Naltrexone

Class: Opiate Antagonists
VA Class: CN102
Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one
Molecular Formula: C₂₀H₂₃NO₄C₂₀H₂₃NO₄•HCl
CAS Number: 16590-41-3
Brands: ReVia, Vivitrol

Medically reviewed on October 3, 2017

Possible dose-related hepatotoxicity.¹ ¹⁰² ²²⁶ ²²⁸ ²⁴⁷ Margin between therapeutic and hepatotoxic dosages may be less than fivefold; hepatotoxicity not apparent at usual dosages.¹ ¹⁰² ²⁴⁷ (See Hepatic Effects under Cautions.)
Contraindicated in patients with acute hepatitis or liver failure;¹ ¹⁰² ²⁴⁷ carefully weigh potential benefits against possible hepatotoxic risks in patients with active liver disease.¹ ²⁴⁷
Instruct patients to discontinue naltrexone and contact a clinician if manifestations of acute hepatitis occur.¹ ²⁴⁷ (See Advice to Patients.)

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for naltrexone to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of naltrexone and consists of the following: medication guide and communication plan. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Introduction

Essentially a pure opiate antagonist.¹ ² ³ ⁷ ¹⁷ ²³ ¹⁰²

Uses for Naltrexone

Opiate Dependence

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

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

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

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

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

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

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

Alcohol Dependence

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

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

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

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

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

Naltrexone Dosage and Administration

General

REMS for Parenteral Naltrexone

FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for parenteral naltrexone.²⁵⁹

The REMS requires that a medication guide be given to the patient each time parenteral naltrexone is dispensed;²⁵⁹ ²⁶⁰ the goal is to inform patients about serious risks associated with parenteral naltrexone.²⁵⁹ (See Advice to Patients and also see Cautions.)

Verification of Opiate Abstinence Prior to Initiation of Therapy

Patients who are physically dependent on opiates should complete detoxification prior to initiation of naltrexone therapy.¹ ¹⁰²
Manufacturers recommend that at least 7–10 days elapse between discontinuance of opiates and initiation of naltrexone therapy because of the risk of precipitating opiate withdrawal (see Accidental Precipitation of Withdrawal under Cautions.)¹ ¹⁰² This waiting period may vary depending on the dose and duration of action of the opiate;¹ ¹⁰² ¹²¹ ¹⁶² allow at least 7 days in patients using relatively short-acting opiates (e.g., heroin, hydromorphone, meperidine, morphine) and at least 10–14 days in those using longer-acting opiates (e.g., methadone).²³⁷
Some clinicians have cautiously precipitated withdrawal using repeated naloxone injections and then rapidly initiated naltrexone therapy with incremental doses of the drug; this procedure can reduce the transition period from opiate dependence to naltrexone maintenance and generally is well accepted by patients.¹⁴ ⁴¹ ¹⁹⁶ ²⁰⁷
In addition to patient verification of abstinence from opiates, perform urinalysis after the minimum 7- to 10-day waiting period, but prior to administration of naltrexone, to confirm the absence of opiates.¹ ¹⁰² If it is uncertain whether the patient is opiate free, perform a naloxone challenge test prior to administering naltrexone.¹ ¹⁰² ²⁴⁷

