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REVEX prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Pharmacodynamic studies have shown that REVEX has a longer duration of action than naloxone at fully reversing doses. REVEX has no opioid agonist activity.
REVEX is not known to produce respiratory depression, psychotomimetic effects, or pupillary constriction. No pharmacological activity was observed when REVEX was administered in the absence of opioid agonists.
REVEX has not been shown to produce tolerance, physical dependence, or abuse potential.
REVEX can produce acute withdrawal symptoms in individuals who are opioid dependent.
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
In Adult Males Following a 1 mg Intravenous Dose
|Parameter||Young, N=18||Elderly, N=11|
|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 T½ (hr)||10.8 (48)||9.4 (49)|
|Clplasma (L/hr/kg)||0.8 (23)||0.8 (18)|
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.
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 2µg/mL. An in vitro determination of the distribution of nalmefene in human blood demonstrated that nalmefene distributed 67% (CV 8.7%) into red blood cells and 39% (CV 6.4%) into plasma. The whole blood to plasma ratio was 1.3 (CV 6.6%) over the nominal concentration range in whole blood from 0.376 to 30 ng/mL.
Nalmefene is metabolized by the liver, primarily by glucuronide conjugation, and excreted in the urine. Nalmefene is also metabolized to trace amounts of an N-dealkylated metabolite. Nalmefene glucuronide is inactive and the N-dealkylated metabolite has minimal pharmacological activity. Less than 5% of nalmefene is excreted in the urine unchanged. Seventeen percent (17%) of the nalmefene dose is excreted in the feces. The plasma concentration-time profile in some subjects suggests that nalmefene undergoes enterohepatic recycling.
After intravenous administration of 1 mg REVEX to normal males (ages 19-32), plasma concentrations declined biexponentially with a redistribution and a terminal elimination half-life of 41 ± 34 minutes and 10.8 ± 5.2 hours, respectively. The systemic clearance of nalmefene is 0.8 ± 0.2 L/hr/kg and the renal clearance is 0.08 ± 0.04 L/hr/kg.
Dose proportionality was observed in nalmefene AUC0-inf following 0.5 to 2 mg intravenous administration to elderly male subjects. Following a 1 mg intravenous nalmefene dose, there were no significant differences between young (19-32 years) and elderly (62-80 years) adult male subjects with respect to plasma clearance, steady-state volume of distribution, or half-life. There was an apparent age-related decrease in the central volume of distribution (young: 3.9±1.1 L/kg, elderly: 2.8 ± 1.1 L/kg) that resulted in a greater initial nalmefene concentration in the elderly group. While initial nalmefene plasma concentrations were transiently higher in the elderly, it would not be anticipated that this population would require dosing adjustment. No clinical adverse events were noted in the elderly following the 1 mg intravenous nalmefene dose.
Patients with Hepatic Impairment
Subjects with hepatic disease, when compared to matched normal controls, had a 28.3% decrease in plasma clearance of nalmefene (0.56 ± 0.21 L/hr/kg versus 0.78 ± 0.24 L/hr/kg, respectively). Elimination half-life increased from 10.2 ± 2.2 hours to 11.9 ± 2.0 hours in the hepatically impaired. No dosage adjustment is recommended since nalmefene will be administered as an acute course of therapy.
Patients with Renal Impairment
There was a statistically significant 27% decrease in plasma clearance of nalmefene in the end-stage renal disease (ESRD) population during interdialysis (0.57± 0.20 L/hr/kg) and a 25% decreased plasma clearance in the ESRD population during intradialysis (0.59 ± 0.18 L/hr/kg) compared to normals (0.79± 0.24 L/hr/kg). The elimination half-life was prolonged in ESRD patients from 10.2 ± 2.2 hours in normals to 26.1 + 9.9 hours. (See DOSAGE AND ADMINISTRATION.)
There has not been sufficient pharmacokinetic study to make a definitive statement as to whether the pharmacokinetics of nalmefene differs between the genders.
REVEX has been administered to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It has also been used to reverse the systemic effects of intrathecal opioids.
Reversal of Postoperative Opioid Depression
REVEX (nalmefene hydrochloride injection) (N=326) was studied in 5 controlled trials in patients who had received morphine or fentanyl intraoperatively. The primary efficacy criterion was the reversal of respiratory depression. A positive reversal was defined as both an increase in respiratory rate by 5 breaths per minute and a minimum respiratory rate of 12 breaths per minute. Five minutes after administration, initial single REVEX doses of 0.1, 0.25, 0.5, or 1.0 µg/kg had effectively reversed respiratory depression in a dose-dependent manner. Twenty minutes after initial administration, respiratory depression had been effectively reversed in most patients receiving cumulative doses within the recommended range (0.1 to 1.0 µg/kg). Total doses of REVEX above 1.0 µg/kg did not increase the therapeutic response. The postoperative administration of REVEX at the recommended doses did not prevent the analgesic response to subsequently administered opioids.
Reversal of the Effect of Intrathecally Administered Opioids
Intravenous REVEX at doses of 0.5 and 1.0 µg/kg was administered to 47 patients given intrathecal morphine. One to 2 doses of 0.5 and 1.0 µg/kg REVEX reversed respiratory depression in most patients. The administration of REVEX at the recommended doses did not prevent the analgesic response to subsequently administered opioids.
Management of Known or Suspected Opioid Overdose
REVEX (N=284) at doses of 0.5 mg to 2.0 mg was studied in 4 trials of patients who were presumed to have taken an opioid overdose. REVEX doses of 0.5 mg to 1.0 mg effectively reversed respiratory depression within 2 to 5 minutes in most patients subsequently confirmed to have opioid overdose. A total dose greater than 1.5 mg did not increase the therapeutic response.
Last reviewed on RxList: 6/11/2012
This monograph has been modified to include the generic and brand name in many instances.
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