Source: Health Products and Food Branch (CA) Revision Year: 2020
REVIA (naltrexone hydrochloride) is contraindicated in:
To prevent occurrence of an acute withdrawalsyndrome,or exacerbation of a preexisting sub-clinical withdrawalsyndrome,patients should remain opioid-free for a minimum of 7-10 days before starting REVIA. Since the absence of an opioid drug in the urine often is not sufficient proof that the patient is opioid-free, a NARCAN" challenge may be required to minimize the possibility of precipitating a withdrawal reaction following administration of REVIA. The NARCAN" challenge test is described in the DOSAGE AND ADMINISTRATION Section.
REVIA (naltrexone hydrochloride) has the capacity to cause dose related hepatocellular injury. Prior to making a decision to initiate treatment with REVIA,the physician should establish whether the patient has subclinicalliver injury or disease (see PRECAUTIONS: Laboratory Tests). REVIA is contraindicated in acute hepatitis or liver failure, and its use even in patients with evidence of less severe liver disease or a history of recent liver disease must be carefully considered in light of its hepatotoxic potential.
The evidence that identified REVIA as a hepatotoxin was not obtained in studies involving its use at the doses recommended for opiate blockade, or for treatment of alcoholdependence (50 mg/day). However, the margin of separation between the apparently safe and the hepatotoxic doses appears to be only five-fold or less.
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/day). In the study, 5 of 26 REVIA recipients developed elevations of serum transaminases (ie, 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 (ie, not an idiosyncratic) hepatotoxin. This conclusion is also supported by evidence from other placebo controlled studies in which exposure to REVIA at doses from one to two-fold the amount recommended for the treatment of alcoholism or opiate blockade (50 mg/day) consistently produced more numerous and more significant elevations of serum transaminase than did placebo, and reports of transaminase elevations in 3 of 9 patients with Alzheimer’s Disease who received REVIA (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.
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 (eg, respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of surmounting the opiate blockade. (See INFORMATION FOR THE CONSUMER.)
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 intoxification (respiratory compromise or arrest, circulatory collapse, etc).
Patients should be aware that they may be more sensitive to lower doses of opioids after naltrexone treatment is discontinued.
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 nonopioid analgesics or general anesthesia. In a situation requiring analgesia which can only be achieved with opioids, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. In such circumstances, 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. No methods to reverse opioid overdose in patient’s receiving naltrexone have been established by clinical trials. However, the use of the opioid antagonist naloxone, should be considered when attempting reversal.
Additionally, non-receptor mediated actions may occur (e.g., facial swelling, itching, generalized erythema, 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 hospital setting equipped and staffed for cardiopulmonary resuscitation.
Patients taking REVIA may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid analgesics. Where a non-opioid containing alternative is available, it should be used.
Severe opioid withdrawal syndromes precipitated by the accidental ingestion of REVIA have been reported in opioid-dependent individuals. 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. In all cases patients were closely monitored and therapy tailored to meet individual requirements.
Use of REVIA does not eliminate or diminish withdrawal symptoms. If REVIA is initiated early in the abstinence process, it will not preclude the patients’s experience of the full range of signs and symptoms that would be experienced if REVIA had not been started. Numerous adverse events are known to be associated with withdrawal.
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: Caution should be exercised when naltrexone hydrochloride is administered to patients with liver disease. An increase in naltrexone AUG 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.
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 (naltrexone hydrochloride) and thioridazine.
The risk of suicide is known to be increased in patients with substance abuse with or without concomitant depression. The risk is not abated by treatment with REVIA (see ADVERSE REACTIONS).
Tests designed to detect hepatic injury should be obtained prior to initiation of REVIA therapy and periodically thereafter (see WARNINGS Section on Hepatotoxicity).
Periodic testing of all patients after initiation of treatment is critical if the occurrence of REVIA induced liver damage is to be detected at the earliest possible time. Evaluations, using appropriate batteries of tests to detect liver injury are recommended on a monthly basis during the first six months of use; thereafter, clinical judgement about the frequency of monitoring must be relied upon.
Laboratory tests which may be used for the separation and detection of morphine, methadone, or quinine in the urine and with which REVIA does not interfere include thin-layer, gas-liquid, and high pressure liquid chromatographic methods.
REVIA (100 mg/kg, approximately 100 times the human therapeutic dose) caused a significant increase in pseudopregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. The relevance of these observations to human fertility is not known.
There are no adequate and well-controlled studies in pregnant women. REVIA should be used in pregnancy only when the potential benefits justify the potential risk to the fetus. Naltrexone hydrochloride has been shown to have embryocidal and fetotoxic effects in rats and rabbits when given in dosages 30 and 60 times, respectively, the human dose.
