warnings
WARNINGS Hepatotoxicity Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses. Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects. The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only five-fold or less. Naltrexone does not appear to be a hepatotoxin at the recommended doses. Patients should be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek medical attention if they experience symptoms of acute hepatitis. Evidence of the hepatotoxic potential of naltrexone is derived primarily from a placebo controlled study in which naltrexone hydrochloride 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 naltrexone 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 naltrexone is a direct (i.e., not idiosyncratic) hepatotoxin. This conclusion is also supported by evidence from other placebo controlled studies in which exposure to naltrexone hydrochloride 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 naltrexone hydrochloride (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 naltrexone 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 naltrexone 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 naltrexone. 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 naltrexone. The naloxone challenge test is described in the DOSAGE AND ADMINISTRATION section. Attempt to Overcome Blockade While naltrexone is a potent antagonist with a prolonged pharmacologic effect (24 to 72 hours), the blockade produced by naltrexone 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 PRECAUTIONS, Information for Patients ). There is also the possibility that a patient who has 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 naltrexone in ultra rapid opiate detoxification programs has not been established (see ADVERSE REACTIONS ).