Revia (Naltrexone HCl)

REVIA®

DuPont Pharma

Naltrexone HCl

Opioid Antagonist

Action And Clinical Pharmacology: Pharmacodynamic Actions: Naltrexone is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of i.v. administered opioids. [In this context, the term opioid is used to describe 1) classic morphine-like agonists and 2) analgesics possessing agonist and antagonist activity (e.g., butorphanol, nalbuphine and pentazocine).]

When coadministered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine and presumably other opioids. Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.

While the mechanism of action is not fully understood, the preponderance of evidence suggests that naltrexone 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 naltrexone in the treatment of alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone, 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 naltrexone has been shown to reduce alcohol consumption in clinical studies.

Naltrexone is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.

The administration of naltrexone is not associated with the development of tolerance or dependence.

In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology.

Clinical studies indicate that 50 mg of naltrexone will block the pharmacologic effects of 25 mg of i.v. administered heroin for periods as long as 24 hours. Other data suggest that doubling the dose of naltrexone provides blockade for 48 hours, and tripling the dose of naltrexone provides blockade for about 72 hours.

Pharmacokinetics/ Bioavailability: Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the gastrointestinal tract. Although well absorbed orally, naltrexone is subject to extensive “first-pass” hepatic metabolism with an oral bioavailability estimate ranging from 5 to 40%. The activity of naltrexone is believed to be due to both parent and the 6-b-naltrexol metabolite.

Following the administration of 50 mg naltrexone tablets to 24 healthy adult male volunteers, the Cmax for naltrexone and its major metabolite, 6-b-naltrexol were 8.6 ng/mL and 99.3 ng/mL, respectively. The maximum concentration (Cmax) and area under the curve (AUC), for both naltrexone and 6-b-naltrexol are dose proportional over the range of 50 to 200 mg. The time to maximum concentration (Tmax) is 1 hour for both naltrexone and 6-b-naltrexol. The mean elimination half-life (T1/2) values for naltrexone and 6-b-naltrexol are 4 hours and 12.9 hours, respectively. The mean elimination half-life (T1/2) and time to maximum concentration (Tmax) for naltrexone and 6-b-naltrexol are independent of dose.

The volume of distribution for naltrexone following i.v. administration is estimated to be 1 350 L. In vitro tests with human plasma show naltrexone to be 21% bound to plasma protein over the therapeutic dose range.

The systemic clearance (after i.v. administration) of naltrexone approximates 3.5 L/min, which exceeds liver blood flow (Þsl1.35 L/min), and suggests that naltrexone is a highly extracted drug (>98% metabolized) and that extrahepatic sites of drug metabolism exist. The major metabolite of naltrexone is 6-b-naltrexol. Two other minor metabolites are 2-hydroxy-3-methoxy-6-b-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone and its metabolites are also conjugated to form additional metabolic products. A renal clearance ranging from 30 to 127 mL/min for naltrexone suggests it is primarily cleared by glomerular filtration. A renal clearance of 230 to 369 mL/min for 6-b-naltrexol suggests an additional renal tubular secretory mechanism. Naltrexone and its metabolites are excreted primarily by the kidney (56 to 79% of the dose), with fecal excretion being a minor elimination pathway. The urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose; urinary excretion of unchanged and conjugated 6-b-naltrexol accounts for approximately 43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that naltrexone and its metabolites undergo enterohepatic recycling.

Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted; however, a recent preliminary communication stated that naltrexone bioavailability is increased in patients with liver cirrhosis as compared to healthy subjects.

Clinical Trials: Treatment of Narcotic Addiction: Naltrexone has been shown to produce complete blockade of the euphoric effects of opioids in both volunteer and addict populations. When administered by means that enforce compliance, it will produce an effective opioid blockade, but has not been shown to affect the use of cocaine or other nonopioid drugs of abuse.

The drug is reported to be of greatest use in good prognosis narcotic addicts who take the drug as part of a comprehensive occupational rehabilitative program, behavioral contract, or other compliance enhancing protocols.

Alcoholism: The efficacy of naltrexone as an aid to the treatment of alcoholism was tested in placebo-controlled, outpatient, double-blind trials. These studies used a dose of naltrexone 50 mg once daily for 12 weeks as an adjunct to social and psychotherapeutic methods. Patients with psychosis, dementia, and secondary psychiatric diagnosis were excluded from these studies.

In one of these studies, 104 alcohol-dependent patients were randomized to receive either naltrexone 50 mg once daily or placebo. In this study, naltrexone proved superior to placebo in measures of drinking including abstention rates (51 vs 23%), number of drinking days, and relapse rates (31 vs 60%). In a second study with 82 alcohol-dependent patients, the group of patients receiving naltrexone were shown to have lower relapse rates (21 vs 41%), less alcohol craving, and fewer drinking days compared with patients who received placebo.

