Identification

Name
Nalmefene
Accession Number
DB06230
Description

Nalmefene is a 6-methylene analogue of naltrexone and opioid system modulator but with no opioid activity Label. It mediates a partial agonist effect on kappa receptors 2. It is primarily used in the management of alcohol dependence in adult patients in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption 4 when it is exists as the hydrochloride dihydrate form under the trade name Selincro. Selincro is orally administered as tablets. Nalmefene works to reduce alcohol consumption in individuals by positive reward effect of alcohol which involves the opioid system, as well as the sedative and dysphoric properties of alcohol 2.

It is also indicated to prevent or reverse the effects of opioids, including respiratory depression, sedation, and hypotension by acting on the opioid receptor as an antagonist Label under the trade name Revex for intramuscular, intravenous and subcutaneous injection, where nalmefene hydrochloride is an active ingredient.

Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Structure
Thumb
Weight
Average: 339.435
Monoisotopic: 339.183443669
Chemical Formula
C21H25NO3
Synonyms
  • Nalmefene
  • Nalmefeno
External IDs
  • JF-1
  • ORF 1167
  • ORF 11676
  • ORF-1167
  • ORF-11676
  • SRD-174
  • SRD174

Pharmacology

Indication

Indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL), without physical withdrawal symptoms and who do not require immediate detoxification 4.

Indicated for the complete or partial reversal of opioid drug effects, including respiratory depression - induced by either natural or synthetic opioids - or in the management of known or suspected opioid overdose Label.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Nalmefene has not been shown to produce tolerance, physical dependence, or abuse potential 4,Label.

When adminsitered as an antidote for opioid overdose, nalmefene is not known to produce any respiratory depression, psychomimetic effects, or pupillary constriction Label. In the absence of opioid agonists, there was no observable pharmacological activity. Nalmefene injection can produce acute withdrawal symptoms in individuals who are opioid-dependent.

Mechanism of action

Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile. It acts as a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor 4,2. Animal studies suggest that the kappa receptor signalling responses lead to antagonism of acute reward and positive reinforcement effects of drugs by decreasing dopamine in the nucleus accumbens 2. Thus it is suggested that nalmefene may be more effective treatment for alcohol dependence than Naltrexone, which is a pure mu and delta receptor antagonist 2. In vivo studies and rat studies have demonstrated that nalmefene reduces self-administration of alcohol, possibly by modulating cortico-mesolimbic functions 4.

Nalmefene, a 6-methylene analogue of naltrexone, is a competitive opioid antagonist which binds with high affinity to the mu opioid receptor. Nalmefene itself does not induce any opioid activity, but prevents or reverses the effects of opioids such as respiratory depression and sedation when injectedLabel. Some pharmacodynamic studies showed that nalmefene has a longer duration of action than naloxone at fully reversing doses Label however the relative potency of these two antagonists are reported to be similar 3.

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Humans
AKappa-type opioid receptor
partial agonist
Humans
ADelta-type opioid receptor
antagonist
Humans
Absorption

Following a single oral administration of 18.06 mg, nalmefene is rapidly absorbed with a peak plasma concentration (Cmax) of 16.5 ng/ml with the time to reach the peak concentration (Tmax) of approxmately 1.5 hours and the exposure (AUC) of 131 ng x h/ml. Although there is little association to clinical relevance, the AUC and Cmax values are expected to increase by 30 to 50%, respectively, and the Tmax is delayed by 30 minutes after consumption of high-fat food. The absolute oral bioavailability of nalmefene is 41% 4.

Nalmefene exhibits dose-proportional pharmacokinetics following intravenous injection. The Tmax following intramuscular or subcutaneous injection is approximately 1.5-2.3 hours. In an emergency setting, however, therapeutic plasma concentrations are likely to be reached within 5-15 minutes after a 1 mg dose given intravenously where the plasma concentration is approximately 3.7 ng/mL at 5 minutes in young adult males Label.

Volume of distribution

The volume of distribution (Vd/F) of oral nalmefene is estimated to be approximately 3200 L 4. According to a PET study after single and repeated daily dosing with 18.06 mg nalmefene, the drug displayed 94% to 100% receptor occupancy within 3 hours after dosing, indicating that nalmefene readily crosses the blood-brain barrier 4.

Nalmefene is reported to be rapidly distributed following a 1mg parenteral dose. Parenteral nalmefene also crosses the blood-brain barrier effectively, where the study of brain receptor occupancy demonstrated the blockage of over 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally (Vc) and at steady-state (Vdss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. In vitro study suggest that 67% of the drug is distributed into red blood cells and 39% of the drug distributed into plasma Label.

Protein binding

The average protein-bound fraction of nalmefene in plasma is approximately 30-45% 4,Label.

Metabolism

Following oral administration, nalmefene undergoes extensive hepatic metabolism where it is metabolized to the major inactive metabolite nalmefene 3-O-glucuronide via glucuronide conjugation. The major enzyme contributing to this reaction is UGT2B7, while UGT1A3 and UGT1A8 also play a minor role. A small proportion of nalmefene is also converted to nalmefene 3-O-sulfate by sulfation, which has a potency comparable to that of nalmefene. However nalmafene 3-O-sulfate is present in concentration less than 10% of that of nalmefene and is less likely to be a major contributor to the pharmacological action of the parent drug. Nalmefene may also be converted to nornalmefene via dealkylation by CYP3A4 or CYP3A5, which is further converted to nornalmefene 3-O-glucuronide and nornalmefene 3-O-sulfate with minimal pharmacological actions 4.

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Route of elimination

Renal excretion is the main route of elimination for nalmefene and its metabolites. 54% of the total dose is excreted in the urine as nalmefene 3-O-glucuronide. Less than 3% of the dose is excreted as nalmefene or other metabolites 4. Approximatly 17% of the total dose is reported to be excreted in the feces Label.