Naloxone Challenge Test

Perform test prior to induction of naltrexone therapy in patients formerly physically dependent on opiates who have completed detoxification and in those suspected of having been dependent on opiates.¹ ² ¹⁴ ¹⁵ ⁴¹ ¹⁰² ¹⁶² ²³⁷
Test should not be performed in patients who are exhibiting signs and/or symptoms of opiate withdrawal, those whose urine shows evidence of opiates, or those in whom there is a high degree of suspicion that opiates are still being used, since naloxone may precipitate potentially severe opiate withdrawal.¹ ¹⁰²
Do not attempt naltrexone therapy if signs and/or symptoms of opiate withdrawal (e.g., nasal stuffiness, rhinorrhea, lacrimation, yawning, sweating, tremor, abdominal cramps, vomiting, piloerection, myalgia, skin crawling) are evident following administration of the naloxone challenge test;¹ ¹⁰² instead, repeat the naloxone challenge test in 24 hours.¹
Naloxone may be administered IV or sub-Q in the challenge test.¹
IV challenge test: Draw 0.8 mg of naloxone hydrochloride into a syringe.¹ Administer 0.2 mg initially; while the needle remains in the vein observe the patient for 30 seconds¹⁹⁶ for evidence of opiate withdrawal.¹ Alternatively, some clinicians recommend 15 minutes for the period of observation. If no evidence of withdrawal is observed, inject the remaining 0.6-mg dose and observe the patient for an additional 20 minutes for evidence of withdrawal.¹
Sub-Q challenge test: Draw 0.8 mg of naloxone hydrochloride into a syringe.¹ Inject the entire 0.8-mg dose and observe the patient for 20 minutes for evidence of opiate withdrawal.¹
If evidence of opiate withdrawal is present, delay naltrexone therapy and repeat the naloxone challenge test in 24 hours with the 0.8-mg dose; repeat the test every 24 hours until results are negative.¹ ¹⁹⁶
If it is uncertain whether the patient is opiate free or is undergoing opiate withdrawal following an initial test, repeat the naloxone challenge test with a 1.6-mg IV dose.¹

Administration

Administer orally or by IM injection.¹ ¹⁰² ²⁴⁷

Do not administer parenteral preparation by IV or sub-Q injection; do not administer into fatty tissue.²⁴⁷ ²⁵⁷

Oral Administration

Administer orally;¹ ¹⁰² minimize adverse GI effects by taking with food¹²³ or antacids¹³¹ or after meals.⁹ ¹⁰² ¹³¹ ¹⁴³

Patients should take naltrexone as directed and not attempt self-administration of opiates during therapy with the drug.¹ ¹⁰² (See Risks Associated with Self-administration of Opiates During Naltrexone Therapy under Cautions.)

IM Administration

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

Administer by deep IM injection into the upper outer quadrant of the gluteal muscle every 4 weeks (or once a month); alternate buttocks for subsequent injections.²⁴⁷

Administer only with needle and other components of dose pack supplied by manufacturer.²⁴⁷

Use aspiration to avoid inadvertent injection into a blood vessel.²⁴⁷ ²⁵⁷

Do not administer by IV or sub-Q injection; do not inadvertently administer into fatty tissue.²⁴⁷ ²⁵⁷ Inadvertent sub-Q injection may increase likelihood of severe injection site reactions.²⁴⁷ (See Local Reactions under Cautions.)

Evaluate the patient's body habitus prior to each injection to ensure that the 1.5-inch needle supplied by the manufacturer is adequate for gluteal IM injection in that patient.²⁴⁷ Consider alternative treatment for any patient whose body habitus (i.e., gluteal fat thickness) precludes IM injection with the provided needle.²⁴⁷ ²⁶¹

Reconstitution

Consult manufacturer’s labeling for instructions for using components of dose pack for reconstitution.²⁴⁷

Allow dose pack to reach room temperature before reconstituting.²⁴⁷

Reconstitute vial labeled as containing 380 mg of naltrexone extended-release microspheres with 3.4 mL of diluent; shake vigorously for 1 minute.²⁴⁷ Use only the diluent supplied by the manufacturer.²⁴⁷ Administer immediately.²⁴⁷

Dosage

Available for oral administration as naltrexone hydrochloride; dosage expressed in terms of the salt.¹

Available for IM administration as naltrexone.²⁴⁷

Adults

Opiate Dependence

Induction of Therapy for Opiate Cessation

Oral

Initiate induction regimen following completion of opiate detoxification and verification that the patient is free of opiates.¹⁰² (See General under Dosage and Administration.)

Initially, 25 mg; if no evidence of withdrawal is present, begin 50 mg daily.¹

Alternatively, some clinicians have administered 12.5 mg initially, followed by incremental increases of 12.5 mg daily until the usual dosage of 50 mg daily has been achieved.⁶² ⁹⁹ ¹²³ ¹⁹⁶

