Hepatotoxicity:

Evidence of the hepatotoxic potential of REVIA is derived primarily from a placebo controlled study in which REVIA was administered to obese subjects at a dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day). In that study, 5 of 26 REVIA recipients developed elevations of serum transaminases (i.e., peak ALT values ranging from a low of 121 to a high of 532; or 3 to 19 times their baseline values) after three to eight weeks of treatment. Although the patients involved were generally clinically asymptomatic and the transaminase levels of all patients on whom follow-up was obtained returned to (or toward) baseline values in a matter of weeks, the lack of any transaminase elevations of similar magnitude in any of the 24 placebo patients in the same study is persuasive evidence that REVIA is a direct (i.e., not idiosyncratic) hepatotoxin.

This conclusion is also supported by evidence from other placebo controlled studies in which exposure to REVIA at doses above the amount recommended for the treatment of alcoholism or opiate blockade (50 mg/day) consistently produced more numerous and more significant elevations of serum transaminases than did placebo. Transaminase elevations in 3 of 9 patients with Alzheimer's Disease who received REVIA (at doses up to 300 mg/day) for 5 to 8 weeks in an open clinical trial have been reported.

Although no cases of hepatic failure due to REVIA administration have ever been reported, physicians are advised to consider this as a possible risk of treatment and to use the same care in prescribing REVIA as they would other drugs with the potential for causing hepatic injury.

Unintended Precipitation of Abstinence:

To prevent occurrence of an acute abstinence syndrome, or exacerbation of a pre-existing subclinical abstinence syndrome, patients must be opioid-free for a minimum of 7-10 days before starting REVIA. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of REVIA. The naloxone challenge test is described in the DOSAGE AND ADMINISTRATION section.

Attempt to Overcome Blockade:

While REVIA is a potent antagonist with a prolonged pharmacologic effect (24 to 72 hours), the blockade produced by REVIA is surmountable. This is useful in patients who may require analgesia, but poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Indeed, any attempt by a patient to overcome the antagonism by taking opioids is very dangerous and may lead to a fatal overdose. Injury may arise because the plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. As a consequence, the patient may be in immediate danger of suffering life endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of trying to overcome the opiate blockade (See Information for Patients ).

There is also the possibility that a patient who had been treated with naltrexone will respond to lower doses of opioids than previously used, particularly if taken in such a manner that high plasma concentrations remain in the body beyond the time that naltrexone exerts its therapeutic effects. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.). Patients should be aware that they may be more sensitive to lower doses of opioids after naltrexone treatment is discontinued.

Ultra Rapid Opioid Withdrawal:

Safe use of ReVia in ultra rapid opiate detoxification programs has not been established (see ADVERSE REACTIONS).

General:

When Reversal of REVIA Blockade is Required: In an emergency situation in patients receiving fully blocking doses of REVIA, a suggested plan of management is regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics or general anesthesia.

In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.

A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction) presumably due to histamine release.

Irrespective of the drug chosen to reverse REVIA blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

Accidentally Precipitated Withdrawal: Severe opioid withdrawal syndromes precipitated by the accidental ingestion of REVIA have been reported in opioid-dependent individuals. Symptoms of withdrawal have usually appeared within five minutes of ingestion of REVIA and have lasted for up to 48 hours. Mental status changes including confusion, somnolence and visual hallucinations have occurred. Significant fluid losses from vomiting and diarrhea have required intravenous fluid administration. In all cases patients were closely monitored and therapy with non-opioid medications was tailored to meet individual requirements.

Use of REVIA does not eliminate or diminish withdrawal symptoms. If REVIA is initiated early in the abstinence process, it will not preclude the patient's experience of the full range of signs and symptoms that would be experienced if REVIA had not been started. Numerous adverse events are known to be associated with withdrawal.

Special Risk Patients:

Renal Impairment:   REVIA and its primary metabolite are excreted primarily in the urine, and caution is recommended in administering the drug to patients with renal impairment.

