Revia Information
Revia ()
Revia () Description
Revia () (naltrexone hydrochloride), an opioid antagonist, is 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. Revia () is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone.
Revia () is a white, crystalline compound. The hydrochloride salt is soluble in water to the extent of about 100 mg/mL. Revia () is available in scored film-coated tablets containing 50 mg of naltrexone hydrochloride.
Revia () Tablets also contain: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, synthetic red iron oxide, synthetic yellow iron oxide and titanium dioxide.
Revia () Clinical Pharmacology
Revia () is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids.
When co-administered 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.
Revia () Indications And Usage
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.
Revia () Contraindications
Revia () is contraindicated in:
Revia () Warnings
Hepatotoxicity
Revia () has the capacity to cause hepatocellular injury when given in excessive doses.
Revia () 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 Revia () and the dose causing hepatic injury appears to be only five-fold or less. Revia () 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 Revia () and seek medical attention if they experience symptoms of acute hepatitis.
Evidence of the hepatotoxic potential of Revia () is derived primarily from a placebo controlled study in which Revia () 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 Revia () 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 Revia () is a direct (i.e., not idiosyncratic) hepatotoxin.
This conclusion is also supported by evidence from other placebo controlled studies in which exposure to Revia () 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 Revia () (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 Revia () 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 Revia () as they would other drugs with the potential for causing hepatic injury.
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 Revia () . 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 Revia () . The naloxone challenge test is described in the section.
While Revia () is a potent antagonist with a prolonged pharmacologic effect (24 to 72 hours), the blockade produced by Revia () 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). (see , ).
There is also the possibility that a patient who had 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.).
Revia () Precautions
It is recommended that the prescribing physician relate the following information to patients being treated with Revia () :
You have been prescribed Revia () as part of the comprehensive treatment for your alcoholism or drug dependence. You should carry identification to alert medical personnel to the fact that you are taking Revia () . A Revia () medication card may be obtained from your physician and can be used for this purpose. Carrying the identification card should help to ensure that you can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the treating physician that you are receiving Revia () therapy.
You should take Revia () as directed by your physician. If you attempt to self-administer heroin or any other opiate drug, in small doses while on Revia () , you will not perceive any effect.
Revia () is well-tolerated in the recommended doses, but may cause liver injury when taken in excess or in people who develop liver disease from other causes. If you develop abdominal pain lasting more than a few days, white bowel movements, dark urine, or yellowing of your eyes, you should stop taking Revia () immediately and see your doctor as soon as possible.
A high index of suspicion for drug-related hepatic injury is critical if the occurrence of liver damage induced by Revia () (naltrexone hydrochloride) is to be detected at the earliest possible time. Evaluations, using appropriate batteries of tests to detect liver injury are recommended at a frequency appropriate to the clinical situation and the dose of Revia () .
Revia () does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone or quinine in the urine. Revia () may or may not interfere with enzymatic methods for the detection of opioids depending on the specificity of the test. Please consult the test manufacturer for specific details.
Studies to evaluate possible interactions between Revia () and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of Revia () and other drugs is required.
The safety and efficacy of concomitant use of Revia () 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 Revia () and thioridazine.
Patients taking Revia () 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 Revia () , the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see ).
The following statements are based on the results of experiments in mice and rats. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-ß-naltrexol are unknown.
In a two-year carcinogenicity study in rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (600 mg/m/day; 16 times the recommended therapeutic dose, based on body surface area) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day (600 mg/m/day) was 4%, but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice.
There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the recessive lethal assay, and in non-specific DNA repair tests with . However, no evidence of genotoxic potential was observed in a range of other tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an mouse micronucleus assay.
Naltrexone (100 mg/kg/day [600 mg/m/day] PO; 16 times the recommended therapeutic dose, based on body surface area) caused a significant increase in pseudopregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.
Revia () Adverse Reactions
During two randomized, double-blind placebo-controlled 12-week trials to evaluate the efficacy of Revia () as an adjunctive treatment of alcohol dependence, most patients tolerated Revia () well. In these studies, a total of 93 patients received Revia () at a dose of 50 mg once daily. Five of these patients discontinued Revia () because of nausea. No serious adverse events were reported during these two trials.
While extensive clinical studies evaluating the use of Revia () in detoxified, formerly opioid-dependent individuals failed to identify any single, serious untoward risk of Revia () use, placebo-controlled studies employing up to fivefold higher doses of Revia () (up to 300 mg per day) than that recommended for use in opiate receptor blockade have shown that Revia () causes hepatocellular injury in a substantial proportion of patients exposed at higher doses (see and , ).
Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence does not incriminate Revia () , 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 Revia () 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, . 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 Revia () .
Among opioid-free individuals, Revia () 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, Revia () may cause serious withdrawal reactions (see , , ).
Revia () Drug Abuse And Dependence
Revia () is a pure opioid antagonist. It does not lead to physical or psychological dependence. Tolerance to the opioid antagonist effect is not known to occur.
Revia () Overdosage
There is limited clinical experience with Revia () overdosage in humans. In one study, subjects who received 800 mg daily Revia () for up to one week showed no evidence of toxicity.
In the mouse, rat and guinea pig, the oral LD50s were 1,100-1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of Revia () (generally ≥1,000 mg/kg) produced salivation, depression/reduced activity, tremors, and convulsions. Mortalities in animals due to high-dose Revia () administration usually were due to clonic-tonic convulsions and/or respiratory failure.
Revia () Dosage And Administration
IF THERE IS ANY QUESTION OF OCCULT OPIOID DEPENDENCE, PERFORM A NALOXONE CHALLENGE TEST AND DO NOT INITIATE Revia () THERAPY UNTIL THE NALOXONE CHALLENGE IS NEGATIVE.
A dose of 50 mg once daily is recommended for most patients (see ). The placebo-controlled studies that demonstrated the efficacy of Revia () as an adjunctive treatment of alcoholism used a dose regimen of Revia () 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not evaluated in these trials.
A patient is a candidate for treatment with Revia () if:
Refer to , , and Sections for additional information.
Revia () 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 Revia () 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.
Initiate treatment with Revia () using the following guidelines
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.
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.
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 Revia () therapy.
Once the patient has been started on Revia () , 50 mg every 24 hours will produce adequate clinical blockade of the actions of parenterally administered opioids (i.e., this dose will block the effects of a 25 mg intravenous heroin challenge). A flexible approach to a dosing regimen may need to be employed in cases of supervised administration. Thus, patients may receive 50 mg of Revia () 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 Revia () 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 and .
Revia () How Supplied
Revia () (naltrexone hydrochloride) beige, round, biconvex, film-coated, scored tablet. Debossed with Revia () on one side and with a stylized /275 on the scored side.
Available in bottles of:
Store at 20° to 25°C (68° to 77°F)[See USP Controlled Room Temperature].
Dispense in a tight container.
Issued FEBRUARY 200911001437
BR-275
Revia () Principal Display Panel
NDC 51285-275-01
Revia () ®
(naltrexone hydrochloride tablets, USP)
50 mg
30 Tablets
Unit-of-Use
Duramed
Rx only