Maintenance Therapy for Opiate Cessation

Oral

50 mg daily following induction of therapy.¹ ² ¹¹ ²⁴ ²⁵ ²⁸ ⁹⁹ ¹⁰²

Alternatively, flexible dosing schedules have been suggested in an attempt to improve compliance.¹ ² ³⁵ ⁶² ⁹⁹ ¹⁰² ¹²² ¹³⁸ ¹⁵⁷ ¹⁵⁸ ¹⁶¹ ¹⁶⁴ ¹⁹⁶ Administration of larger doses at longer intervals (e.g., 48–72 hours) may reduce opiate antagonist activity somewhat, but may improve compliance.¹ ¹⁰² ¹²¹ Single doses >50 mg may increase risk of hepatic injury; weigh possible risks against probable benefits of flexible dosing.¹

50 mg daily Monday through Friday and 100 mg on Saturday¹ ¹⁰²
100 mg every other day¹ ¹⁰²
150 mg every third day¹ ¹⁰²
100 mg on Monday and Wednesday and 150 mg on Friday¹ ⁸ ³⁵ ⁹⁹ ¹⁰² ¹²¹ ¹²² ¹²³ ¹⁵⁷ ¹⁵⁸ ¹⁶⁴
150 mg on Monday and 200 mg on Thursday¹⁹⁶

Ingestion of the naltrexone dose generally should be observed in a clinic setting or by a responsible family member to ensure compliance, in which case, regimens requiring less frequent visits may be more acceptable to the patient.⁸ ⁹⁹ ¹⁰² ¹⁸² ¹⁹⁴ ¹⁹⁶

Monitor patient compliance by random testing of urine for naltrexone and 6-β-naltrexol or for the presence of opiates.⁶² ¹⁰² ¹⁶¹

Optimum duration of maintenance therapy not established;¹²¹ base on individual requirements and response.¹⁰²

In patients who discontinue naltrexone prematurely and then desire to resume therapy following a relapse to opiate abuse, perform urinalysis for the presence of opiates and, if necessary, a naloxone challenge test prior to resuming therapy.¹⁶¹ ¹⁹⁶ If there is evidence of opiate dependence, conduct detoxification prior to reinitiation of naltrexone therapy.¹⁰² ¹⁶¹

Opiate Detoxification†

Oral

Various dosage regimens have been used for rapid or ultrarapid detoxification† of opiate dependence.² ³⁸ ¹⁶² ¹⁶⁸ ¹⁶⁹ ²⁴⁶

The following regimen of naltrexone, given in conjunction with clonidine to attenuate withdrawal manifestations, has been studied.³⁸

Day of Detoxification Therapy	Clonidine Hydrochloride	Naltrexone Hydrochloride
Day 1	0.005 mg/kg initially; then titrated according to the severity of withdrawal and the adverse effects induced by clonidine² ³⁸
Day 2	Administered every 4 hours to attenuate the withdrawal induced by naltrexone³⁸	Administered every 4 hours; 1 mg initially; then increased in 1-mg increments during the daytime on day 2 ³⁸
Day 3	Administered every 4 hours to attenuate the withdrawal induced by naltrexone; highest mean dosage was 2.3 mg daily on day 3³⁸	Administered every 4 hours; dosage increased in 2-mg increments during the daytime on day 3³⁸
Day 4	Administered only as needed to reduce signs and symptoms of withdrawal³⁸	10 mg 3 times daily³⁸
Day 5	Administered only as needed to reduce signs and symptoms of withdrawal³⁸	50 mg once daily² ³⁸

Alcohol Dependence

Oral

50 mg once daily,¹ ²³⁴ ²³⁷ following verification that the patient is free of opiates.¹ (See General under Dosage and Administration.)

Optimum duration of therapy not established;²³⁷ safety and efficacy established only in short-term (up to 12 weeks) studies.¹ ²³¹ ²³² ²³³ ²³⁴ ²³⁶ ²³⁷

IM

380 mg every 4 weeks or once a month following verification that the patient is free of opiates. ²⁴⁷ (See General under Dosage and Administration.)

