Identification

Name
Levomilnacipran
Accession Number
DB08918
Type
Small Molecule
Groups
Approved, Investigational
Description

Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor. Chemically, levomilnacipran is the 1S,2R-enantiomer of milnacipran. FDA approved on July 25, 2013.

Structure
Thumb
Synonyms
  • (1S,2R)-milnacipran
External IDs
F 2695 / F-2695 / F2695
Product Ingredients
IngredientUNIICASInChI Key
Levomilnacipran hydrochloride371U2ZK31U175131-60-9XNCDYJFPRPDERF-NQQJLSKUSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FetzimaCapsule, extended release120 mgOralAllergan Pharma Co.2016-04-22Not applicableCanada
FetzimaCapsule, extended release20 mgOralAllergan Pharma Co.2015-11-19Not applicableCanada
FetzimaCapsule, extended release120 mg/1OralAllergan2013-07-25Not applicableUs
FetzimaCapsule, extended release20 mg/1OralAllergan2013-07-25Not applicableUs00456 2220 30 nlmimage10 6b4a3581
FetzimaCapsule, extended release80 mgOralAllergan Pharma Co.2016-04-22Not applicableCanada
FetzimaCapsule, extended release80 mg/1OralAllergan2013-07-25Not applicableUs
FetzimaCapsule, extended release40 mg/1OralAvera McKennan Hospital2015-03-09Not applicableUs69189 224120180907 15195 bav8mw
FetzimaCapsule, extended release40 mgOralAllergan Pharma Co.2015-11-19Not applicableCanada
FetzimaCapsule, extended release40 mg/1OralAllergan2013-07-25Not applicableUs0456 224020180913 8702 550nju
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
FetzimaLevomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1)KitOralAllergan2013-07-25Not applicableUs
FetzimaLevomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1)KitOralAllergan2013-07-25Not applicableUs
Categories
UNII
UGM0326TXX
CAS number
96847-54-0
Weight
Average: 246.348
Monoisotopic: 246.173213336
Chemical Formula
C15H22N2O
InChI Key
GJJFMKBJSRMPLA-DZGCQCFKSA-N
InChI
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+/m0/s1
IUPAC Name
(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
SMILES
CCN(CC)C(=O)[C@]1(C[C@H]1CN)C1=CC=CC=C1

Pharmacology

Indication

Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor and is indicated for the treatment of major depressive disorder (MDD).

Associated Conditions
Pharmacodynamics

Levomilnacipran binds with high affinity to human serotonin (5-HT) and norepinephrine (NE) transporters (Ki = 11 and 91 nM, respectively). It potently inhibits 5-HT and NE reuptake (IC50 = 16 - 19 and 11 nM, respectively). Levomilnacipran does not bind to any other receptors, ion channels, or transporters, including serotonergic (5HT1-7), α- and β adrenergic, muscarinic, or histaminergic receptors and Ca2+, Na+, K+ or Cl- channels to a significant degree. Levomilnacipran did not inhibit monoamine oxidase (MAO). Furthermore, levomilnacipran does not prolong the QTc interval to a clinically relevant extent.

Mechanism of action

The exact mechanism of the antidepressant action of levomilnacipran is unknown but is thought to be related to the potentiation of serotonin and norephinephrine in the central nervous system through inhibition of reuptake at serotonin and norepinephrine transporters.

TargetActionsOrganism
ASodium-dependent serotonin transporter
inhibitor
Human
ASodium-dependent noradrenaline transporter
inhibitor
Human
Absorption

The relative bioavailability after administration of the extended-release capsule was 92% when compared to oral solution. Food does not affect the concentration of levomilnacipran. After daily dosing of levomilnacipran (extended-release capsule) the mean Cmax is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. The Tmax is 6 - 8 hours after oral administration. Interconversion of stereoisomers does not occur in humans.

Volume of distribution
  • 387 - 473 L [apparent volume of distribution]
Protein binding

22% bound to human plasma protein over concentration range of 10 to 1000 ng/mL.

Metabolism

Hepatic. Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Desethylation is facilitated primarily by CYP3A4 and by CYP2C8, 2C19, 2D6, and 2J2 to a lesser extent. Both metabolites undergo further conjugation with glucuronide to form conjugates.

