Naltrexone Hydrochloride

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.

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 tablets treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose When initiating and renewing treatment with naltrexone hydrochloride tablets, USP, inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose after naltrexone hydrochloride tablets, USP treatment is discontinued, or after a dose of naltrexone hydrochloride tablets, USP is missed, strongly consider recommending or prescribing an overdose reversal agent naloxone for the emergency treatment of opioid overdose (see WARNINGS ). Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter (some products), or as part of a community-based program) (see WARNINGS ) . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 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 tablets; 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 tablets 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 tablets 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 tablets. 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 tablets are of proven value only when given as part of a comprehensive plan of management that includes some measure to ensure the patient takes the medicat …

CONTRAINDICATIONS Naltrexone hydrochloride is contraindicated in: 1. Patients receiving opioid analgesics. 2. Patients currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine). 3. Patients in acute opioid withdrawal (see WARNINGS ). 4. Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids. 5. 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.

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 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 hydrochloride clinic …

Drug Interactions Studies to evaluate possible interactions between naltrexone hydrochloride and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of naltrexone hydrochloride and other drugs is required. The safety and efficacy of concomitant use of naltrexone hydrochloride 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 naltrexone hydrochloride and thioridazine. Patients taking naltrexone hydrochloride 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 naltrexone hydrochloride, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see PRECAUTIONS ).

DESCRIPTION Naltrexone hydrochloride, an opioid antagonist, are a synthetic congener of oxymorphone with no opioid agonist properties. Naltrexone differs in structure from oxymorphone in that the methyl group on the nitrogen atom is replaced by a cyclopropylmethyl group. Naltrexone hydrochloride is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone. The chemical name for naltrexone hydrochloride is Morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-, hydrochloride, (5a)-. The structural formula is as follows: C 20 H 23 NO 4 ∙HCl Molecular Weight: 377.86 Naltrexone hydrochloride is a white, crystalline compound. The hydrochloride salt is soluble in water to the extent of about 100 mg/mL. Naltrexone Hydrochloride Tablets USP are available in scored film-coated tablets containing 50 mg of naltrexone hydrochloride. Naltrexone Hydrochloride Tablets USP also contain: carnauba wax powder, colloidal silicon dioxide, croscarmellose sodium, hypromellose, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide and yellow iron oxide. Chemical Structure

OVERDOSAGE There is limited clinical experience with naltrexone hydrochloride overdosage in humans. In one study, subjects who received 800 mg daily of naltrexone hydrochloride for up to one week showed no evidence of toxicity. In the mouse, rat and guinea pig, the oral LD50s were 1,1 DO 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.

HOW SUPPLIED Naltrexone Hydrochloride Tablets, USP are available as: 50 mg; yellow, round film-coated tablets, bisected on one side, debossed with "EL" on one side of the bisect and "15" on the other side of the bisect. NDC 68094-853-62 Unit Dose Packages of 30 Tablets (3 × 10) per carton NDC 68094-853-61 Unit Dose Packages of 100 Tablets (10 × 10) per carton NDC 68094-853-66 Unit Dose Packages of 20 Tablets (2 × 10) per carton Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light. KEEP THIS AND ALL MEDICATIONS OUT DF THE REACH OF CHILDREN. These are not all the possible side effects of Naltrexone Hydrochloride Tablets, USP. Call your doctor for medical advice about side effects. You may report side effects to Precision Dose, Inc. at 1-800-397-9228 or to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.