Half-life

The terminal half-life is approximately 12.5 hours following oral administration 4. After intravenous administration of 1 mg in adult males, the terminal half life was 10.8 ± 5.2 hours Label.

Clearance

The oral clearance of nalmefene (CL/F) was estimated as 169 L/h 4. After intravenous administration of 1 mg in adult males, the systemic clearance of was 0.8 ± 0.2 L/hr/kg and the renal clearance was 0.08 ± 0.04 L/hr/kg Label.

Adverse Effects
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Toxicity

Studies in animals do not indicate direct effect in the reproductive system. In a rabbit embryo-foetal developmental toxicity study, reduced fetal weight and delayed ossification were observed in the fetus but did not result in abnormalities. Studies in rats have shown excretion of nalmefene or its metabolites in milk. The nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, or carcinogenic potential 4.

Affected organisms
Not Available
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
AbacavirAbacavir may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Nalmefene which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AclidiniumNalmefene may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineNalmefene may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Nalmefene which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Product Ingredients
IngredientUNIICASInChI Key
Nalmefene hydrochlorideK7K69QC05X58895-64-0GYWMRGWFQPSQLK-OPHZJPRHSA-N
Nalmefene hydrochloride dihydrate52Z0G7QVJX1228646-70-5XOBQQQVDLSMXCE-JVRGSUDVSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RevexInjection, solution0.1 mg/1mLIntravenousBaxter Laboratories2006-06-19Not applicableUS flag
RevexInjection, solution1 mg/1mLIntravenousBaxter Laboratories2006-06-19Not applicableUS flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
N07BB05 — Nalmefene
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenanthrenes and derivatives
Sub Class
Not Available
Direct Parent
Phenanthrenes and derivatives
Alternative Parents
Tetralins / Coumarans / Aralkylamines / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Piperidines / Tertiary alcohols / Trialkylamines / Cyclic alcohols and derivatives / 1,2-aminoalcohols
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Substituents
1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / Alcohol / Alkyl aryl ether / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Coumaran / Cyclic alcohol
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
morphinane alkaloid (CHEBI:7457)

Chemical Identifiers

UNII
TOV02TDP9I
CAS number
55096-26-9
InChI Key
WJBLNOPPDWQMCH-MBPVOVBZSA-N
InChI
InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1
IUPAC Name
(1S,5R,13S,17S)-4-(cyclopropylmethyl)-14-methylidene-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-triene-10,17-diol
SMILES
[H][[email protected]@]12OC3=C(O)C=CC4=C3[[email protected]@]11CCN(CC3CC3)[[email protected]]([H])(C4)[[email protected]]1(O)CCC2=C

References

General References
  1. Ingman K, Hagelberg N, Aalto S, Nagren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H: Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005 Dec;30(12):2245-53. [PubMed:15956985]
  2. Paille F, Martini H: Nalmefene: a new approach to the treatment of alcohol dependence. Subst Abuse Rehabil. 2014 Aug 8;5:87-94. doi: 10.2147/SAR.S45666. eCollection 2014. [PubMed:25187751]
  3. Glass PS, Jhaveri RM, Smith LR: Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg. 1994 Mar;78(3):536-41. [PubMed:8109774]
  4. European Medicines Agency (EMA) Summary of product characteristics: Selincro [Link]
KEGG Drug
D05111
KEGG Compound
C08027
ChemSpider
4447642
BindingDB
50045776
RxNav
31479
ChEBI
7457
ChEMBL
CHEMBL982
ZINC
ZINC000000403529
Wikipedia
Nalmefene
FDA label
Download (69.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAlcohol Dependence1
4TerminatedTreatmentAlcohol Dependence1
3CompletedTreatmentAlcohol Dependence5
3Unknown StatusTreatmentAlcohol Dependence / Liver Cirrhosis / Nalmefene1
2CompletedTreatmentCessation, Smoking1
2CompletedTreatmentHarmful; Use, Alcohol / Opioid Use Disorder (OUD) / Opioid-use Disorder1
2CompletedTreatmentPruritus, Atopic Dermatitis1
2RecruitingTreatmentAlcohol Use Disorder (AUD)1
2Unknown StatusTreatmentImpulse-control disorder / Parkinson's Disease (PD)1
2, 3CompletedTreatmentPathological Gambling1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous0.1 mg/1mL
Injection, solutionIntravenous1 mg/1mL
TabletOral18 MG
Tablet, coatedOral18 MG
Tablet, film coatedOral18 mg
Tablet, coated18 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityFreely soluble in water up to 130 mg/mLFDA Label
pKa7.6FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.839 mg/mLALOGPS
logP2.24ALOGPS
logP1.95ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)10.35ChemAxon
pKa (Strongest Basic)9.57ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area52.93 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity95.21 m3·mol-1ChemAxon
Polarizability37.27 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Partial agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da
References
  1. Kreek MJ, Schluger J, Borg L, Gunduz M, Ho A: Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. J Pharmacol Exp Ther. 1999 Jan;288(1):260-9. [PubMed:9862779]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. Ingman K, Hagelberg N, Aalto S, Nagren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H: Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005 Dec;30(12):2245-53. [PubMed:15956985]
  2. Paille F, Martini H: Nalmefene: a new approach to the treatment of alcohol dependence. Subst Abuse Rehabil. 2014 Aug 8;5:87-94. doi: 10.2147/SAR.S45666. eCollection 2014. [PubMed:25187751]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A8
Uniprot ID
Q9HAW9
Uniprot Name
UDP-glucuronosyltransferase 1-8
Molecular Weight
59741.035 Da

Drug created on March 19, 2008 10:18 / Updated on October 19, 2020 06:38

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