Revia

Before taking naltrexone,

• tell your doctor and pharmacist if you are allergic to naltrexone naloxone, other opioid medications, or any other medications.
• tell your doctor if you are taking any opioid (narcotic) medications or street drugs including levomethadyl acetate (LAAM, ORLAAM) (not available in the US), or methadone (Dolophine, Methadose); and certain medications for diarrhea, cough, or pain. Also tell your doctor if you have taken any of these medications in the past 7 to 10 days. Ask your doctor if you are not sure if a medication you have taken is an opioid. Your doctor may order certain tests to see if you have taken any opioid medications or used any opioid street drugs during the past 7 to 10 days. Your doctor will tell you not to take naltrexone if you have taken or used opioids in the past 7 to 10 days.
• do not take any opioid medications or use opioid street drugs during your treatment with naltrexone. Naltrexone blocks the effects of opioid medications and opioid street drugs. You may not feel the effects of these substances if you take or use them at low or normal doses. If you take or use higher doses of opioid medications or drugs during your treatment with naltrexone, it may cause serious injury, coma (long-lasting unconscious state), or death.
• you should know that if you took opioid medications before your treatment with naltrexone, you may be more sensitive to the effects of these medications after you finish your treatment. After you finish your treatment, tell any doctor who may prescribe medications for you that you were previously treated with naltrexone.
• tell your doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention disulfiram (Antabuse) and thioridazine. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had depression or kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking naltrexone, call your doctor.
• if you need medical treatment or surgery, including dental surgery, tell the doctor or dentist that you are taking naltrexone. Wear or carry medical identification so that healthcare providers who treat you in an emergency will know that you are taking naltrexone.
• you should know that people who overuse drugs or alcohol often become depressed and sometimes try to harm or kill themselves. Receiving naltrexone does not decrease the risk that you will try to harm yourself. You or your family should call the doctor right away if you experience symptoms of depression such as feelings of sadness, anxiousness, hopelessness, guilt, worthlessness, or helplessness, or thinking about harming or killing yourself or planning or trying to do so. Be sure that your family knows which symptoms may be serious so they can call the doctor right away if you are unable to seek treatment on your own.

Unless your doctor tells you otherwise, continue your normal diet.

REVIA is indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids.

REVIA has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions.

Pharmacodynamic Actions

REVIA 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, REVIA blocks the physical dependence to morphine, heroin and other opioids.

REVIA 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 REVIA is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, REVIA will precipitate withdrawal symptomatology.

Clinical studies indicate that 50 mg of REVIA 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 REVIA provides blockade for 48 hours, and tripling the dose of REVIA provides blockade for about 72 hours.

REVIA 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 REVIA in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. REVIA, 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 REVIA has been shown to reduce alcohol consumption in clinical studies.

REVIA is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.

Pharmacokinetics

REVIA 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 6β-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-½) 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 Cmax over the range of 50 to 200 mg and do not accumulate after 100 mg daily doses.

Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the gastrointestinal tract. Peak plasma levels of both naltrexone and 6-β-naltrexol occur within one hour of dosing.

The volume of distribution for naltrexone following intravenous administration is estimated to be 1350 liters. In vitro tests with human plasma show naltrexone to be 21% bound to plasma proteins over the therapeutic dose range.

The systemic clearance (after intravenous administration) of naltrexone is ~3.5 L/min, which exceeds liver blood flow (~1.2 L/min). This suggests both that naltrexone is a highly extracted drug ( > 98% metabolized) and that extrahepatic sites of drug metabolism exist. The major metabolite of naltrexone is 6-β-naltrexol. Two other minor metabolites are 2-hydroxy-3-methoxy-6-β-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone and its metabolites are also conjugated to form additional metabolic products.

The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration. In comparison, the renal clearance for 6β-naltrexol ranges from 230 to 369 mL/min, suggesting an additional renal tubular secretory mechanism. The urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose; urinary excretion of unchanged and conjugated 6-β-naltrexol accounts for 43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that naltrexone and its metabolites may undergo enterohepatic recycling.

