Levomilnacipran

Identification

Summary

Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used to treat major depressive disorder (MDD).

Brand Names
Fetzima
Generic Name
Levomilnacipran
DrugBank Accession Number
DB08918
Background

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

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 246.348
Monoisotopic: 246.173213336
Chemical Formula
C15H22N2O
Synonyms
  • (1S,2R)-milnacipran
  • Levomilnacipran
External IDs
  • F 2695
  • F-2695
  • F2695

Pharmacology

Indication

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

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Associated Conditions
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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
Humans
ASodium-dependent noradrenaline transporter
inhibitor
Humans
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]
Adverse Effects
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Toxicity

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

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when 1,2-Benzodiazepine is combined with Levomilnacipran.
AbacavirAbacavir may decrease the excretion rate of Levomilnacipran which could result in a higher serum level.
AbametapirThe serum concentration of Levomilnacipran can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Levomilnacipran can be increased when combined with Abatacept.
AbciximabThe risk or severity of hemorrhage can be increased when Levomilnacipran is combined with Abciximab.
AbirateroneThe metabolism of Levomilnacipran can be decreased when combined with Abiraterone.
AcarboseThe risk or severity of hypoglycemia can be increased when Levomilnacipran is combined with Acarbose.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Levomilnacipran.
AceclofenacThe risk or severity of gastrointestinal bleeding can be increased when Levomilnacipran is combined with Aceclofenac.
AcemetacinThe risk or severity of gastrointestinal bleeding can be increased when Levomilnacipran is combined with Acemetacin.
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Food Interactions
  • Avoid alcohol. Ingesting alcohol may compromise the extended-release dosage form of levomilnacipran, causing an accelerated release of the drug, increasing its serum concentration.
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Taking herbs with antiplatelet or anticoagulant activity may increase the risk of bleeding. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
  • Exercise caution with grapefruit products. Grapefruit is a moderate to strong CYP3A4 inhibitor. Do not exceed a maximum levomilnacipran dose of 80mg daily when taking strong CYP3A4 inhibitors.
  • Exercise caution with St. John's Wort. Administering levomilnacipran with St. John's Wort may increase the risk of serotonin syndrome.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Levomilnacipran hydrochloride371U2ZK31U175131-60-9XNCDYJFPRPDERF-NQQJLSKUSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FetzimaCapsule, extended release20 mg/1OralAllergan, Inc.2013-07-25Not applicableUS flag
FetzimaCapsule, extended release120 mgOralAbbvie2016-04-22Not applicableCanada flag
FetzimaCapsule, extended release20 mgOralAbbvie2015-11-19Not applicableCanada flag
FetzimaCapsule, extended release80 mg/1OralAllergan, Inc.2013-07-25Not applicableUS flag
FetzimaCapsule, extended release80 mgOralAbbvie2016-04-22Not applicableCanada flag
FetzimaCapsule, extended release40 mg/1OralAvera McKennan Hospital2015-03-092017-05-24US flag
FetzimaCapsule, extended release40 mg/1OralAllergan, Inc.2013-07-25Not applicableUS flag
FetzimaCapsule, extended release40 mgOralAbbvie2015-11-19Not applicableCanada flag
FetzimaCapsule, extended release120 mg/1OralAllergan, Inc.2013-07-25Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LevomilnacipranCapsule, extended release20 mg/1OralAmneal Pharmaceuticals LLC2019-02-04Not applicableUS flag
LevomilnacipranCapsule, extended release80 mg/1OralAmneal Pharmaceuticals LLC2019-02-04Not applicableUS flag
LevomilnacipranCapsule, extended release40 mg/1OralAmneal Pharmaceuticals LLC2019-02-04Not applicableUS flag
LevomilnacipranCapsule, extended release120 mg/1OralAmneal Pharmaceuticals LLC2019-02-04Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
FetzimaLevomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1)KitOralAllergan, Inc.2013-07-25Not applicableUS flag
FetzimaLevomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1)KitOralAllergan, Inc.2013-07-25Not applicableUS flag

Categories

ATC Codes
N06AX28 — Levomilnacipran
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Amine / Amino acid or derivatives / Aralkylamine / Aromatic homomonocyclic compound / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Cyclopropanecarboxylic acid or derivatives / Hydrocarbon derivative / Organic nitrogen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
UGM0326TXX
CAS number
96847-54-0
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

References

General References
Not Available
KEGG Drug
D10072
PubChem Compound
6917779
PubChem Substance
175427154
ChemSpider
5293005
BindingDB
50032379
RxNav
1433212
ChEBI
136040
ChEMBL
CHEMBL99946
ZINC
ZINC000000000506
Wikipedia
Levomilnacipran
FDA label
Download (530 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingBasic ScienceNone (i.e. Healthy Volunteers)1
4CompletedTreatmentMajor Depressive Disorder (MDD)2
4RecruitingTreatmentMajor Depressive Disorder (MDD)1
3CompletedTreatmentDepression / Major Depressive Disorder (MDD)1
3CompletedTreatmentIschemic Stroke1
3CompletedTreatmentMajor Depressive Disorder (MDD)8
2CompletedTreatmentMajor Depressive Disorder (MDD)1
1CompletedTreatmentSubject1
Not AvailableCompletedOtherTobacco Use Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule, extended releaseOral120 mg
Capsule, extended releaseOral20 mg
Capsule, extended releaseOral40 mg
Capsule, extended releaseOral80 mg
KitOral
Capsule, extended releaseOral120 mg/1
Capsule, extended releaseOral20 mg/1
Capsule, extended releaseOral40 mg/1
Capsule, extended releaseOral80 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
USRE43879No2012-12-252023-06-03US flag
US8481598No2013-07-092031-03-02US flag
US8865937No2014-10-212032-05-23US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.23 mg/mLALOGPS
logP1.72ALOGPS
logP1.42Chemaxon
logS-2.3ALOGPS
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
Polarizability28.34 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

Targets

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Kind
Protein
Organism
Humans
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
Humans
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
Humans
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
Humans
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. [Article]
Kind
Protein
Organism
Humans
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
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. [Article]
Kind
Protein
Organism
Humans
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
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. [Article]
Kind
Protein
Organism
Humans
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
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. [Article]

Transporters

Kind
Protein
Organism
Humans
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 at August 01, 2013 20:17 / Updated at January 03, 2023 04:24