The clinical use of naltrexone as adjunctive pharmacotherapy for the treatment of alcoholism was also evaluated in a multicentre safety study. This study of 865 individuals with alcoholism included patients with comorbid psychiatric conditions, concomitant medications, polysubstance abuse and HIV disease. Results of this study demonstrated that the side-effect profile of naltrexone appears to be similar in both alcoholic and opioid dependent populations.

Naltrexone was not uniformly helpful to all patients, and the expected effect of the drug is a modest improvement in the outcome of conventional treatment.

Indications And Clinical Uses: To provide blockade of the pharmacologic effects of exogenously administered opioids as an adjunct to the maintenance of the opioid-free state in detoxified, formerly opioid-dependent individuals. There are no data that demonstrate an unequivocally beneficial effect of naltrexone on the rates of recidivism among detoxified formerly opioid-dependent individuals who self-administer the drug. Naltrexone is expected to have a therapeutic effect only when given under conditions that support continued use of the medication.

Naltrexone is indicated in the treatment of alcohol dependence, as a component of a comprehensive psychotherapeutic or psychological alcoholism counselling program to support abstinence, and reduce the risk of relapse. The efficacy of naltrexone beyond 12 weeks of treatment has not been established.

Contra-Indications: Patients receiving opioid analgesics. Opioid dependent patients. Patients in acute opioid withdrawal (see Warnings). Any individual who has failed to pass the Narcan challenge (see Dosage). Any individual who has a positive urine screen for opioids. Any individual with a history of sensitivity to naltrexone. It is not known if there is any cross-sensitivity with naloxone or other phenanthrene containing opioids.

Any individual with acute hepatitis or liver failure.

Manufacturers’ Warnings In Clinical States: Unintended Precipitation of Withdrawal: To prevent occurrence of an acute withdrawal syndrome, or exacerbation of a pre-existing subclinical withdrawal syndrome, patients should remain opioid-free for a minimum of 7 to 10 days before starting naltrexone. 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 naltrexone. The Narcan challenge test is described in the Dosage Section.

Hepatotoxicity: Naltrexone has the capacity to cause dose related hepatocellular injury. Prior to making a decision to initiate treatment with naltrexone, the physician should establish whether the patient has subclinical liver injury or disease (see Precautions, Laboratory Tests). Naltrexone 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 naltrexone as a hepatotoxin was not obtained in studies involving its use at the doses recommended for opiate blockade, or for treatment of alcohol dependence (50 mg/day). However, the margin of separation between the apparently safe and the hepatotoxic doses appears to be only 5-fold or less.

Patients should be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek medical attention if they experience symptoms of acute hepatitis.

Evidence of naltrexone’s hepatotoxic potential is derived primarily from a placebo controlled study in which naltrexone was administered to obese subjects at a dose approximately 5-fold that recommended for the blockade of opiate receptors (300 mg/day). In the study, 5 of 26 naltrexone 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 3 to 8 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 naltrexone is a direct (i.e., not an idiosyncratic) hepatotoxin. This conclusion is also supported by evidence from other placebo controlled studies in which exposure to naltrexone at doses from 1-to 2-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 naltrexone (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 naltrexone 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 naltrexone as they would other drugs with the potential for causing hepatic injury.

Self-Administration of Exogenous Opiates: While naltrexone is a potent antagonist with a prolonged pharmacologic effect (24 to 72 hours), the blockade produced by naltrexone 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). Also, lesser amounts of exogenous opioids may prove dangerous if they are taken in a manner (i.e., relatively long after the last dose of naltrexone) and in an amount so that they persist in the body longer than effective concentrations of naltrexone and its metabolites. Patients should be told of the serious consequences of surmounting the opiate blockade (see Information for the Patient).

Precautions General: Emergency Pain Management in Patients Receiving Fully Blocking Doses of Naltrexone: In an emergency situation in patients receiving fully blocking doses of naltrexone, 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 patients receiving naltrexone have been established by clinical trials. However, the use of the opioid antagonist naloxone, should be considered when attempting reversal.

Additionally, nonreceptor mediated actions may occur (e.g., facial swelling, itching, generalized erythema, presumably due to histamine release). Irrespective of the drug chosen to reverse naltrexone blockade, the patient should be monitored closely by appropriately trained personnel in a hospital setting equipped and staffed for cardiopulmonary resuscitation.

Interference with the Action of Narcotic Containing Drug Product: Patients taking naltrexone may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid analgesics. Where a nonopioid containing alternative is available, it should be used.