If a dose is missed, reschedule administration with a health-care professional as soon as possible.²⁴⁷

Therapy may be initiated with parenteral preparation; not necessary to initiate therapy with oral naltrexone and then switch to parenteral preparation.²⁴⁷

Special Populations

Hepatic Impairment

Alcohol Dependence

IM

Dosage adjustment not needed in patients with mild to moderate (Child-Pugh class A or B) hepatic impairment.²⁴⁷

Renal Impairment

Alcohol Dependence

IM

Dosage adjustment not needed in patients with mild renal impairment (Cl_cr of 50–80 mL/minute).²⁴⁷

Cautions for Naltrexone

Contraindications

Patients receiving opiate agonists (except for emergency situations).¹ ¹⁰² ²⁴⁷
Nondetoxified patients physically dependent on opiates, including those receiving maintenance treatment with opiates (e.g., methadone).¹ ¹⁰² ²⁴⁷
Patients experiencing acute opiate withdrawal.¹ ¹⁰² ²⁴⁷
Patients who experience opiate withdrawal following administration of the naloxone challenge test or in patients in whom urinalysis for the presence of opiates is positive.¹ ¹⁰² ²⁴⁷
Patients with acute hepatitis or hepatic failure.¹ ²⁴⁷
Patients with known hypersensitivity to the drug or any ingredient in the formulation.¹ ²⁴⁷ Not known whether cross-sensitivity exists between naltrexone and naloxone or phenanthrene-derivative opiate agonists (e.g., codeine, morphine, oxymorphone).¹

Warnings/Precautions

Warnings

Hepatic Effects

Possible dose-related hepatocellular injury, manifested as increases in serum hepatic enzyme concentrations.¹ ¹⁰² ²²⁶ ²²⁸ ²⁴⁷ (See Boxed Warning.)

Manufacturers state that naltrexone-induced hepatocellular injury appears to be a direct toxic rather than an idiosyncratic effect.¹ Some clinicians suggest that liver function abnormalities may be caused by noroxymorphone, a minor metabolite of naltrexone that has opiate agonist activity.¹⁹⁶ ²⁰⁶

Manufacturer of oral naltrexone recommends monitoring liver function at intervals deemed appropriate for the naltrexone dosage employed and the clinical status of the patient.¹

Local Reactions

IM injection associated with injection site reactions (e.g., tenderness, induration, pain, pruritus, ecchymosis, nodules, swelling) in most patients.²⁴⁷ Cellulitis,²⁴⁷ hematoma,²⁴⁷ abscess,²⁴⁷ sterile abscess,²⁴⁷ and necrosis²⁴⁷ also reported.²⁴⁷ Injection site reactions occur predominantly in females.²⁴⁷

Some reactions may be very severe, result in substantial scarring, or require surgery, including debridement of necrotic tissue.²⁴⁷ Inadvertent sub-Q injection may increase likelihood of a severe injection reaction.²⁴⁷

Patients should monitor the injection site and contact clinician if injection site reactions worsen or persist.²⁵⁷ ²⁵⁸ (See Advice to Patients.) Promptly evaluate patients with signs of abscess, cellulitis, necrosis, or extensive swelling to determine if referral to a surgeon is warranted.²⁴⁷

Verification of Opiate Abstinence Prior to Initiation of Therapy

Naltrexone may precipitate mild to severe withdrawal in patients physically dependent on opiates.¹ ² ⁷ ¹¹ ¹⁵ ³¹ ³⁵ ³⁸ ⁴² ⁸² ²⁴⁷

To minimize the risk of precipitating signs and symptoms of withdrawal, instruct opiate-dependent individuals who are candidates for naltrexone therapy to remain free of opiates for a minimum of 7–10 days prior to initiating therapy with the drug.¹ ¹⁰² ²⁴⁷

Absence of opiates in urine is frequently insufficient evidence that a patient is free of opiates.¹ ¹⁰² ²⁴⁷ If it is uncertain whether the patient is opiate free, perform a naloxone challenge test prior to administering naltrexone.¹ ¹⁰² ²⁴⁷ (See Naloxone Challenge Test under Dosage and Administration.)

Risks Associated with Self-administration of Opiates During Naltrexone Therapy

Self-administration of large doses of opiates in an attempt to overcome the antagonist activity of naltrexone may produce signs and symptoms of acute opiate overdosage (e.g., respiratory arrest, circulatory collapse, death).¹ ²⁴⁷

Signs and symptoms of opiate overdosage also may occur following administration of smaller doses of opiate agonists relatively long after the last naltrexone dose or in an amount that results in a longer duration of agonist activity than the antagonist activity of naltrexone and its metabolites.¹ ²⁴⁷

Advise patients of the serious consequences of self-administration of opiates during naltrexone therapy.¹ ¹⁰² ²⁴⁷ (See Advice to Patients.)