Route of elimination

Levomilnacipran and its metabolites are eliminated primarily by renal excretion. 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl-levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxylevomilnacipran (1%). The metabolites are inactive.

Half life

12 hours

Clearance
  • 21 - 29 L/h [mean apparent total clearance]
Toxicity

The most common adverse reactions are nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineLevomilnacipran may increase the tachycardic activities of 4-Methoxyamphetamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Levomilnacipran.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the serotonergic activities of Levomilnacipran.
AbciximabLevomilnacipran may increase the antiplatelet activities of Abciximab.
AbirateroneThe serum concentration of Levomilnacipran can be increased when it is combined with Abiraterone.
AcarboseLevomilnacipran may increase the hypoglycemic activities of Acarbose.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Levomilnacipran.
AceclofenacLevomilnacipran may increase the antiplatelet activities of Aceclofenac.
AcenocoumarolThe risk or severity of adverse effects can be increased when Levomilnacipran is combined with Acenocoumarol.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Levomilnacipran.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Drug
D10072
PubChem Compound
6917779
PubChem Substance
175427154
ChemSpider
5293005
BindingDB
50032379
ChEBI
136040
ChEMBL
CHEMBL99946
Wikipedia
Levomilnacipran
AHFS Codes
  • 28:16.04.92 — Miscellaneous Antidepressants
FDA label
Download (530 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentSubject1
2CompletedTreatmentMajor Depressive Disorder (MDD)1
3CompletedTreatmentMajor Depressive Disorder (MDD)5
3CompletedTreatmentStroke, Ischemic1
3RecruitingTreatmentMajor Depressive Disorder (MDD)3
4Active Not RecruitingTreatmentMajor Depressive Disorder (MDD)1
4RecruitingTreatmentMajor Depressive Disorder (MDD)1
Not AvailableCompletedOtherTobacco Use Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, extended releaseOral120 mg/1
Capsule, extended releaseOral120 mg
Capsule, extended releaseOral20 mg
Capsule, extended releaseOral20 mg/1
Capsule, extended releaseOral40 mg
Capsule, extended releaseOral40 mg/1
Capsule, extended releaseOral80 mg/1
Capsule, extended releaseOral80 mg
KitOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
USRE43879No2003-06-032023-06-03Us
US8481598No2011-03-022031-03-02Us
US8865937No2012-05-232032-05-23Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP1.42ChemAxon
pKa (Strongest Basic)9.83ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area46.33 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity73.81 m3·mol-1ChemAxon
Polarizability28.33 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9889
Caco-2 permeable+0.5914
P-glycoprotein substrateSubstrate0.5928
P-glycoprotein inhibitor INon-inhibitor0.902
P-glycoprotein inhibitor IINon-inhibitor0.8787
Renal organic cation transporterNon-inhibitor0.8119
CYP450 2C9 substrateNon-substrate0.8494
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6514
CYP450 1A2 substrateNon-inhibitor0.6383
CYP450 2C9 inhibitorNon-inhibitor0.7697
CYP450 2D6 inhibitorNon-inhibitor0.7718
CYP450 2C19 inhibitorNon-inhibitor0.8587
CYP450 3A4 inhibitorNon-inhibitor0.6327
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7004
Ames testNon AMES toxic0.8013
CarcinogenicityNon-carcinogens0.5456
BiodegradationNot ready biodegradable0.9972
Rat acute toxicity2.6162 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.993
hERG inhibition (predictor II)Non-inhibitor0.6823
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylacetamides. These are amide derivatives of phenylacetic acids.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenylacetamides
Direct Parent
Phenylacetamides
Alternative Parents
Aralkylamines / Cyclopropanecarboxylic acids and derivatives / Tertiary carboxylic acid amides / Amino acids and derivatives / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Phenylacetamide / Aralkylamine / Cyclopropanecarboxylic acid or derivatives / Tertiary carboxylic acid amide / Amino acid or derivatives / Carboxamide group / Carboxylic acid derivative / Organopnictogen compound / Organic oxygen compound / Primary amine
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. [PubMed:26572745]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
Molecular Weight
57610.165 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on August 01, 2013 14:17 / Updated on September 25, 2018 17:45