CLINICAL PHARMACOLOGY:
Pharmacodynamics
Mechanism of Action
Naltrexone is an opioid antagonist with highest affinity for the mu opioid receptor. 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 is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, VIVITROL will precipitate withdrawal symptomatology.
Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. 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 is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.
Pharmacokinetics
Absorption
VIVITROL is an extended-release, microsphere formulation of naltrexone designed to be administered by intramuscular (IM) 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 6β-naltrexol (the major metabolite) following VIVITROL 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 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 6β-naltrexol upon repeat administration of VIVITROL.
Distribution
In vitro data demonstrate that naltrexone plasma protein binding is low (21%).
Metabolism
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
Elimination of naltrexone and its metabolites occurs primarily via urine, with minimal excretion of unchanged naltrexone.
The elimination half life of naltrexone following VIVITROL administration is 5 to 10 days and is dependent on the erosion of the polymer. The elimination half life of 6β-naltrexol following VIVITROL administration is 5 to 10 days.
Special Populations
Hepatic Impairment: The pharmacokinetics of VIVITROL are not altered in subjects with mild to moderate hepatic impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required in subjects with mild or moderate hepatic impairment. VIVITROL pharmacokinetics were not evaluated in subjects with severe hepatic impairment (see PRECAUTIONS ).
Renal Impairment: A population pharmacokinetic analysis indicated mild renal insufficiency (creatinine clearance of 50-80 mL/min) had little or no influence on VIVITROL pharmacokinetics and that no dosage adjustment is necessary (see PRECAUTIONS ). VIVITROL pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency (see PRECAUTIONS ).
Gender: In a study in healthy subjects (n=18 females and 18 males), gender did not influence the pharmacokinetics of VIVITROL.
Age: The pharmacokinetics of VIVITROL have not been evaluated in the geriatric population.
Race: The effect of race on the pharmacokinetics of VIVITROL has not been studied.
Pediatrics: The pharmacokinetics of VIVITROL have not been evaluated in a pediatric population.
Drug-Drug Interactions
Clinical drug interaction studies with VIVITROL have not been performed.
Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations and opioid analgesics (see PRECAUTIONS ).
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