Actions Suggested when Withdrawal is Accidently Precipitated with Naltrexone: Severe opioid withdrawal syndromes precipitated by the accidental ingestion of naltrexone have been reported in opioid-dependent individuals. Symptoms of withdrawal have usually appeared within 5 minutes of ingestion of naltrexone 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 i.v. fluid administration. In all cases patients were closely monitored and therapy tailored to meet individual requirements.

Hepatic-Renal Failure: Since naltrexone is extensively metabolized by the liver and excreted predominantly in the urine, caution should be observed in administering the drug to patients with impaired hepatic or renal function.

Drug Interactions: Studies to evaluate possible interactions between naltrexone and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of naltrexone and other drugs is required.

The safety and efficacy of concomitant use of naltrexone and disulfiram is unknown, and the concomitant use of 2 potentially hepatotoxic medications is not ordinarily recommended unless the probable benefits outweigh the known risks.

Lethargy and somnolence have been reported following doses of naltrexone and thioridazine.

Suicide: 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 naltrexone (see Adverse Effects).

Laboratory Tests: Tests designed to detect hepatic injury should be obtained prior to initiation of naltrexone therapy and periodically thereafter (see Warnings, Hepatotoxicity).

Periodic testing of all patients after initiation of treatment is critical if the occurrence of naltrexone 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 6 months of use; thereafter, clinical judgment 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 naltrexone does not interfere include thin-layer, gas-liquid, and high pressure liquid chromatographic methods.

Impairment of Fertility: Naltrexone (100 mg/kg, approximately 140 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.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Naltrexone should be used in pregnancy only when the potential benefits justify the potential risk to the fetus.

Labor and Delivery: It is not known whether naltrexone affects the duration of labor and delivery.

Lactation: It is not known whether naltrexone is excreted in human milk. Because many drugs are excreted in human milk, naltrexone should be administered to a nursing mother only when the potential benefits justify the potential risk to the infant.

Children: The safe use of naltrexone in subjects younger than 18 years of age has not been established.

Adverse Reactions: While extensive clinical studies evaluating the use of naltrexone in detoxified, formerly opioid dependent individuals failed to identify any single, serious untoward risk of naltrexone use, placebo controlled studies employing up to 5-fold higher doses of naltrexone (up to 300 mg/day) than that recommended for use in opiate receptor blockade have shown that naltrexone causes 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 naltrexone, 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 naltrexone can precipitate or exacerbate withdrawal signs and symptoms in any individual who is not completely free of exogenous opioids (see Contraindications, Warnings and Dosage).

Opioid Withdrawal-like Symptoms: 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).

Narcotic Addiction: Events Other than Hepatocellular Injury Reported During Clinical Testing: The following adverse reactions have been reported both at baseline and during the naltrexone clinical trials in narcotic 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, nonspecific 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 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”.

Other: Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of narcotic dependence. No causal relationship has been demonstrated.

Laboratory Tests: With the exception of liver test abnormalities in investigator studies (see Warnings and Precautions), results of laboratory tests, like adverse reports, have not shown consistent patterns of abnormalities that can be attributed to treatment with naltrexone.

In the trials evaluating naltrexone 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 naltrexone.

Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitized to naltrexone in a previous course of treatment with naltrexone. The condition cleared without sequelae after discontinuation of naltrexone and corticosteroid treatment.

Alcoholism: In two randomized, double-blind placebo controlled 12-week trials to evaluate the efficacy of naltrexone as adjunctive treatment of alcohol dependence, a total of 93 patients received naltrexone at a dose of 50 mg once daily. The most common (incidence greater than 10%) adverse events associated with the use of naltrexone 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 naltrexone 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 2 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: 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 ³ 1% of patients: nausea (6%); headache (3%); dizziness (3%); anxiety (2%); nervousness (2%); fatigue (1%); vomiting (1%); depression (1%); euphoria (1%); mouth dry (1%); insomnia (1%).

Depression (up to 6%), suicidal ideation/attempted suicide (up to 2%) have been reported in individuals on naltrexone, placebo and in concurrent control groups undergoing treatment for alcoholism. Although no causal relationship with naltrexone is suspected, physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in these patients (see Precautions).

Drug Abuse and Dependence: Naltrexone 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.

Symptoms And Treatment Of Overdose: Symptoms: There is limited clinical experience with naltrexone overdosage in humans. In one study, subjects who received 800 mg daily of naltrexone for up to 1 week showed no evidence of toxicity.

Treatment: Consideration should be given to contacting a Poison Control Centre for the most up-to-date information. In view of the lack of actual experience in the treatment of naltrexone overdose, patients should be treated symptomatically in a closely supervised environment.

