Naltrexone

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 to 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.

Treatment of Overdosage

In view of the lack of actual experience in the treatment of REVIA 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.

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 WARNINGS and PRECAUTIONS, Laboratory Tests).

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, 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 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 CONTRAINDICATIONS, WARNINGS, DOSAGE AND ADMINISTRATION).

Reported Adverse Events

REVIA 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 REVIA, 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

Although no causal relationship with REVIA is suspected, physicians should be aware that treatment with REVIA 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 REVIA 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:

Nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath.

Nose bleeds, phlebitis, edema, increased blood pressure, non-specific ECG changes, palpitations, tachycardia.

Excessive gas, hemorrhoids, diarrhea, ulcer.

Painful shoulders, legs or knees; tremors, twitching.

Increased frequency of, or discomfort during, urination; increased or decreased sexual interest.

Oily skin, pruritus, acne, athlete's foot, cold sores, alopecia.

Depression, paranoia, fatigue, restlessness, confusion, disorientation, hallucinations, nightmares, bad dreams.

Eyes-blurred, burning, light sensitive, swollen, aching, strained; ears-“clogged,” aching, tinnitus.

Increased appetite, weight loss, weight gain, yawning, somnolence, fever, dry mouth, head “pounding,” inguinal pain, swollen glands, “side” pains, cold feet, “hot spells.”

Data collected from postmarketing use of REVIA 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 REVIA in ultra rapid opiate detoxification programs. The cause of death in these cases is not known (see WARNINGS).

In 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), 19% (5/26) of REVIA 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 REVIA 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 REVIA (at doses up to 300 mg/day) for 5 to 8 weeks in an open clinical trial.

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.

Read the entire FDA prescribing information for Revia (Naltrexone)

Opiate Dependence

Used as an adjunct to a medically supervised behavior modification program1 35 99 102 147 160 161 162 163 164 165 166 170 in the maintenance of opiate cessation (opiate-free state) in individuals who were formerly physically dependent on opiates and who have successfully undergone detoxification1 14 35 102 143 147 158 162 163 164 165 (designated an orphan drug by FDA for this use).217

Behavior modification is an integral component in maintaining opiate cessation; behavior modification programs involve supervised programs of counseling, psychologic support and therapy, education, and changes in life-style (social rehabilitation).1 2 35 37 102 143 147 159 160 162 170 189 192 193 204

May diminish or eliminate opiate-seeking behavior by blocking opiate euphoria and by preventing the conditioned abstinence syndrome (i.e., heightened sensitivity to stimuli, abnormal autonomic responses, dysphoria, intense opiate craving) that occurs following opiate withdrawal.1 2 27 102 158 190 191

Efficacy in maintaining long-term cessation appears to be low;2 11 14 15 42 123 125 135 161 182 203 poor compliance appears to be the major limiting factor.1 2 8 13 42 99 182 204 Because noncompliance with naltrexone is not associated with unpleasant symptoms of withdrawal, compliance depends more on voluntary efforts; successful cessation may be more likely in highly motivated individuals.1 2 8 13 15 35 36 99 102 130 147 162 163 167 172

Has been used for rapid or ultrarapid detoxification in the management of opiate withdrawal† in opiate-dependent individuals, both in inpatient and outpatient settings.246

Rapid opiate detoxification involves the administration of opiate antagonists (e.g., naltrexone and/or naloxone) to shorten the time period of detoxification.246

Ultrarapid detoxification is similar but involves the administration of opiate antagonists while the patient is sedated or under general anesthesia.246 Consider the risk of adverse respiratory and cardiovascular effects associated with this procedure, as well as the costs of general anesthesia and hospitalization.246

Alcohol Dependence

Management of alcohol dependence in conjunction with a behavior modification program1 232 233 234 235 236 237 247 involving supervised programs of counseling, psychologic support and therapy, and education and changes in life-style (social rehabilitation).1 232 238

Used IM in individuals who are able to abstain from alcohol in an outpatient setting and are abstinent when treatment is initiated.247 249

Behavior modification is an integral component in maintaining alcohol cessation; naltrexone has not been shown to provide any therapeutic benefit except as part of an appropriate plan of addiction management.1 232 234 237 239 245

When used in conjunction with behavior modification, naltrexone reportedly decreases alcohol craving, reduces alcohol consumption, decreases the number of drinking days, maintains abstinence from alcohol ingestion, and prevents, decreases, or ameliorates the severity of relapse.1 232 235 237 238

Naltrexone is not uniformly effective; the expected effect is a modest improvement in the outcome of conventional therapy.1 232 233 244 245

Storage

Oral

20–25°C.1

Parenteral

Store entire dose pack at 2–8°C.247 May be stored at temperatures not >25°C for ≤7 days prior to administration.247 Do not freeze.247

After mixing with diluent, use immediately.247

In the U.S.

• Revia

Available Dosage Forms:

• Tablet

Therapeutic Class: Antidote

Pharmacologic Class: Opioid Antagonist

• Naltrexone Hydrochloride

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension Reconstituted, Intramuscular:

Vivitrol: 380 mg (1 ea)

Tablet, Oral, as hydrochloride:

ReVia: 50 mg [DSC] [scored]

Generic: 50 mg

• Antidote
• Opioid Antagonist

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); naltrexone AUC increased ~5- and 10-fold in patients with compensated or decompensated hepatic cirrhosis respectively.

Liver function tests (baseline and periodic); monitor for opioid withdrawal, injection site reactions with IM administration, and depression and/or suicidal thinking

Adverse events were observed in animal reproduction studies. Information related to the use of naltrexone during pregnancy is limited (Farid 2008). Clinical practice guidelines recommend that if a women being treated with naltrexone for the treatment of opioid use disorder becomes pregnant, naltrexone should be discontinued if the patient and physician agree that the risk of relapse if low. If patient is concerned about relapse and wishes to continue naltrexone, the patient should be informed of the potential risks of continuing treatment and consent for ongoing treatment should be obtained. If naltrexone is discontinued and the patient subsequently relapses, consideration should be given for treatment with methadone or buprenorphine (Kampman [ASAM 2015]).

• When used to treat opioid (narcotic) addiction or dependence, naltrexone blocks the euphoric effects (feelings of well-being) of opioids, so the user gains no psychological benefit from the opioid. It also helps to reduce cravings. Naltrexone will precipitate withdrawal symptoms in people physically dependent on opioids.
• Naltrexone is also used in the treatment of alcohol addiction and has also been shown to improve abstention rates, reduce the number of drinking days, and reduce the risk of relapse. It also reduces alcohol cravings.
• Naltrexone itself does not cause physical or psychological dependence and is not considered a drug of abuse. Tolerance to naltrexone's effect does not appear to occur.
• Apart from its opioid blocking effects and some pupillary constriction (a decrease in the size of the pupil of the eye), naltrexone has few, if any, other reported effects.
• Naltrexone is available in combination with morphine to prevent the misuse of morphine. Naltrexone blocks feelings of well-being that can contribute to the abuse of morphine.

• Peak plasma levels of naltrexone and its active metabolite occur within an hour of oral administration. The duration of naltrexone's effect depends on the dosage of naltrexone. Studies have shown that 50mg of naltrexone will block the effects of 25mg heroin administered intravenously for up to 24 hours; doubling the naltrexone dose extends the blockade to 48 hours.

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