NALTREXONE HYDROCHLORIDE TABLETS, USP

Naltrexone hydrochloride is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids.

When co-administered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and 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.

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

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 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.

Naltrexone 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 6-ß-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-1/2) values for naltrexone and 6-ß-naltrexol are 4 hours and 13 hours, respectively. Naltrexone and 6-ß-naltrexol are dose proportional in terms of AUC and C_max over the range of 50 to 200 mg and do not accumulate after 100 mg daily doses.

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-ß-naltrexol occur within one hour of dosing.

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.

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 extra-hepatic sites of drug metabolism exist. The major metabolite of naltrexone is 6-ß-naltrexol. Two other minor metabolites are 2-hydroxy-3-methoxy-6-ß-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone and its metabolites are also conjugated to form additional metabolic products.

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 6-ß-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-ß-naltrexol accounts for 43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that naltrexone and its metabolites may undergo enterohepatic recycling.

Naltrexone appears to have extra-hepatic sites of drug metabolism and its major metabolite undergoes active tubular secretion (see Metabolism above). Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted (see PRECAUTIONS, Special Risk Patients).

Evidence of the hepatotoxic potential of naltrexone is derived primarily from a placebo controlled study in which naltrexone hydrochloride was administered to obese subjects at a dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day). In that 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 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 naltrexone is a direct (i.e., not idiosyncratic) hepatotoxin.

This conclusion is also supported by evidence from other placebo controlled studies in which exposure to naltrexone hydrochloride at doses above the amount recommended for the treatment of alcoholism or opiate blockade (50 mg/day) consistently produced more numerous and more significant elevations of serum transaminases than did placebo. Transaminase elevations in 3 of 9 patients with Alzheimer’s Disease who received naltrexone hydrochloride (at doses 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.

To prevent occurrence of an acute abstinence syndrome, or exacerbation of a pre-existing subclinical abstinence syndrome, patients must be opioid-free for a minimum of 7 to 10 days before starting naltrexone. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of naltrexone. The naloxone challenge test is described in the DOSAGE AND ADMINISTRATION section.

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). Patients should be told of the serious consequences of trying to overcome the opiate blockade. (see PRECAUTIONS, Information for Patients).

There is also the possibility that a patient who has 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 intoxication (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.

Safe use of naltrexone in rapid opioid detoxification programs has not been established (see ADVERSE REACTIONS).

It is recommended that the prescribing physician relate the following information to patients being treated with naltrexone:

You have been prescribed naltrexone hydrochloride tablets as part of the comprehensive treatment for your alcoholism or drug dependence. You should carry identification to alert medical personnel to the fact that you are taking naltrexone hydrochloride. A naltrexone medication card may be obtained from your physician and can be used for this purpose. Carrying the identification card should help to ensure that you can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the treating physician that you are receiving naltrexone therapy.

You should take naltrexone as directed by your physician. If you attempt to self-administer heroin or any other opiate drug, in small doses while on naltrexone, you will not perceive any effect. Most important, however, if you attempt to self-administer large doses of heroin or any other opioid (including methadone or LAAM) while on naltrexone, you may die or sustain serious injury, including coma.

Naltrexone is well-tolerated in the recommended doses, but may cause liver injury when taken in excess or in people who develop liver disease from other causes. If you develop abdominal pain lasting more than a few days, white bowel movements, dark urine, or yellowing of your eyes, you should stop taking naltrexone immediately and see your doctor as soon as possible.

A high index of suspicion for drug-related hepatic injury is critical if the occurrence of liver damage induced by naltrexone is to be detected at the earliest possible time. Evaluations, using appropriate batteries of tests to detect liver injury are recommended at a frequency appropriate to the clinical situation and the dose of naltrexone.

Naltrexone 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. Naltrexone 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.

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 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 naltrexone and thioridazine.

Patients taking naltrexone 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 naltrexone, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see PRECAUTIONS).

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 Drosphilia 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.

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 metabolites, 6-β-naltrexol; therefore, the potential reproductive toxicity of the metabolites in rats is not known.

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

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

In animal studies, naltrexone and 6-β-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone.

Whether or not naltrexone is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when naltrexone is administered to a nursing woman.

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

Naltrexone 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 (see CLINICAL PHARMACOLOGY, Clinical Trials, Individualization of Dosage).

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%) 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.

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).

The following adverse reactions have been reported both at baseline and during the naltrexone 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:

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

A dose of 50 mg once daily is recommended for most patients (see CLINICAL PHARMACOLOGY, Clinical Trials, Individualization of Dosage). The placebo-controlled studies that demonstrated the efficacy of naltrexone as an adjunctive treatment of alcoholism used a dose regimen of naltrexone 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not evaluated in these trials. A patient is a candidate for treatment with naltrexone if:

• the patient is willing to take a medicine to help with alcohol dependence
• the patient is opioid free for 7 to 10 days
• the patient does not have severe or active liver or kidney problems. (Typical guidelines suggest liver function tests no greater than 3 times the upper limits of normal, and bilirubin normal.)
• the patient is not allergic to naltrexone, and no other contraindications are present

Refer to CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections for additional information.

Naltrexone 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 naltrexone 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.

Initiate treatment with Naltrexone using the following guidelines

1. Treatment should not be attempted unless the patient has remained opioid-free for at least 7 to 10 days. Self-reporting of abstinence from opioids in opioid addicts 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 naloxone challenge test. If signs of opioid withdrawal are still observed following naloxone challenge, treatment with naltrexone should not be attempted. The naloxone challenge can be repeated in 24 hours.
3. Treatment should be initiated carefully, with an initial dose of 25 mg of naltrexone hydrochloride. If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter.

Once the patient has been started on naltrexone hydrochloride, 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 intravenous heroin challenge). A flexible approach to a dosing regimen may need to be employed in cases of supervised administration. Thus, patients may receive 50 mg of naltrexone hydrochloride 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 naltrexone 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 and CLINICAL PHARMACOLOGY, Clinical Trials, Individualization of Dosage).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Protect from light.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Additional barcode labeling by:
Physicians Total Care, Inc.
Tulsa, Oklahoma        74146

NDC 54868-5574-0

NALTREXONE

HYDROCHLORIDE

Tablets, USP

50 mg

Rx only