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 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 include but are not limited to: nausea, vomiting, dysphoria, yawning, sweating, tearing, rhinorrhea, stuffy nose, craving for opioids, poor appetite, abdominal cramps, sense of fear, skin erythema, disrupted sleep patterns, fidgeting, uneasiness, poor ability to focus, mental lapses, muscle aches or cramps, pupillary dilation, piloerection, fever, changes in blood pressure, pulse or temperature, anxiety, depression, irritability, backache, bone or joint pains, tremors, sensations of skin crawling, or fasciculations. If signs or symptoms of withdrawal appear, the test is positive and no additional naloxone should be administered. Warning: If the test is positive, do NOT initiate naltrexone hydrochloride therapy. Repeat the challenge in 24 hours. If the test is negative, naltrexone hydrochloride therapy may be started if no other contraindications are present. If there is any doubt about the result of the test, hold naltrexone hydrochloride and repeat the challenge in 24 hours. Alternative Dosing Schedules A flexible approach to a dosing regimen may need to be employed in cases of supervised administration. Thus, patients may receive naltrexone hydrochloride tablets 50 mg every weekday with a 100 mg dose on Saturday, 100 mg every other day, or 150 mg every third day. The degree of blockade produced by naltrexone hydrochloride may be reduced by these extended dosing intervals. There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits (see WARNINGS .) Patient Compliance Naltrexone hydrochloride should be considered as only one of many factors determining the success of treatment. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, including medication compliance.

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 hydrochloride clinical trials in opioid addiction at an incidence rate of more than 10%: Difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint and muscle pain, and headache. The incidence was less than 10% for: Loss of appetite, diarrhea, constipation, increased thirst, increased energy, feeling down, irritability, dizziness, skin rash, delayed ejaculation, decreased potency, and chills. The following events occurred in less than 1% of subjects: Respiratory: Nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath. Cardiovascular: Nose bleeds, phlebitis, edema, increased blood pressure, non-specific ECG changes, palpitations, tachycardia. Gastrointestinal: Excessive gas, hemorrhoids, diarrhea, ulcer. Musculoskeletal: Painful shoulders, legs or knees; tremors, twitching. Genitourinary: Increased frequency of, or discomfort during, urination; increased or decreased sexual interest. Dermatologic: Oily skin, pruritus, acne, athlete's foot, cold sores, alopecia. Psychiatric: Depression, paranoia, fatigue, restlessness, confusion, disorientation, hallucinations, nightmares, bad dreams. Special senses: Eyes-blurred, burning, light sensitive, swollen, aching, strained; ears-“clogged”, aching, tinnitus. General: Increased appetite, weight loss, weight gain, yawning, somnolence, fever, dry mouth, head“pounding”, inguinal pain, swollen glands,“side” pains, cold feet,“hot spells.” Postmarketing Experience Data collected from postmarketing use of naltrexone hydrochloride show that most events usually occur early in the course of drug therapy and are transient. It is not always possible to distinguish these occurrences from those signs and symptoms that may result from a withdrawal syndrome. Events that have been reported include anorexia, asthenia, chest pain, fatigue, headache, hot flushes, malaise, changes in blood pressure, agitation, dizziness, hyperkinesia, nausea, vomiting, tremor, abdominal pain, diarrhea, palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia, nervousness, somnolence, abnormal thinking, dyspnea, rash, increased sweating, vision abnormalities, and idiopathic thrombocytopenic purpura. In some individuals the use of opioid antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of such changes is not fully understood. Adverse events, including withdrawal symptoms and death, have been reported with the use of naltrexone hydrochloride in ultra rapid opiate detoxification programs. The cause of death in these cases is not known (see WARNINGS ). Laboratory Tests In 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), 19% (5/26) of naltrexone hydrochloride recipients and 0% (0/24) of placebo-treated patients developed elevations of serum transaminases (i.e., peak ALT values ranging from 121 to 532; or 3 to 19 times their baseline values) after three to eight weeks of treatment. 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. Transaminase elevations were also observed in other placebo controlled studies in which exposure to naltrexone hydrochloride at doses above the amount recommended for the treatment of alcoholism or opioid blockade consistently produced more numerous and more significant elevations of serum transaminases than did placebo. Transaminase elevations occurred 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.

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 )

HOW SUPPLIED Product: 50090-4925 NDC: 50090-4925-0 30 TABLET, FILM COATED in a BOTTLE