Singapore Drugs Database

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 [L1024]. 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 [FDA Label].

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 [L1024, A31301]. 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 [A31301]. Thus it is suggested that nalmefene may be more effective treatment for alcohol dependence than [DB00704], which is a pure mu and delta receptor antagonist [A31301]. In vivo studies and rat studies have demonstrated that nalmefene reduces self-administration of alcohol, possibly by modulating cortico-mesolimbic functions [L1024]. 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[FDA Label]. Some pharmacodynamic studies showed that nalmefene has a longer duration of action than naloxone at fully reversing doses [FDA Label] however the relative potency of these two antagonists are reported to be similar [A31302].

Pharmacokinetics

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% [L1024]. 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 [FDA Label].

Distribution

The volume of distribution (Vd/F) of oral nalmefene is estimated to be approximately 3200 L [L1024]. 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 [L1024]. 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 [FDA 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 [L1024].

Elimination

Clearance

The oral clearance of nalmefene (CL/F) was estimated as 169 L/h [L1024]. 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 [FDA Label].

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 [L1024].

Active Ingredient/Synonyms

Nalmefene | Nalmefene |