REVIA Tablet Ref.[50411] Active ingredients: Naltrexone

REVIA (naltrexone hydrochloride), an opioid antagonist is a synthetic congener of oxymorphone, and differs in structure from oxymorphone in that the methyl group on the nitrogen atom is replaced by a cyclopropylmethyl group. Naltrexone is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone (NARCAN*), and is, technically, a thebaine derivative. However, it has no opioid agonist properties.

Naltrexone has been shown to be a potent orally effective and safe antagonist of a variety of opioid responses in rodents.

Naltrexone was 16 times more potent than naloxone in preventing etonitazene-induced Straub tail in female mice when administered p.o., but was only 1.6 times as potent when administered s.c.. In male mice, naltrexone was 11 times as potent as naloxone p.o., but was only 1.5 times as potent as naloxone s.c.. The greater relative oral potency suggests that in mice, naltrexone may be better absorbed orally than naloxone. Naltrexone was also shown to be a potent antagonist of:

1. oxycodone-induced Straub tail in mice (p.o.)
2. oxycodone blockade of phenylquinone-induced writhing in mice (p.o.)
3. morphine-induced catalepsy in rats (p.o., s.c.)
4. oxymorphone-induced loss of righting reflex in rats (s.c., i.v.)

Naltrexone competitively inhibited ^3^H-naloxone and ^3^H-dihydromorphine binding to the µ-receptor in rat brain membranes, and had a 5 times greater affinity for the µ-receptor than did naloxone.

Naltrexone has no selective anti-writhing activity in the phenylquinone-induced writhing test in mice (p.o., s.c.). The naltrexone antiphenylquinone effects were seen only at doses close to the toxic level, which suggests that they were not due to analgesia. Naltrexone had no analgesic activity in rats, and was virtually inactive in the rat phenylquinone-induced writhing test.

Naltrexone had an anesthetic effect 1.4 times as potent as naloxone and 0.27 times as potent as lidocaine on the sciatic nerve in rats when injected perineurally. In a study on the behavioral and autonomic effects and acute toxicity of naltrexone orally in mice and rats, naltrexone showed a low order of toxicity. Naltrexone caused only ataxia and loss of auditory pinna reflex in mice and no behavioral effect up to and including 324 mg/kg in rats.

Preclinical studies have demonstrated interactions between alcohol and opioid receptor activity. Morphine suppresses alcohol withdrawal in mice and alcohol suppresses morphine withdrawal in rats, indicating pharmacological cross-tolerance. In addition, opioid antagonists (i.e., naltrexone) have been shown to block some of the effects of alcohol, including behavioural symptoms of alcohol withdrawal in mice and rats. Naloxone also blocks alcohol-elicited increases in motor activity in mice.

Preclinical evidence suggests that opiate antagonists can decrease alcohol consumption. For example, rats increase alcohol intake following inescapable but not escapable shock. Injections of naltrexone were found to block this increase in drinking following inescapable shock, when compared with rats given placebo injections.

Volpicelli (1987) and Volpicelli et al. (1986) studied a model of alcohol drinking in rats based on the observation that alcohol drinking often occurs following uncontrollable events. He referred to human studies supporting the notion that alcohol drinking increases following, but not during arousing situations. Alcohol-drinking rats increased their consumption of alcohol following the receipt of an inescapable electric shock. The large increases in alcohol consumption did not occur on days in which shock was administered but increased on the day after inescapable shock. Naltrexone,10 mg/kg subcutaneously, blocked post-shock alcohol consumption whereas placebo-treated post-shock rats increased their consumption of alcohol.

The effects of naltrexone and naloxone were studied on the ability to train rats to consume various concentrations of alcohol. Sprague-Dawley rats were treated with either naltrexone or naloxone administered intraperitoneally (i.p.) 15 minutes prior to a 30-minute alcohol drinking access period. Both naltrexone and naloxone dose-dependently decreased the voluntary consumption of a 20% weight/volume solution of alcohol (p <0.01).

The effects of naltrexone in decreasing alcohol intake has also been demonstrated in rhesus monkeys. Eight drug-naive rhesus monkeys were trained to self-administer at least 1.0 g/kg/day intravenous alcohol during a 4 hour daily session. Intramuscular administration of either saline or naltrexone (1, 3, or 5 mg/kg) was given 30 minutes before each daily session. Saline pretreatment periods were 10 days in duration and were alternated with 15 days of naltrexone treatment. Naltrexone decreased the self-administration of alcohol in a dosedependent manner. Altshuler et al. (1980) suggested that the blockade of opioid receptors by naltrexone was responsible for the attenuation of the reinforcing effects of alcohol.

Naltrexone also decreased the consumption of alcohol in another experimental model in rhesus monkeys. Monkeys were trained to drink an alcohol solution under experimental conditions where they had free access to a continuous supply of water and alcohol. The effect of intramuscularly-administered naltrexone was studied (a) during the continuous supply of alcohol, and (b) after a two-day period of imposed abstinence from alcohol. Naltrexone significantly decreased the voluntary consumption of alcohol compared to placebo during both the continuous supply condition and after the two-day abstinence from alcohol. The decrease of drinking was selective since water drinking was not significantly affected by naltrexone.