Eosinophilic Pneumonia

Eosinophilic pneumonia reported rarely in patients receiving parenteral naltrexone.²⁴⁷ Consider eosinophilic pneumonia in patients with pneumonia who have not responded to anti-infective therapy.²⁴⁷

General Precautions

Therapeutic Use of Opiates in Naltrexone-treated Patients

In an emergency situation when adequate analgesia can be achieved only by administration of an opiate agonist in naltrexone-treated patients, cautious administration of an opiate may afford adequate analgesia, but higher than usual dosages may be required.¹ ¹⁰² Whenever possible, use nonopiate analgesics, regional analgesia, conscious sedation with a benzodiazepine, or general anesthesia.¹ ¹⁰² ²⁴⁷

If an opiate is required as a component of anesthesia or analgesia, the patient should be continuously monitored in an anesthesia care setting by individuals who are trained in the use of anesthetic agents and in the management of respiratory depressant effects of potent opiates and who are not involved in the conduct of the surgical or diagnostic procedure.²⁴⁷

Respiratory depression produced by the opiate may be deeper and more prolonged.¹ ¹⁰² Patients may experience apparent nonopiate receptor-induced effects such as facial swelling, pruritus, generalized erythema, or bronchoconstriction that are probably caused by opiate-induced histamine release and/or other mechanisms.¹

Use of a short-acting opiate with minimal respiratory depression is preferable; adjust dosage of the opiate agonist carefully according to individual requirements and response.¹ ¹⁰² Closely monitor the patient in a setting equipped and staffed by health-care personnel appropriately trained in CPR.¹ ²⁴⁷

Discontinue oral naltrexone ≥48 hours prior to elective surgical procedures requiring opiate analgesia.¹²¹

Avoid use of other opiate-agonist-containing preparations (e.g., those used for the management of cough or diarrhea) when alternative nonopiate therapy is available, since adequate therapeutic benefit may be difficult to achieve with an opiate.¹ ¹⁰²

Accidental Precipitation of Withdrawal

Accidental ingestion of naltrexone has precipitated severe withdrawal in some patients physically dependent on opiates; signs and symptoms of withdrawal usually appeared within 5 minutes of naltrexone ingestion and continued for up to 48 hours.¹ ³¹ ¹⁰² ¹²⁴

Suicide

Increased risk of suicide in substance abusers with or without depression;¹ ²⁴⁷ risk is not abated by naltrexone therapy.¹

Individuals with Bleeding Disorders

Use IM preparation with caution in individuals with thrombocytopenia or a coagulation disorder (e.g., hemophilia).²⁴⁷

Specific Populations

Pregnancy

Category C.¹ ¹⁰² ²⁴⁷

Not known whether naltrexone affects the duration of labor and delivery.¹ ¹⁰² ²⁴⁷

Lactation

Naltrexone and the active metabolite (6-β-naltrexol) are distributed into human milk.²⁴⁷ ²⁵⁴ Discontinue nursing or the drug.²⁴⁷

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹ ¹⁰² ¹²¹ ²⁴⁷ ²⁴⁸

Hepatic Impairment

Contraindicated in patients with acute hepatitis or hepatic failure.¹ ¹⁰² ²⁴⁷ (See Boxed Warning and see Hepatic Effects under Cautions.)

Use with caution in patients with hepatic impairment.¹ When administered orally, possible increased systemic exposure to the drug.¹

Renal Impairment

Use with caution in patients with moderate to severe renal impairment.¹ ²⁴⁷

Common Adverse Effects

Treatment of opiate dependence: insomnia,¹ anxiety,¹ nervousness,¹ abdominal pain and cramps,¹ nausea,¹ vomiting,¹ fatigue,¹ joint and muscle pain,¹ headache.¹

Treatment of alcohol dependence: nausea,¹ ²⁴⁷ headache,¹ ²⁴⁷ dizziness,¹ ²⁴⁷ nervousness,¹ fatigue,¹ insomnia,¹ ²⁴⁷ vomiting,¹ ²⁴⁷ anxiety,¹ ²⁴⁷ somnolence,¹ ²⁴⁷ injection site reaction.²⁴⁷ ²⁵⁷

