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Revia

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Revia

Warnings
Precautions

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 REVIA wanes and eventually dissipates completely, patients who have been treated with REVIA 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 REVIA 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 PATIENT INFORMATION).

There is also the possibility that a patient who is treated with REVIA could overcome the opioid blockade effect of REVIA. Although REVIA is a potent antagonist, the blockade produced by REVIA 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 PATIENT INFORMATION).

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 REVIA 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 REVIA 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 medications because 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; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use. Patients treated for alcohol dependence with REVIA should also be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with REVIA. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids.

Hepatotoxicity

Cases of hepatitis and clinically significant liver dysfunction were observed in association with REVIA exposure during the clinical development program and in the postmarketing period. Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials and postmarketing period. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury.

Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of REVIA should be discontinued in the event of symptoms and/or signs of acute hepatitis.

Depression and Suicidality

Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with REVIA (naltrexone hydrochloride) used in the treatment of opioid dependence. No causal relationship has been demonstrated. In the literature, endogenous opioids have been theorized to contribute to a variety of conditions.

Alcohol-and opioid-dependent patients, including those taking REVIA, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with REVIA should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient's healthcare provider.

Ultra Rapid Opioid Withdrawal

Safe use of REVIA in ultra rapid opiate detoxification programs has not been established (see ADVERSE REACTIONS).

PRECAUTIONS

General

When Reversal of REVIA Blockade is Required for Pain Management

In an emergency situation in patients receiving fully blocking doses of REVIA, a suggested plan of management is regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics or general anesthesia.

In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.

A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction) presumably due to histamine release.

Irrespective of the drug chosen to reverse REVIA blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

Special Risk Patients

Renal Impairment

REVIA and its primary metabolite are excreted primarily in the urine, and caution is recommended in administering the drug to patients with renal impairment.

Hepatic Impairment

An increase in naltrexone AUC of approximately 5-and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with normal liver function has been reported. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity.

Laboratory Tests

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.

Carcinogenesis, Mutagenesis and Impairment of Fertility

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-β-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/m²/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/m²/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 Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli. However, no evidence of genotoxic potential was observed in a range of other in vitro 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 in vivo mouse micronucleus assay.

Naltrexone (100 mg/kg/day [600 mg/m²/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.

Pregnancy

Teratogenic Effects - Category C

Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥ 30 mg/kg/day (180 mg/m²/day; 5 times the recommended therapeutic dose, based on body surface area) and to rabbits at oral doses ≥ 60 mg/kg/day (720 mg/m²/day; 18 times the recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (32 and 65 times the recommended therapeutic dose, respectively, based on body surface area).

Rats do not form appreciable quantities of the major human metabolite, 6-β-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known.

There are no adequate and well-controlled studies in pregnant women. REVIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

Whether or not REVIA affects the duration of labor and delivery is unknown.

Nursing Mothers

In animal studies, naltrexone and 6-β-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone. Whether or not REVIA is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when REVIA is administered to a nursing woman.

Pediatric Use

The safe use of REVIA in pediatric patients younger than 18 years old has not been established.

Last reviewed on RxList: 10/21/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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