Nalmefene
Identification
- Summary
Nalmefene is an opioid antagonist used in conjunction with psychosocial support to help adults with alcohol dependence reduce alcohol consumption.
- Brand Names
- Revex, Selincro
- Generic Name
- Nalmefene
- DrugBank Accession Number
- DB06230
- Background
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- Approved, Investigational, Withdrawn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
Structure for Nalmefene (DB06230)
- 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.
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- Contraindications & Blackbox Warnings
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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.
Target Actions Organism AMu-type opioid receptor antagonistHumans AKappa-type opioid receptor partial agonistHumans ADelta-type opioid receptor antagonistHumans - 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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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.
- 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 softwareAbacavir Abacavir may decrease the excretion rate of Nalmefene which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Nalmefene which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Nalmefene which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Nalmefene which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Nalmefene which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Nalmefene which could result in a higher serum level. Aclidinium Nalmefene may decrease the excretion rate of Aclidinium which could result in a higher serum level. Acrivastine Nalmefene may decrease the excretion rate of Acrivastine which could result in a higher serum level. Acyclovir Acyclovir may decrease the excretion rate of Nalmefene which could result in a higher serum level. Adefovir dipivoxil Adefovir dipivoxil may decrease the excretion rate of Nalmefene which could result in a higher serum level. 
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- No interactions found.
Products
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Ingredient UNII CAS InChI Key Nalmefene hydrochloride K7K69QC05X 58895-64-0 GYWMRGWFQPSQLK-OPHZJPRHSA-N Nalmefene hydrochloride dihydrate 52Z0G7QVJX 1228646-70-5 XOBQQQVDLSMXCE-JVRGSUDVSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Revex Injection, solution 0.1 mg/1mL Intravenous Baxter Laboratories 2006-06-19 Not applicable US 
Revex Injection, solution 1 mg/1mL Intravenous Baxter Laboratories 2006-06-19 Not applicable US Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU 
Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU Selincro Tablet, film coated 18 mg Oral H. Lundbeck A/S 2016-09-08 Not applicable EU
Categories
- ATC Codes
- N07BB05 — Nalmefene
- Drug Categories
- Alkaloids
- Antipruritics
- Appetite Depressants
- Central Nervous System Agents
- Drugs that are Mainly Renally Excreted
- Drugs Used in Addictive Disorders
- Drugs Used in Alcohol Dependence
- Heterocyclic Compounds, Fused-Ring
- Morphinans
- Nervous System
- Neuroprotective Agents
- Opiate Alkaloids
- Opioid Antagonists
- Peripheral Nervous System Agents
- Phenanthrenes
- Sensory System Agents
- UGT1A3 substrates
- UGT2B7 substrates
- 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 show 4 more
- 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)
- Affected organisms
- Not Available
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][C@@]12OC3=C(O)C=CC4=C3[C@@]11CCN(CC3CC3)[C@]([H])(C4)[C@]1(O)CCC2=C
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- European Medicines Agency (EMA) Summary of product characteristics: Selincro [Link]
- External Links
- FDA label
- Download (69.6 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Alcohol Dependency 1 4 Not Yet Recruiting Treatment Resuscitations 1 4 Terminated Treatment Alcohol Dependency 1 3 Completed Treatment Alcohol Dependency 5 3 Unknown Status Treatment Alcohol Dependency / Cirrhosis of the Liver / Nalmefene 1 2 Completed Treatment Alcohol Use Disorders (AUD) 1 2 Completed Treatment Pruritus, Atopic Dermatitis 1 2 Completed Treatment Smoking, Cessation 1 2 Unknown Status Treatment Impulse-control disorder / Parkinson's Disease (PD) 1 2, 3 Completed Treatment Pathological Gambling Disorder 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 0.1 mg/1mL Injection, solution Intravenous 1 mg/1mL Tablet Oral 18 MG Tablet, coated Oral 18 MG Tablet, film coated Oral 18 MG Tablet, film coated Oral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Freely soluble in water up to 130 mg/mL FDA Label pKa 7.6 FDA Label - Predicted Properties
Property Value Source Water Solubility 0.839 mg/mL ALOGPS logP 2.24 ALOGPS logP 1.95 ChemAxon logS -2.6 ALOGPS pKa (Strongest Acidic) 10.35 ChemAxon pKa (Strongest Basic) 9.57 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 4 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 52.93 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 95.21 m3·mol-1 ChemAxon Polarizability 37.27 Å3 ChemAxon Number of Rings 6 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
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key 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
- 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
- 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. [Article]
- 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
- 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. [Article]
- 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. [Article]
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 16:18 / Updated on September 25, 2021 14:59