Naltrexone

INDICATIONS AND USAGE Naltrexone hydrochloride tablets USP 50 mg is indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. Naltrexone hydrochloride tablets USP 50 mg has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions.

CLINICAL PHARMACOLOGY Pharmacodynamic Actions Naltrexone hydrochloride is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. When coadministered with morphine, on a chronic basis, naltrexone hydrochloride blocks the physical dependence to morphine, heroin and other opioids. Naltrexone hydrochloride 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 naltrexone hydrochloride is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, naltrexone hydrochloride will precipitate withdrawal symptomatology. Clinical studies indicate that 50 mg of naltrexone hydrochloride will block the pharmacologic effects of 25 mg of intravenously administered heroin for periods as long as 24 hours. Other data suggest that doubling the dose of naltrexone hydrochloride provides blockade for 48 hours, and tripling the dose of naltrexone hydrochloride provides blockade for about 72 hours. Naltrexone hydrochloride blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition of enzymes) at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of very high doses of opiates has resulted in excessive symptoms of histamine release in experimental subjects. The mechanism of action of naltrexone hydrochloride in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone hydrochloride, an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids. Opioid antagonists have been shown to reduce alcohol consumption by animals, and naltrexone hydrochloride has been shown to reduce alcohol consumption in clinical studies. Naltrexone hydrochloride is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion. Pharmacokinetics Naltrexone hydrochloride is a pure opioid receptor antagonist. Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%. The activity of naltrexone is believed to be due to both parent and the 6-β-naltrexol metabolite. Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The mean elimination half-life (T 1/2 ) values for naltrexone and 6-β-naltrexol are 4 hours and 13 hours, respectively. Naltrexone and 6-β-naltrexol are dose proportional in terms of AUC and C max over the range of 50 to 200 mg and do not accumulate after 100 mg d

DOSAGE AND ADMINISTRATION To reduce the risk of precipitated withdrawal in patients dependent on opioids, or exacerbation of a preexisting subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting naltrexone hydrochloride treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids. Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone There are no systematically collected data that specifically address the switch from buprenorphine or methadone to naltrexone hydrochloride; however, review of postmarketing case reports have indicated that some patients may experience severe manifestations of precipitated withdrawal when being switched from opioid agonist therapy to opioid antagonist therapy (see WARNINGS ).Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers should be prepared to manage withdrawal symptomatically with non-opioid medications. Treatment of Alcoholism A dose of 50 mg once daily is recommended for most patients The placebo-controlled studies that demonstrated the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcoholism used a dose regimen of naltrexone hydrochloride 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not evaluated in these trials. Naltrexone hydrochloride should be considered as only one of many factors determining the success of treatment of alcoholism. Factors associated with a good outcome in the clinical trials with naltrexone hydrochloride were the type, intensity, and duration of treatment; appropriate management of comorbid conditions; use of community-based support groups; and good medication compliance. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, especially medication compliance. Treatment of Opioid Dependence Treatment should be initiated with an initial dose of 25 mg of naltrexone hydrochloride. If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter. A dose of 50 mg once a day will produce adequate clinical blockade of the actions of parenterally administered opioids. As with many non-agonist treatments for addiction, naltrexone hydrochloride is of proven value only when given as part of a comprehensive plan of management that includes some measure to ensure the patient takes the medication. Naloxone Challenge Test Clinicians are reminded that there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. A naloxone challenge test may be helpful if there is any question of occult opioid dependence,If signs of opioid withdrawal are still observed following naloxone challenge, treatment with, naltrexone hydrochloride should not be attempted. The naloxone challenge can be repeated in 24 hours. The naloxone challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal, or in a patient whose urine contains opioids. The naloxone challenge test may be administered by either the intravenous or subcutaneous routes. Intravenous Inject 0.2 mg naloxone. Observe for 30 seconds for signs or symptoms of withdrawal. If no evidence of withdrawal, inject 0.6 mg of naloxone. Observe for an additional 20 minutes. Subcutaneous Administer 0.8 mg naloxone. Observe for 20 minutes for signs or symptoms of withdrawal. Note: Individual patients, especially those with opioid dependence, may respond to lower doses of naloxone. In some cases, 0.1 mg IV naloxone has produced a diagnostic response. Interpretation of the Challenge Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal. These may

