	15961146
The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.	2005 May	15845695
Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress.	2005 May	15619117
The effect of milnacipran (serotonin noradrenaline reuptake inhibitor) on memory in Korsakoff's syndrome after encephalitis.	2005 May-Jun	15882773
Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.	2013 Jul	23499664

Patents

Sample Use Guides

In Vivo Use Guide

Milnacipran and the L enantiomer were effective in reducing immobility in the forced swim test in rodents (EC50 ~10 mg/kg PO and ~3 mg/kg PO, respectively) compared with D enantiomer (EC50 ≥100 mg/kg PO).

Route of Administration: Oral

In Vitro Use Guide

Dextromilnacipran inhibits norepinephrine and serotonin reuptake in rat hypothalamic synaptosomes with IC50 values of 750 and 600 nM, respectively

Name

Type

Language

MILNACIPRAN

Official Name

English

Milnacipran [WHO-DD]

Common Name

English

MILNACIPRAN [MI]

Common Name

English

milnacipran [INN]

Common Name

English

(1RS,2SR)-2-(AMINOMETHYL)-N,N-DIETHYL-1-PHENYLCYCLOPROPANECARBOXAMIDE

Systematic Name

English

MILNACIPRAN [VANDF]

Common Name

English

IMPULSOR

Brand Name

English

MILNACIPRAN [EMA EPAR]

Common Name

English

MILNACIPRAN PIERRE FABRE MEDICAMENT

Brand Name

English

CYCLOPROPANECARBOXAMIDE, 2-(AMINOMETHYL)-N,N-DIETHYL-1-PHENYL-, (1R,2S)-REL-

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C29747