Revia

REVIA® (naltrexone hydrochloride) beige, round, biconvex, film-coated, scored tablet. Debossed with REVIA on one side and with a stylized b/275 on the scored side. Available in bottles of:

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight container.

Duramed Pharmaceuticals, Inc. Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970. Revised:. 10/2013

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.

To reduce the risk of precipitated withdrawal in patients dependent on opioids, or exacerbation of a preexisting 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.

Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone

There are no systematically collected data that specifically address the switch from buprenorphine or methadone to REVIA; however, review of postmarketing case reports have indicated that some patients may experience severe manifestations of precipitated withdrawal when being switched from opioid agonist therapy to opioid antagonist therapy (see WARNINGS). Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers should be prepared to manage withdrawal symptomatically with non-opioid medications.

Treatment of Alcoholism

A dose of 50 mg once daily is recommended for most patients. 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.

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.

Treatment of Opioid Dependence

Treatment should be initiated with an initial dose of 25 mg of REVIA. If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter.

A dose of 50 mg once a day will produce adequate clinical blockade of the actions of parenterally administered opioids. As with many non-agonist treatments for addiction, REVIA is of proven value only when given as part of a comprehensive plan of management that includes some measure to ensure the patient takes the medication.

Naloxone Challenge Test

Clinicians are reminded that 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 if there is any question of occult opioid dependence. If signs of opioid withdrawal are still observed following naloxone challenge, treatment with REVIA should not be attempted. The naloxone challenge can be repeated in 24 hours.

The naloxone challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal, or in a patient whose urine contains opioids. The naloxone challenge test may be administered by either the intravenous or subcutaneous routes.

Intravenous

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.

Subcutaneous

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.

Interpretation of the Challenge

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. Repeat the challenge in 24 hours. If the test is negative, REVIA therapy may be started if no other contraindications are present. If there is any doubt about the result of the test, hold REVIA and repeat the challenge in 24 hours.

Alternative Dosing Schedules

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 WARNINGS).

Patient Compliance

REVIA should be considered as only one of many factors determining the success of treatment. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, including medication compliance.

REVIA is contraindicated in:

1. Patients receiving opioid analgesics.
2. Patients currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine).
3. Patients in acute opioid withdrawal (see WARNINGS).
4. Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids.
5. Any individual with a history of sensitivity to REVIA or any other components of this product. It is not known if there is any cross-sensitivity with naloxone or the phenanthrene containing opioids.

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.

SIDE EFFECTS

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:

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 ECG changes, palpitations, tachycardia.

Gastrointestinal

Excessive gas, hemorrhoids, 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 sores, 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.”

Postmarketing Experience

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).

Laboratory Tests

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.

DRUG INTERACTIONS

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 PRECAUTIONS).

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.

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:

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 ECG changes, palpitations, tachycardia.

Gastrointestinal

Excessive gas, hemorrhoids, 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 sores, 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.”

Postmarketing Experience

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).

Laboratory Tests

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.

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.

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.

Absorption

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.

Distribution

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.

Metabolism

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.

Elimination

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.