Nalmefene

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Approved, Investigational, Withdrawn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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Nalmefene (DB06230)

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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

• Alcohol Dependence
• Opioid Intoxication
• Opioid Overdose

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 injected^Label. 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	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.

Hover over products below to view reaction partners

• Nalmefene
  • Nalmefene 3-O-glucuronide
  • Nalmefene 3-O-sulfate
  • Nornalmefene
    • Nornalmefene 3-O-sulfate
    • Nornalmefene 3-O-glucuronide

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Nalmefene which could result in a higher serum level.
Acarbose	Acarbose 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.

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

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
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Revex	Injection, solution	1 mg/1mL	Intravenous	Baxter Laboratories	2006-06-19	Not applicable
Revex	Injection, solution	0.1 mg/1mL	Intravenous	Baxter Laboratories	2006-06-19	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable
Selincro	Tablet, film coated	18 mg	Oral	H. Lundbeck A/S	2013-02-25	Not applicable

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

• N07BB — Drugs used in alcohol dependence
• N07B — DRUGS USED IN ADDICTIVE DISORDERS
• N07 — OTHER NERVOUS SYSTEM DRUGS
• N — NERVOUS SYSTEM

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 / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives

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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 / Ether / Hydrocarbon derivative / Organic nitrogen compound / Organic oxygen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Phenanthrene / Piperidine / Tertiary alcohol / Tertiary aliphatic amine / Tertiary amine / Tetralin

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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]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Alcohol Dependence	1
4	Terminated	Treatment	Alcohol Dependence	1
3	Completed	Treatment	Alcohol Dependence	5
3	Unknown Status	Treatment	Alcohol Dependence / Liver Cirrhosis / Nalmefene	1
2	Completed	Treatment	Cessation, Smoking	1
2	Completed	Treatment	Harmful; Use, Alcohol / Opioid Use Disorder (OUD) / Opioid-use Disorder	1
2	Completed	Treatment	Pruritus, Atopic Dermatitis	1
2	Recruiting	Treatment	Alcohol Use Disorder (AUD)	1
2	Unknown Status	Treatment	Impulse-control disorder / Parkinson's Disease (PD)	1
2, 3	Completed	Treatment	Pathological Gambling	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, coated		18 mg

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

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Drug created on March 19, 2008 10:18 / Updated on October 27, 2020 09:44