Hepatic and Renal Impairment

Naltrexone appears to have extra-hepatic sites of drug metabolism and its major metabolite undergoes active tubular secretion (see Metabolism above). Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted (see PRECAUTIONS, Special Risk Patients).

Clinical Trials

The efficacy of REVIA as an aid to the treatment of alcoholism was tested in placebo-controlled, outpatient, double blind trials. These studies used a dose of REVIA 50 mg once daily for 12 weeks as an adjunct to social and psychotherapeutic methods when given under conditions that enhanced patient compliance. Patients with psychosis, dementia, and secondary psychiatric diagnoses were excluded from these studies.

In one of these studies, 104 alcohol-dependent patients were randomized to receive either REVIA 50 mg once daily or placebo. In this study, REVIA proved superior to placebo in measures of drinking including abstention rates (51% vs. 23%), number of drinking days, and relapse (31% vs. 60%). In a second study with 82 alcohol-dependent patients, the group of patients receiving REVIA were shown to have lower relapse rates (21% vs. 41%), less alcohol craving, and fewer drinking days compared with patients who received placebo, but these results depended on the specific analysis used.

The clinical use of REVIA as adjunctive pharmacotherapy for the treatment of alcoholism was also evaluated in a multicenter safety study. This study of 865 individuals with alcoholism included patients with comorbid psychiatric conditions, concomitant medications, polysubstance abuse and HIV disease. Results of this study demonstrated that the side effect profile of REVIA appears to be similar in both alcoholic and opioid dependent populations, and that serious side effects are uncommon.

In the clinical studies, treatment with REVIA supported abstinence, prevented relapse and decreased alcohol consumption. In the uncontrolled study, the patterns of abstinence and relapse were similar to those observed in the controlled studies. REVIA was not uniformly helpful to all patients, and the expected effect of the drug is a modest improvement in the outcome of conventional treatment.

REVIA has been shown to produce complete blockade of the euphoric effects of opioids in both volunteer and addict populations. When administered by means that enforce compliance, it will produce an effective opioid blockade, but has not been shown to affect the use of cocaine or other non-opioid drugs of abuse.

There are no data that demonstrate an unequivocally beneficial effect of REVIA on rates of recidivism among detoxified, formerly opioid-dependent individuals who self-administer the drug. The failure of the drug in this setting appears to be due to poor medication compliance.

The drug is reported to be of greatest use in good prognosis opioid addicts who take the drug as part of a comprehensive occupational rehabilitative program, behavioral contract, or other compliance-enhancing protocol. REVIA, unlike methadone or LAAM (levoalpha-acetyl-methadol), does not reinforce medication compliance and is expected to have a therapeutic effect only when given under external conditions that support continued use of the medication.

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For alcoholism:
    • Adults—50 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.
  • For narcotic addiction:
    • Adults—At first, 25 milligrams (mg) (one-half tablet) for the first dose, then another 25 mg 1 hour later. After that, the dose is 350 mg per week. Your doctor will direct you to divide up this weekly dose and take naltrexone according to one of the following schedules:
      • 50 mg (one tablet) every day; or
      • 50 mg a day during the week and 100 mg (two tablets) on Saturday; or
      • 100 mg every other day; or
      • 150 mg every 3 days.
    • Children—Use and dose must be determined by your doctor.

ReVia is part of the drug class:

• Drugs used in alcohol dependence

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.

Naltrexone will block the effects of any narcotic medicines you take (such as prescription medicine for pain, cough, or diarrhea). Harmful side effects could also occur.

Other drugs may interact with naltrexone, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Revia® (naltrexone hydrochloride tablets USP) is available as:

50 mg: Beige, round, biconvex, film-coated, scored tablet, debossed with Revia on one side and stylized b/275 on the scored side. Available in bottles of 30 (unit-of-use).

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 OF THE REACH OF CHILDREN.

Teva Select Brands

Horsham, PA 19044

Division of Teva Pharmaceuticals USA

Iss. 10/2013

Revia® (naltrexone hydrochloride tablets USP) 50 mg 30 Tablets Unit-of-Use Label Text

NDC 51285-275-01

Revia®
(naltrexone hydrochloride tablets USP)

50 mg

30 Tablets
Unit-of-Use

TEVA

Rx only