Chengdu New Radiomedicine

NALMEFENE HYDROCHLORIDE

nalmefene hydrochloride injection

Post-LOE

INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS · SOLUTION

CLINICAL PHARMACOLOGY Pharmacodynamics Nalmefene hydrochloride injection prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Pharmacodynamic studies have shown that nalmefene hydrochloride injection has a longer duration of action than naloxone at fully reversing doses. Nalmefene hydrochloride injection has no opioid agonist activity. Nalmefene hydrochloride injection is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when nalmefene hydrochloride injection was administered in the absence of opioid agonists. Nalmefene hydrochloride injection has not been shown to produce tolerance, physical dependence, or abuse potential. Nalmefene hydrochloride injection can produce acute withdrawal symptoms in individuals who are opioid dependent. Pharmacokinetics Nalmefene exhibited dose proportional pharmacokinetics following intravenous administration of 0.5 mg to 2.0 mg. Pharmacokinetic parameters for nalmefene after a 1 mg intravenous administration in adult male volunteers are listed in Table 1. Table 1: Mean (CV%) Nalmefene Pharmacokinetic Parameters InAdult Males Following a 1 mg Intravenous Dose Parameter Young, N=18 Elderly, N=11 Age 19-32 62-80 Cp at 5 min. (ng/mL) 3.7 (29) 5.8 (38) Vdss (L/kg) 8.6 (19) 8.6 (29) Vc (L/kg) 3.9 (29) 2.8 (41) AUC0-inf (ng-hr/mL) 16.6 (27) 17.3 (14) Terminal T1/2 (hr) 10.8 (48) 9.4 (49) Clplasma (L/hr/kg) 0.8 (23) 0.8 (18) ABSORPTION Nalmefene was completely bioavailable following intramuscular or subcutaneous administration in 12 male volunteers relative to intravenous nalmefene. The relative bioavailabilities of intramuscular and subcutaneous routes of administration were 101.5% ± 8.1% (Mean ± SD) and 99.7% ± 6.9%, respectively. Nalmefene will be administered primarily as an intravenous bolus, however, nalmefene can be given intra-muscularly (IM) or subcutaneously (SC) if venous access cannot be established. While the time to maximum plasma nalmefene concentration was 2.3 ± 1.1 hours following intramuscular and 1.5 ± 1.2 hours following subcutaneous administrations, therapeutic plasma concentrations are likely to be reached within 5-15 minutes after a 1 mg dose in an emergency. Because of the variability in the speed of absorption for IM & SC dosing, and the inability to titrate to effect, great care should be taken if repeated doses must be given by these routes. DISTRIBUTION Following a 1 mg parenteral dose, nalmefene was rapidly distributed. In a study of brain receptor occupancy, a 1 mg dose of nalmefene blocked 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. Ultrafiltration studies of nalmefene have demonstrated that 45% (CV 4.1%) is bound to plasma proteins over a concentration range of 0.1 to 2 µg/mL. An in vitro det

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