It is not known whether REVIA affects the duration of labour and delivery.
It is not known whether REVIA is excreted in human milk. Because many drugs are excreted in human milk, REVIA should be administered to a nursing mother only when the potential benefits justify the potential risk to the infant.
The safe use of REVIA in subjects younger than 18 years of age has not been established.
REVIA (naltrexone hydrochloride) 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.
While extensive clinical studies evaluating the use of REVIA (naltrexone hydrochloride) in detoxified, formerly opioid dependent individuals failed to identify any single, serious untoward risk of REVIA use, placebo controlled studies employing up to five-fold higher doses of REVIA (up to 300 mg/day) than that recommended for use in opiate receptor blockade have shown that REVIA caused hepatocellular injury in 5 of 26 patients exposed at this higher dose (see WARNINGS and PRECAUTIONS: Laboratory Tests).
Aside from this finding, however, available evidence does not incriminate REVlA, used at any dose, as a cause of any other serious untoward event for the patient who is “opioid free”. It is critical to recognize that REVIA can precipitate or exacerbate withdrawal signs and symptoms in any individual who is not completely free of exogenous opioids. (see CONTRAINDICATIONS, WARNINGS, DOSAGE AND ADMINISTRATION).
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. (see Individualization of Dosage).
Events Other than Hepatocellular Injury Reported During Clinical Testing: 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, 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 EGG changes, palpitations, tachycardia.
Gastrointestinal: excessive gas, haemorrhoids, 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 sore, 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”.
Data collected from post-marketing 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, elevations in liver enzymes or bilirubin, hepatic function abnormalities or hepatitis, palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia, nervousness, somnolence, abnormal thinking, dyspnea, rash, increased sweating, and vision abnormalities.
Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with REVIA 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. In some individuals the use of opioid antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, or gonadal hormones. The clinical significance of such changes is not fully understood.
With the exception of liver test abnormalities in investigator studies (see WARNINGS, PRECAUTIONS), results of laboratory tests, like adverse reports, have not shown consistent patterns of abnormalities that can be attributed to treatment with REVIA.
In the trials evaluating REVIA for the blockade of opiate receptors, abnormal liver function tests and lymphocytosis were the two most common categories of abnormalities reported. These abnormalities are common among populations of parenteral opioid users and alcoholics. As is the case with the untoward events described above, a large proportion of patients had abnormal tests at baseline, further supporting the conclusion that the abnormalities observed are not attributable to REVIA.
Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitized to REVIA in a previous course of treatment with REVIA. The condition cleared without sequelae after discontinuation of REVIA and corticosteroid treatment.
In two randomized, double-blind placebo controlled 12 week trials to evaluate the efficacy of REVIA as adjunctive treatment of alcohol dependence, a total of 93 patients received REVIA at a dose of 50 mg once daily. The most common (incidence greater than 10%) adverse events associated with the use of REVIA in these trials (incidence at least 5% greater than in patients receiving placebo} were: somnolence, nervousness, vomiting, weight decrease, dry mouth and decreased libido. The incidences of adverse events leading to discontinuation of REVIA in these trials were: vomiting (5%); agitation (2%); insomnia (2%); nervousness (1%); drowsiness (1%); and malaise (1%). Discontinuation rate for headache was 1% for patients on naltrexone and 2% for patients on placebo. No serious adverse events were reported during these two trials.
In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone, the following new onset adverse reactions occurred in 2% or more of the patients:
| Adverse Reaction | Percent (%) |
| Nausea | 10% |
| Headache | 7% |
| Dizziness | 4% |
| Nervousness | 4% |
| Fatigue | 4% |
| Insomnia | 3% |
| Vomiting | 3% |
| Anxiety | 2% |
| Somnolence | 2% |
| Dry Mouth | 2% |
| Dyspepsia | 2% |
In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone, the following adverse events were responsible for discontinuation in ≥1% of patients:
| Adverse Reaction | Incidence of Discontinuation |
| Nausea | 6% |
| Headache< | 3% |
| Dizziness | 3% |
| Anxiety | 2% |
| Nervousness | 2% |
| Fatigue | 1% |
| Vomiting | 1% |
| Depression | 1% |
| Euphoria | 1% |
| Mouth Dry | 1% |
| Insomnia | 1% |
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:
| New Onset Event | Naltrexone | Placebo |
| Depression | 0-15% | 0-17% |
| Suicide Attempt/Ideation | 0-1% | 0-3% |
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).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
