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
Structure for Levomilnacipran (DB08918)
- 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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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- 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.
Target Actions Organism ASodium-dependent serotonin transporter inhibitorHumans ASodium-dependent noradrenaline transporter inhibitorHumans - 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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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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of adverse effects can be increased when 1,2-Benzodiazepine is combined with Levomilnacipran. Abacavir Abacavir may decrease the excretion rate of Levomilnacipran which could result in a higher serum level. Abametapir The serum concentration of Levomilnacipran can be increased when it is combined with Abametapir. Abatacept The metabolism of Levomilnacipran can be increased when combined with Abatacept. Abciximab The risk or severity of hemorrhage can be increased when Levomilnacipran is combined with Abciximab. Abiraterone The metabolism of Levomilnacipran can be decreased when combined with Abiraterone. Acarbose The risk or severity of hypoglycemia can be increased when Levomilnacipran is combined with Acarbose. Acebutolol The serum concentration of Acebutolol can be increased when it is combined with Levomilnacipran. Aceclofenac The risk or severity of gastrointestinal bleeding can be increased when Levomilnacipran is combined with Aceclofenac. Acemetacin The risk or severity of gastrointestinal bleeding can be increased when Levomilnacipran is combined with Acemetacin. 
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- 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Levomilnacipran hydrochloride 371U2ZK31U 175131-60-9 XNCDYJFPRPDERF-NQQJLSKUSA-N - Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fetzima Capsule, extended release 20 mg/1 Oral Allergan, Inc. 2013-07-25 Not applicable US 
Fetzima Capsule, extended release 120 mg Oral Abbvie 2016-04-22 Not applicable Canada 
Fetzima Capsule, extended release 20 mg Oral Abbvie 2015-11-19 Not applicable Canada Fetzima Capsule, extended release 80 mg/1 Oral Allergan, Inc. 2013-07-25 Not applicable US Fetzima Capsule, extended release 80 mg Oral Abbvie 2016-04-22 Not applicable Canada Fetzima Capsule, extended release 40 mg/1 Oral Avera McKennan Hospital 2015-03-09 2017-05-24 US 
Fetzima Capsule, extended release 40 mg/1 Oral Allergan, Inc. 2013-07-25 Not applicable US 
Fetzima Capsule, extended release 40 mg Oral Abbvie 2015-11-19 Not applicable Canada Fetzima Capsule, extended release 120 mg/1 Oral Allergan, Inc. 2013-07-25 Not applicable US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Levomilnacipran Capsule, extended release 20 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US Levomilnacipran Capsule, extended release 80 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US Levomilnacipran Capsule, extended release 40 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US Levomilnacipran Capsule, extended release 120 mg/1 Oral Amneal Pharmaceuticals LLC 2019-02-04 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Fetzima Levomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1) Kit Oral Allergan, Inc. 2013-07-25 Not applicable US Fetzima Levomilnacipran hydrochloride (20 mg/1) + Levomilnacipran hydrochloride (40 mg/1) Kit Oral Allergan, Inc. 2013-07-25 Not applicable US
Categories
- ATC Codes
- N06AX28 — Levomilnacipran
- Drug Categories
- Adrenergic Uptake Inhibitors
- Agents producing tachycardia
- Antidepressive Agents
- Antidepressive Agents Indicated for Depression
- Central Nervous System Agents
- Central Nervous System Depressants
- Combined Inhibitors of Serotonin/Norepinephrine Reuptake
- Cycloparaffins
- Cyclopropanes
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Hypoglycemia-Associated Agents
- Membrane Transport Modulators
- Miscellaneous Antidepressants
- Nervous System
- Neurotransmitter Agents
- Neurotransmitter Uptake Inhibitors
- Norepinephrine Uptake Inhibitors
- P-glycoprotein substrates
- Psychoanaleptics
- Psychotropic Drugs
- Selective Serotonin Reuptake Inhibitors
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Serotonin Agents
- Serotonin and Noradrenaline Reuptake Inhibitors
- Serotonin Modulators
- 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
- External Links
- KEGG Drug
- D10072
- PubChem Compound
- 6917779
- PubChem Substance
- 175427154
- ChemSpider
- 5293005
- BindingDB
- 50032379
- 1433212
- ChEBI
- 136040
- ChEMBL
- CHEMBL99946
- ZINC
- ZINC000000000506
- Wikipedia
- Levomilnacipran
- FDA label
- Download (530 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Basic Science None (i.e. Healthy Volunteers) 1 4 Completed Treatment Major Depressive Disorder (MDD) 2 4 Recruiting Treatment Major Depressive Disorder (MDD) 1 3 Completed Treatment Depression / Major Depressive Disorder (MDD) 1 3 Completed Treatment Ischemic Stroke 1 3 Completed Treatment Major Depressive Disorder (MDD) 8 2 Completed Treatment Major Depressive Disorder (MDD) 1 1 Completed Treatment Subject 1 Not Available Completed Other Tobacco Use Disorders 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule, extended release Oral 120 mg Capsule, extended release Oral 20 mg Capsule, extended release Oral 40 mg Capsule, extended release Oral 80 mg Kit Oral Capsule, extended release Oral 120 mg/1 Capsule, extended release Oral 20 mg/1 Capsule, extended release Oral 40 mg/1 Capsule, extended release Oral 80 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region USRE43879 No 2012-12-25 2023-06-03 US US8481598 No 2013-07-09 2031-03-02 US US8865937 No 2014-10-21 2032-05-23 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 1.23 mg/mL ALOGPS logP 1.72 ALOGPS logP 1.42 Chemaxon logS -2.3 ALOGPS pKa (Strongest Basic) 9.83 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 46.33 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 73.81 m3·mol-1 Chemaxon Polarizability 28.34 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9889 Caco-2 permeable + 0.5914 P-glycoprotein substrate Substrate 0.5928 P-glycoprotein inhibitor I Non-inhibitor 0.902 P-glycoprotein inhibitor II Non-inhibitor 0.8787 Renal organic cation transporter Non-inhibitor 0.8119 CYP450 2C9 substrate Non-substrate 0.8494 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Non-substrate 0.6514 CYP450 1A2 substrate Non-inhibitor 0.6383 CYP450 2C9 inhibitor Non-inhibitor 0.7697 CYP450 2D6 inhibitor Non-inhibitor 0.7718 CYP450 2C19 inhibitor Non-inhibitor 0.8587 CYP450 3A4 inhibitor Non-inhibitor 0.6327 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7004 Ames test Non AMES toxic 0.8013 Carcinogenicity Non-carcinogens 0.5456 Biodegradation Not ready biodegradable 0.9972 Rat acute toxicity 2.6162 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.993 hERG inhibition (predictor II) Non-inhibitor 0.6823
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not 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
- 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
- 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
- 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
- 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