The pharmacokinetics, tissue distribution and metabolism of naltrexone have been studied in male New Zealand White rabbits. After an intravenous bolus, the plasma half-life of naltrexone between 30 minutes and 3 hours was 55 ± 5 minutes and 53 ± 3 minutes for 1 and 5 mg/kg doses of naltrexone HCI, respectively. The drug concentration in the semen reached a maximum value between 15 and 30 minutes after the injection. At 120 minutes, the semen/plasma drug concentration ratio was 14 and 11 for the 1 and 5 mg/kg doses, respectively. Three minutes after injection 95% of the drug had left the plasma. After 5 minutes the conjugate levels exceeded the free drug levels in the plasma, suggesting rapid glucuronidation of the drug. Ninety minutes after injection, most of the tissues had concentrations of naltrexone and 6-β-naltrexol which exceeded the concurrent plasma concentration. Highest concentrations were observed in the submaxillary gland. Relatively high amounts of 6-β-naltrexol were found in the brain, fat, spleen, heart, testis, kidney and urine. The principal urinary metabolite was the glucuronide of naltrexone with 6-β-naltrexol and Ndealkylated naltrexone as minor metabolites.

The serum kinetics of 5 mg/kg intravenous naltrexone were studied in the dog. Serum samples were obtained from 2 minutes to 2 hours after injection and drug concentrations determined by radioimmunoassay. Serum levels of naltrexone fell rapidly; serum half-life during the elimination phase was 85.1 ± 9.0 minutes (mean ± SE).

Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A total body clearance of 51-55 ml/min/kg was demonstrated in two dogs. Urine (0-24 hours) contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hours and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys suggests, together with the extremely low renal excretion of naltrexone, the existence of elimination mechanisms besides liver metabolism and renal excretion.

In rabbits, monkeys and rats, naltrexone is reduced primarily to β-naltrexol. Monkeys receiving a daily oral dose of 12 mg/kg chronically, excreted very little free β-naltrexol and exhibited an apparent sex-related difference in excretion patterns, with females excreting more than twice as much total base as males. Rabbits given an intraperitoneal dose of 30 mg/kg for 4 days excreted conjugated naltrexone as the predominant urinary metabolite, accounting for 80% of total base recovered in 24 hours. In rats receiving 100 mg/kg orally, less than 1% of the administered dose could be accounted for in the 24 hour urine, indicating that although the βnaltrexol is produced as a urinary metabolite, other means of disposition of the drug must exist. Thus, in man and the monkey, β-naltrexol is the predominant and persistent urinary metabolite.

The extent of binding of (15,16-³H)-naltrexone is independent of naltrexone concentration over the concentration range of 1-500 ng/mL for dog plasma and of 0.1-500 ng/mL for human, monkey, guinea pig, rat and mouse plasma, ranging from 20% bound in rat plasma to 26% in plasma from beagle and mongrel dogs. This is consistent with previous findings of a large apparent volume of distribution in the dog. Determination of the tissue levels of radioactivity in mice at 1, 5, and 15 minutes after intravenous administration of (8-³H)-naltrexone showed that naltrexone was rapidly distributed from plasma to tissues, with less than 4% of the dose present in plasma at one minute after injection.

The elimination of radioactivity after (15,16-³H)-naltrexone administration i.v. was studied in rats and guinea pigs. An average of 42% of the dose was eliminated in urine and 55% in feces. Radioactivity levels in the excreta of one rat dosed i.m. yielded similar results. Guinea pigs which received 1 mg/kg i.v. excreted only 14% of the dose in feces and 84% in urine. Similar results were obtained following i.m. administration to guinea pigs. In guinea pig excreta, an average of 64% of the dose corresponded to naltrexone and conjugates, 19% to β-naltrexol and conjugates, and 2% to a-naltrexol and conjugates. In urine, the radioactivity corresponding to αnaltrexol and naltrexone was present mainly in conjugated form, whereas apparent β-naltrexol was mainly unconjugated. The radioactivity in feces corresponded principally to unconjugated naltrexone and β-naltrexol.

After subcutaneous injection of (15,16-³H)-naltrexone (10 mg/kg) in male Wistar rats, peak concentrations of drug occurred in brain and plasma within 0.5 hours. Levels of naltrexone were sustained in brain between 2 and 24 hours and were barely detectable at 48 hours. The half-lives of naltrexone in brain and plasma were approximately 8.0 and 11.4 hours, respectively. The brain/plasma ratios of naltrexone at earlier times (0.5-1 hours) were higher than those at later times. The binding of naltrexone in vitro with rat plasma proteins in concentrations of 1-10 IJg/mL ranged between 41% and 59%. 6-β-naltrexol was present in very small amounts in brain but not in plasma. In addition to 7,8-dihydro-14-hydroxynormorphinone and 7,8-dihydro-14- hydroxynormorphine, tentative evidence was obtained for three other metabolites of naltrexone in brain. These metabolites were also present in plasma in addition to free and conjugated naltrexone and its N-dealkylated metabolites.

Test parameters and drug-related findings of toxicology studies carried out with naltrexone are summarized in the following table:

^* two tests

In the acute toxicity studies in the mouse, rat, and dog, cause of death was due to clonic-tonic convulsions and/or respiratory failure.

In the two-year carcinogenicity study in rats, there were small increases in the numbers of mesotheliomas in males, and tumours of vascular origin in both sexes. The number of tumours were within the range seen in historical control groups, except for the vascular tumours in females, where the 4% incidence exceeded the historical maximum of 2%.

Mutagenesis: A total of twenty-two distinct tests were performed using bacterial, mammalian, and tissue culture systems. All tests were negative except for weakly positive findings in the Drosophila recessive lethal assay and non-specific DNA repair tests with E. coli. The significance of these findings is undetermined.

Reproduction Studies: REVIA (naltrexone hydrochloride) has been shown to have embryocidal and fetotoxic effects in rats and rabbits when given in dosages 30 and 60 times, respectively, the human dose.