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: https://www.tga.gov.au/sites/default/files/auspar-milnacipran-hydrochloride-120124.pdf

Dextromilnacipran (1R, 2S/F2696) is an enantiomer of milnacipran, a serotonin/norepinephrine (5-HT/NE) reuptake inhibitor. Dextromilnacipran is pharmacologically less active as compared with racemic mixture and levomilnacipran (1S, 2R/F2695).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serotonin transporter 178 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8297	290.0 nM [Ki]
Serotonin transporter 178 Target ID: CHEMBL228 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8297	16.9 nM [Ki]
Norepinephrine transporter 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23499664	Inhibitor 8297	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 8429	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 2009
Unknown 2578

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 1587 substrate 1737	inhibitor 1767 inducer 389	inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2C19 1478 CYP2E1 882	P-gp 1537 CYP2C19 991 CYP1A2 1054	CYP1A2 701 CYP2B6 547 CYP2C8 168 CYP2C19 293 CYP3A4/5 124

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=27 Page: 27.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022256lbl.pdf#page=18 Page: 18.0	no
CYP3A4/5 335	inducer 1573 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 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022256s000_ClinPharmR_P1.pdf#page=7 Page: 7.0	no
CYP2C19 991	substrate 3367 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 1054	substrate 3367 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 1217	substrate 3367 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 1737	substrate 3367 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 1647	inhibitor 1626 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
[Experience with ixel (milnacipran hydrochloride) use in the treatment of patients with post-stroke depression].	2003	14669603
Milnacipran and pindolol: a randomized trial of reduction of antidepressant latency.	2003 Dec	14696018
Differential effects of milnacipran, fluvoxamine and paroxetine for depression, especially in gender.	2003 Dec	14680720
A method for designing conformationally restricted analogues based on allylic strain: synthesis of a novel class of noncompetitive NMDA receptor antagonists having the acrylamide structure.	2003 Dec 4	14640541
Milnacipran for the treatment of chronic pain.	2003 Oct	14533142
Effects of milnacipran on the inhibitory postsynaptic potential in neurons of the rat locus coeruleus.	2004	15682825
Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum disorders.	2004 Apr	15009832
Milnacipran treatment of a terminally ill cancer patient with major depressive disorder.	2004 Aug	15303248
Differential effects of fluvoxamine, paroxetine and milnacipran for depression, especially with regard to age.	2004 Aug	15303244
Prevalence of induced mania in patients treated with milnacipran: a comparison with paroxetine.	2004 Aug	15276667
[Review of antidepressants from the TCAs to the third generation drugs].	2004 Dec	15825674
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
A comparative study of milnacipran and paroxetine in outpatients with major depression.	2004 Dec	15555719
Ejaculation after defecation without orgasm induced by milnacipran.	2004 Fall	15616184
[Acute hepatitis associated with milnacipran treatment].	2004 Feb	15060467
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
Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers.	2004 Jan	14716705
A case of temporo-mandibular disorder with fibromyalgia treated with the antidepressant, milnacipran.	2004 Jul	15252831
Subjective and polysomnographic effects of milnacipran on sleep in depressed patients.	2004 Jul	15252822
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
Milnacipran: a dual norepinephrine and serotonin reuptake pump inhibitor.	2004 Mar	15330407
Peripheral nerve injury sensitizes the response to visceral distension but not its inhibition by the antidepressant milnacipran.	2004 Mar	15108984
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
Differential effects of milnacipran, fluvoxamine and paroxetine for inhibited and agitated depression.	2004 Nov	15504656
Controlled comparison of two different doses of milnacipran in major depressive outpatients.	2004 Nov	15486520
Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.	2004 Nov	15254142
Characterization of the anxiolytic-like effects of fluvoxamine, milnacipran and risperidone in mice using the conditioned fear stress paradigm.	2004 Nov 3	15507225
Nociceptin/orphanin FQ, hedonic state and the response to abused drugs.	2004 Oct	15658507
The effectiveness of lithium augmentation of milnacipran: preliminary data using the modified Japanese Psychopharmacology Algorithm.	2004 Oct	15658504
Serotonin and noradrenaline reuptake inhibitors in animal models of pain.	2004 Oct	15378668
Clinical experience with dual action antidepressants in different chronic pain syndromes.	2004 Oct	15378667
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
Opioid and monoamine systems mediate the discriminative stimulus of tramadol in rats.	2004 Sep 13	15363988
Effectiveness of milnacipran for the treatment of chronic pain: a case series.	2004 Sep-Oct	15602099
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
Lithium augmentation in milnacipran-refractory depression for the prevention of relapse following electroconvulsive therapy.	2005 Jan-Feb	15660714
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
Peripheral circulatory disturbance induced by milnacipran.	2005 Winter	15746495

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of Savella (Milnacipran) is 100 mg/day (50 mg twice daily). Based on efficacy and tolerability dosing may be titrated according to the following schedule: Day 1: 12.5 mg once Days 2-3: 25 mg/day (12.5 mg twice daily) Days 4-7: 50 mg/day (25 mg twice daily) After Day 7: 100 mg/day (50 mg twice daily) Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 200 mg/day have not been studied.

Route of Administration: Oral

In Vitro Use Guide

Milnacipran inhibits norepinephrine and serotonin reuptake in rat hypothalamic synaptosomes with IC50 values of 30 and 150 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