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Mechanism of action
Naltrexone is an opioid antagonist with highest affinity for the mu opioid receptor. Naltrexone has little or no opioid agonist activity.
Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.
The administration of VIVITROL (naltrexone xr inj) is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, VIVITROL (naltrexone xr inj) will precipitate withdrawal symptomatology.
Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. It markedly attenuates or completely blocks, reversibly, the subjective effects of exogenous opioids. The neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-dependent patients treated with naltrexone are not entirely understood. However, involvement of the endogenous opioid system is suggested by preclinical data.
Naltrexone blocks the effects of opioids by competitive binding at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of opioids may result in non-opioid receptor-mediated symptoms such as histamine release.
VIVITROL (naltrexone xr inj) is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.
VIVITROL is an extended-release, microsphere formulation of naltrexone designed to be administered by intramuscular (EVI) gluteal injection every 4 weeks or once a month. After IM injection, the naltrexone plasma concentration time profile is characterized by a transient initial peak, which occurs approximately 2 hours after injection, followed by a second peak observed approximately 2-3 days later. Beginning approximately 14 days after dosing, concentrations slowly decline, with measurable levels for greater than 1 month.
Maximum plasma concentration (Cmax) and area under the curve (AUC) for naltrexone and 60-naltrexol (the major metabolite) following VIVITROL (naltrexone xr inj) administration are dose proportional. Compared to daily oral dosing with naltrexone 50 mg over 28 days, total naltrexone exposure is 3 to 4-fold higher following administration of a single dose of VIVITROL (naltrexone xr inj) 380 mg. Steady state is reached at the end of the dosing interval following the first injection. There is minimal accumulation ( < 15%) of naltrexone or 6p-naltrexol upon repeat administration of VIVITROL (naltrexone xr inj) .
In vitro data demonstrate that naltrexone plasma protein binding is low (21%).
Naltrexone is extensively metabolized in humans. Production of the primary metabolite, 6β-naltrexol, is mediated by dihydrodiol dehydrogenase, a cytosolic family of enzymes. The cytochrome P450 system is not involved in naltrexone metabolism. Two other minor metabolites are 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. Naltrexone and its metabolites are also conjugated to form glucuronide products.
Significantly less 6β-naltrexol is generated following IM administration of VIVITROL compared to administration of oral naltrexone due to a reduction in first-pass hepatic metabolism.
Elimination of naltrexone and its metabolites occurs primarily via urine, with minimal excretion of unchanged naltrexone.
The elimination half life of naltrexone following VIVITROL (naltrexone xr inj) administration is 5 to 10 days and is dependent on the erosion of the polymer. The elimination half life of 6β-naltrexol following VIVITROL (naltrexone xr inj) administration is 5 to 10 days.
Pediatric: Pharmacokinetics of VIVITROL (naltrexone xr inj) have not been evaluated in a pediatric population.
Geriatric: Pharmacokinetics of VIVITROL (naltrexone xr inj) have not been evaluated in the geriatric population [see Use In Specific Populations].
Race: Effect of race on the pharmacokinetics of VIVITROL (naltrexone xr inj) has not been studied.
Gender: In a study in healthy subjects (n=18 females and 18 males), gender did not influence the pharmacokinetics of VIVITROL (naltrexone xr inj) .
Renal Insufficiency: A population pharmacokinetic analysis indicated mild renal insufficiency (creatinine clearance of 50-80 mL/min) had little or no influence on VIVITROL (naltrexone xr inj) pharmacokinetics and that no dosage adjustment is necessary. VIVITROL (naltrexone xr inj) pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency [see Use In Specific Populations].
Hepatic Insufficiency: The pharmacokinetics of VIVITROL (naltrexone xr inj) are not altered in subjects with mild to moderate hepatic impairment (Groups A and B of the Child-Pugh classification). VIVITROL (naltrexone xr inj) pharmacokinetics were not evaluated in subjects with severe hepatic impairment [see Use In Specific Populations].
In vitro Studies: Because naltrexone is not a substrate for CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes are unlikely to change the clearance of VIVITROL (naltrexone xr inj) . An in vitro CYP inhibition study demonstrated that naltrexone is not an inhibitor of major CYP enzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4). An in vitro CYP induction study demonstrated that naltrexone is not an inducer of CYP3A4 and CYP1A2.
The efficacy of VIVITROL (naltrexone xr inj) in the treatment of alcohol dependence was evaluated in a 24 week, placebo-controlled, multi-center, double-blind, randomized trial of alcohol-dependent (DSM-IV criteria) outpatients. Subjects were treated with an injection every 4 weeks of VIVITROL 190 mg, VIVITROL 380 mg or placebo. Oral naltrexone was not administered prior to the initial or subsequent injections of study medication. Psychosocial support was provided to all subjects in addition to medication.
Subjects treated with VIVITROL (naltrexone xr inj) 380 mg demonstrated a greater reduction in days of heavy drinking than those treated with placebo. Heavy drinking was defined as self-report of 5 or more standard drinks consumed on a given day for male patients and 4 or more drinks for female patients. Among the subset of patients (n=53, 8% of the total study population) who abstained completely from drinking during the week prior to the first dose of medication, compared with placebo-treated patients, those treated with VIVITROL (naltrexone xr inj) 380 mg had greater reductions in the number of drinking days and the number of heavy drinking days. In this subset, patients treated with VIVITROL (naltrexone xr inj) were also more likely than placebo-treated patients to maintain complete abstinence throughout treatment. The same treatment effects were not evident among the subset of patients (n=571, 92% of the total study population) who were actively drinking at the time of treatment initiation.
The efficacy of VIVITROL (naltrexone xr inj) in the treatment of opioid dependence was evaluated in a 24 week, placebo-controlled, multi-center, double-blind, randomized trial of opioid-dependent (DSM-IV) outpatients, who were completing or had recently completed detoxification. Subjects were treated with an injection every 4 weeks of VIVITROL 380 mg or placebo. Oral naltrexone was not administered prior to the initial or subsequent injections of study medication. Standardized, manual-based psychosocial support was provided on a biweekly basis to all subjects in addition to medication.
Figure 1, below, displays the cumulative percentage of subjects with opioid-free weeks ranging from no visits (0%) to all visits (100%). An opioid-free week was one in which urine drug test results were negative for opioids and self-reported opioid use was also zero. An initial period of engagement in treatment was permitted during which opiate use, if it occurred, was not considered in the analysis. Subjects discontinuing from the trial were assumed to have had opioid-use weeks for the weeks after dropout.
The cumulative percentage of subjects achieving each observed percentage of opioid-free weeks was greater in the VIVITROL (naltrexone xr inj) group compared to the placebo group. Complete abstinence (opioid-free at all weekly visits) was sustained by 23% of subjects in the placebo group compared with 36% of subjects in the VIVITROL (naltrexone xr inj) group from Week 5 to Week 24.
Figure 1: Subjects Sustaining Varying Percentages of Opioid-Free
A greater percentage of subjects in the VIVITROL (naltrexone xr inj) group remained in the study compared to the placebo group.
Last reviewed on RxList: 11/8/2010
This monograph has been modified to include the generic and brand name in many instances.
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