ADVERSE REACTIONS During two randomized, double-blind placebo-controlled 12 week trials to evaluate the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcohol dependence, most patients tolerated naltrexone hydrochloride well. In these studies, a total of 93 patients received naltrexone hydrochloride at a dose of 50 mg once daily. Five of these patients discontinued naltrexone hydrochloride because of nausea. No serious adverse events were reported during these two trials. While extensive clinical studies evaluating the use of naltrexone hydrochloride in detoxified, formerly opioid-dependent individuals failed to identify any single, serious untoward risk of naltrexone hydrochloride use, placebo-controlled studies employing up to five-fold higher doses of naltrexone hydrochloride (up to 300 mg per day) than that recommended for use in opiate receptor blockade have shown that naltrexone hydrochloride causes hepatocellular injury in a substantial proportion of patients exposed at higher doses (see WARNINGS and PRECAUTIONS: Laboratory Tests ). Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence does not incriminate naltrexone hydrochloride, used at any dose, as a cause of any other serious adverse reaction for the patient who is“opioid free.” It is critical to recognize that naltrexone hydrochloride can precipitate or exacerbate abstinence signs and symptoms in any individual who is not completely free of exogenous opioids. Patients with addictive disorders, especially opioid addiction, are at risk for multiple numerous adverse events and abnormal laboratory findings, including liver function abnormalities. Data from both controlled and observational studies suggest that these abnormalities, other than the dose-related hepatotoxicity described above, are not related to the use of naltrexone hydrochloride. Among opioid free individuals, naltrexone hydrochloride administration at the recommended dose has not been associated with a predictable profile of serious adverse or untoward events. However, as mentioned above, among individuals using opioids, naltrexone hydrochloride may cause serious withdrawal reactions (see CONTRAINDICATIONS , WARNINGS , DOSAGE AND ADMINISTRATION ). Reported Adverse Events Naltrexone hydrochloride has not been shown to cause significant increases in complaints in placebo-controlled trials in patients known to be free of opioids for more than 7 to 10 days. Studies in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid withdrawal-like symptom complex consisting of tearfulness, mild nausea, abdominal cramps, restlessness, bone or joint pain, myalgia, and nasal symptoms. This may represent the unmasking of occult opioid use, or it may represent symptoms attributable to naltrexone. A number of alternative dosing patterns have been recommended to try to reduce the frequency of these complaints. Alcoholism In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone hydrochloride, the following new-onset adverse reactions occurred in 2% or more of the patients: nausea (10%), headache (7%), dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting (3%), anxiety (2%) and somnolence (2%). Depression, suicidal ideation, and suicidal attempts have been reported in all groups when comparing naltrexone, placebo, or controls undergoing treatment for alcoholism. RATE RANGES OF NEW ONSET EVENTS Naltrexone Placebo Depression 0 to 15% 0 to 17% Suicide Attempt/Ideation 0 to 1% 0 to 3% Although no causal relationship with naltrexone hydrochloride is suspected, physicians should be aware that treatment with naltrexone hydrochloride does not reduce the risk of suicide in these patients (see PRECAUTIONS ). Opioid Addiction The following adverse reactions have been reported both at baseline and during the naltrexone hydrochl

WARNINGS Vulnerability to Opioid Overdose After opioid detoxification, patients are likely to have reduced tolerance to opioids. As the blockade of exogenous opioids provided by naltrexone hydrochloride wanes and eventually dissipates completely, patients who have been treated with naltrexone hydrochloride may respond to lower doses of opioids than previously used, just as they would shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients after discontinuing treatment. Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after naltrexone hydrochloride treatment is discontinued. It is important that patients inform family members, and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose. (see PRECAUTIONS, Information for Patients ). There is also the possibility that a patient who is treated with naltrexone hydrochloride could overcome the opioid blockade effect of naltrexone hydrochloride. Although naltrexone hydrochloride is a potent antagonist , the blockade produced by naltrexone hydrochloride is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids.Any attempt by a patient to overcome the antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade (see PRECAUTIONS, Information for Patients ). Precipitated Opioid Withdrawal The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal syndrome can be severe enough to require hospitalization. Symptoms of withdrawal have usually appeared within five minutes of ingestion of naltrexone hydrochloride 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. Review of postmarketing cases of precipitated opioid withdrawal in association with naltrexone treatment has identified cases with symptoms of withdrawal severe enough to require hospital admission, and in some cases, management in the intensive care unit. To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or exacerbation of a pre-existing subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting naltrexone hydrochloride treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks. If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed. In every case, healthcare providers should always be prepared to manage withdrawal symptomatically with non-opioid med

CONTRAINDICATIONS Naltrexone hydrochloride is contraindicated in Patients receiving opioid analgesics. Patients currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone ) or partial agonists (e.g., buprenorphine) Patients in acute opioid withdrawal (see WARNINGS ). Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids. Any individual with a history of sensitivity to naltrexone hydrochloride or any other components of this product.It is not known if there is any cross-sensitivity with naloxone or the phenanthrene containing opioids.

OVERDOSAGE There is limited clinical experience with naltrexone hydrochloride overdosage in humans. In one study, subjects who received 800 mg daily naltrexone hydrochloride for up to one week showed no evidence of toxicity. In the mouse, rat and guinea pig, the oral LD 50s were 1,100 to 1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone hydrochloride (generally ≥ 1,000 mg/kg) produced salivation, depression/reduced activity, tremors, and convulsions. Mortalities in animals due to high-dose naltrexone hydrochloride administration usually were due to clonic-tonic convulsions and/or respiratory failure. Treatment of Overdosage In view of the lack of actual experience in the treatment of naltrexone hydrochloride overdose, patients should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date information.