Dosage And Administration: Initiation of Naltrexone Therapy: Do not attempt treatment with naltrexone unless, in the medical judgment of the prescribing physician, there is no reasonable possibility of opioid use within the past 7 to 10 days. If there is any question of occult opioid dependence, perform a Narcan challenge test and do not attempt to initiate naltrexone therapy until Narcan challenge is negative (see below).

Treatment of Narcotic Dependence: Initiate treatment with naltrexone using the following guidelines:

1. Treatment should not be attempted until the patient has remained opioid-free for 7 to 10 days. Self-reporting of abstinence from opioids should be verified by analysis of the patient’s urine for absence of opioids. The patient should not be manifesting withdrawal signs or reporting withdrawal symptoms.

2. If there is any question of occult opioid dependence perform a Narcan challenge test (see below). If signs of opioid withdrawal are still observed following Narcan challenge, treatment with naltrexone should not be attempted. The Narcan challenge can be repeated in 24 hours.

3. Treatment should be initiated carefully, slowly increasing the dose of naltrexone administered. This can be accomplished by administration of 25 mg of naltrexone initially. The patient should be observed for 1 hour. If no withdrawal signs occur, the patient may be given the rest of the daily dose.

Once the patient has been started on naltrexone, 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 i.v. heroin challenge). A flexible approach to a dosing regimen may be employed in cases of supervised administration. Thus, patients may receive 50 mg of naltrexone every weekday with a 100 mg dose on Saturday or patients may receive 100 mg every other day, or 150 mg every third day. While the degree of opioid blockade may be somewhat reduced by using higher doses at longer dosing intervals, improved patient compliance may result from dosing every 48 to 72 hours.

Several of the clinical studies reported in the literature have employed the following dosing regimen: 100 mg on Monday, 100 mg on Wednesday, and 150 mg on Friday. This dosing schedule appeared to be acceptable to many naltrexone patients successfully maintaining their opioid-free state.

Treatment of Alcoholism: A dose of 50 mg once daily is recommended.

Naltrexone should be used as part of a comprehensive treatment program for alcohol dependence. Factors associated with a good outcome include: 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.

The efficacy of naltrexone beyond 12 weeks of treatment has not been established.

Narcan Challenge Test: The Narcan 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 Narcan challenge test may be administered by either the i.v. or s.c. routes.

I.V. Challenge: Following appropriate screening of the patient, 2 mL (0.8 mg) of Narcan (0.4 mg/mL), should be drawn into a sterile syringe. If the i.v. route of administration is selected, 0.5 mL (0.2 mg) of Narcan should be injected, and while the needle is still in the patient’s vein, the patient should be observed for 30 seconds for evidence of withdrawal signs or symptoms. If there is no evidence of withdrawal, the remaining 1.5 mL (0.6 mg) of Narcan should be injected, and the patient observed for an additional period of 20 minutes for signs and symptoms of withdrawal.

S.C. Challenge: If the s.c. route is selected, 2 mL (0.8 mg) should be administered s.c. and the patient observed for signs or symptoms of withdrawal for 45 minutes.

Conditions and Technique for Observation of Patients: During the appropriate period of observation, the patient’s vital signs should be monitored and the patient should be observed for signs of withdrawal. It is also important to question the patient carefully. The signs and symptoms of opioid withdrawal include, but are not limited to, the following: withdrawal signs: stuffiness or running nose, tearing, yawning, sweating, tremor, vomiting or piloerection; withdrawal symptoms: feeling of temperature change, joint or bone and muscle pain, abdominal cramps, skin crawling, etc.

Interpretation of the Challenge: Warning: The elicitation of the enumerated signs or symptoms indicates a potential risk for the subject, and naltrexone should not be administered. If no signs or symptoms of withdrawal are observed, elicited, or reported, naltrexone may be administered. If there is any doubt in the observer’s mind that the patient is not in an opioid-free state, or is in continuing withdrawal, naltrexone should be withheld for 24 hours and Narcan should be readministered as follows: Confirmatory rechallenge (if necessary): 4 mL (1.6 mg) of Narcan (0.4 mg/mL) should be injected i.v. and the patient again observed for signs and symptoms of withdrawal. If none are present, naltrexone may be administered. If signs and symptoms of withdrawal are present, administration of naltrexone should be delayed until repeated Narcan challenge indicates the patient is no longer at risk.

Availability And Storage: Each pale yellow, film-coated, capsule-shaped tablet, debossed on one side with “DuPont” and scored and debossed “11” on the other, contains: naltrexone HCl 50 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and Pale Yellow Opadry YS-1-6378-G. Bottles of 50. Store at controlled room temperature (15 to 30°C). Dispense in a tight container as defined in the USP.

REVIA® DuPont Pharma Naltrexone HCl Opioid Antagonist

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