Hepatic Impairment:   Caution should be exercised when naltrexone hydrochloride is administered to patients with liver disease. An increase in naltrexone AUC of approximately 5- and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with normal liver function has been reported. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity.

Suicide:   The risk of suicide is known to be increased in patients with substance abuse with or without concomitant depression. This risk is not abated by treatment with REVIA (see ADVERSE REACTIONS).

Information for Patients:   It is recommended that the prescribing physician relate the following information to patients being treated with REVIA:

You have been prescribed REVIA as part of the comprehensive treatment for your alcoholism or drug dependence. You should carry identification to alert medical personnel to the fact that you are taking REVIA. A REVIA medication card may be obtained from your physician and can be used for this purpose. Carrying the identification card should help to ensure that you can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the treating physician that you are receiving REVIA therapy.

You should take REVIA as directed by your physician. If you attempt to self-administer heroin or any other opiate drug, in small doses while on REVIA, you will not perceive any effect. Most important, however, if you attempt to self-administer large doses of heroin or any other opioid while on REVIA, you may die or sustain serious injury, including coma.

REVIA is well-tolerated in the recommended doses, but may cause liver injury when taken in excess or in people who develop liver disease from other causes. If you develop abdominal pain lasting more than a few days, white bowel movements, dark urine, or yellowing of your eyes, you should stop taking REVIA immediately and see your doctor as soon as possible.

Laboratory Tests:    A high index of suspicion for drug-related hepatic injury is critical if the occurrence of liver damage induced by REVIA is to be detected at the earliest possible time. Evaluations, using appropriate batteries of tests to detect liver injury are recommended at a frequency appropriate to the clinical situation and the dose of REVIA.

REVIA (naltrexone hydrochloride) does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone or quinine in the urine. REVIA may or may not interfere with enzymatic methods for the detection of opioids depending on the specificity of the test. Please consult the test manufacturer for specific details.

Drug Interactions:   Studies to evaluate possible interactions between REVIA and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of REVIA and other drugs is required.

The safety and efficacy of concomitant use of REVIA and disulfiram is unknown, and the concomitant use of two potentially hepatotoxic medications is not ordinarily recommended unless the probable benefits outweigh the known risks.

Lethargy and somnolence have been reported following doses of REVIA and thioridazine.

Patients taking REVIA may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid analgesics. In an emergency situation when opioid analgesia must be administered to a patient receiving REVIA, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see ).

Carcinogenesis, Mutagenesis and Impairment of Fertility:

The following statements are based on the results of experiments in mice and rats. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-(beta)-naltrexol are unknown.

In a two-year carcinogenicity study in rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (600 mg/m ² /day; 16 times the recommended therapeutic dose, based on body surface area) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day (600 mg/m ² /day) was 4%, but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice.

There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli. However, no evidence of genotoxic potential was observed in a range of other in vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in vivo mouse micronucleus assay. Naltrexone (100 mg/kg/day [600 mg/m ² /day] PO; 16 times the recommended therapeutic dose, based on body surface area) caused a significant increase in pseudopregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.

Pregnancy: Category C. Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥30 mg/kg/day (180 mg/m ² /day; 5 times the recommended therapeutic dose, based on body surface area) and to rabbits at oral doses ≥60 mg/kg/day (720 mg/m ² /day; 18 times the recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (32 and 65 times the recommended therapeutic dose, respectively, based on body surface area).

Rats do not form appreciable quantities of the major human metabolite, 6-(beta)-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known.

There are no adequate and well-controlled studies in pregnant women. ReVia should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery:    Whether or not REVIA affects the duration of labor and delivery is unknown.

Nursing Mothers:    In animal studies, naltrexone and 6-(beta)-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone. Whether or not REVIA is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when REVIA is administered to a nursing woman.

Pediatric Use:   The safe use of REVIA in pediatric patients younger than 18 years old has not been established.

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