Interactions for Naltrexone

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Clonidine	Concomitant administration may reduce the duration of opiate withdrawal by decreasing opiate-induced postsynaptic supersensitivity³⁸ ¹⁶⁸ ²³⁰
Disulfiram	Both drugs are potentially hepatotoxic¹	Manufacturers recommend concomitant use only if the potential benefits justify the possible risks¹
Opiate agonists	Patients receiving naltrexone may not benefit therapeutically from opiate-containing preparations, including those used for the management of cough and cold, diarrhea, and pain¹ ¹⁰² ²⁴⁷ Naltrexone can precipitate potentially severe opiate withdrawal¹ ¹⁰² ²⁴⁷	Avoid use of opiate-containing preparations during naltrexone therapy when alternative nonopiate therapy is available¹ Avoid use of naltrexone in patients receiving opiates or in nondetoxified patients physically dependent on opiates¹ ¹⁰² ²⁴⁷
Phenothiazines (thioridazine)	Possible increased lethargy and somnolence¹ ²²⁰ ²²¹ ²²² ²³⁷
Tests, urinary opiates	Possible interference with some enzymatic assays for opiates¹ ²⁴⁷ No interference reported with thin-layer (TLC), gas-liquid (GLC), or high-performance liquid (HPLC) chromatography assays for methadone or morphine¹
Tests, urinary quinine	No interference reported with TLC, GLC, or HPLC methods¹

Naltrexone Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely (about 96%) absorbed following oral administration,¹ ² ³ ²² ⁶⁷ ⁷¹ ⁷² ¹⁰⁰ ¹⁰² ¹⁰⁵ but undergoes extensive first-pass metabolism in the liver;¹ ² ³ ³³ ⁶² ⁷¹ ¹⁰² only 5–40% reaches systemic circulation unchanged.¹ ² ⁶⁷ ⁷¹ ⁷² ⁷⁴ ¹⁰²

Peak plasma concentrations of naltrexone and the active metabolite (6-β-naltrexol) usually occur within 1 hour following oral administration.¹ ⁷¹ ⁷²

Following IM administration of the extended-release injection, naltrexone is released slowly and gradually from the microspheres by diffusion and erosion as the polylactide co-glycolide polymer degrades.²⁴⁷ ²⁴⁹ ²⁵¹ ²⁵² Peak plasma concentrations of naltrexone and the active metabolite (6-β-naltrexol) occur in about 2–3 days; ²⁴⁷ ²⁵¹ ²⁵² steady-state plasma concentrations of naltrexone and 6-β-naltrexol are attained by the end of the dosing interval after the first injection.²⁴⁷ ²⁵¹

Following administration of a single IM dose of naltrexone 380 mg, total naltrexone exposure is three- to fourfold higher and 6-β-naltrexol exposure is 3.4-fold lower than exposure following oral administration of naltrexone 50 mg daily for 28 days.²⁴⁷ ²⁵¹

Onset

Onset of opiate antagonism occurred 15–30 minutes following oral administration in a limited number of patients who had been receiving morphine chronically.²⁵

Decreases opiate craving within 3–5 weeks after start of oral naltrexone in individuals formerly dependent on opiates;⁴² ⁶⁶ ¹⁵⁸ ¹⁶⁰ reduction in opiate craving has occurred during the first week of therapy in some individuals, with further decreases occurring in subsequent weeks.¹⁰² ¹⁸²

Duration

Duration of opiate antagonist activity appears to be dose dependent¹ ⁷ ¹² ¹⁰² and is longer than that of equipotent doses of naloxone.⁵ ⁷ ²² ²⁵ ³³ ⁷²

Special Populations

Changes in oral bioavailability appear to be related to severity of liver disease.¹ AUC increased 5- or 10-fold in patients with compensated or decompensated cirrhosis, respectively.¹

Following IM administration, plasma concentrations of naltrexone and 6-β-naltrexol in individuals with mild to moderate hepatic impairment (Child-Pugh class A and B) are similar to those in healthy individuals with normal hepatic function.²⁴⁷ ²⁵²

Distribution

Extent

Widely distributed throughout the body;⁶⁹ ⁷⁵ considerable interindividual variation in distribution parameters during the first 24 hours following a single oral dose.⁶² ⁷¹ ⁷²

Not known whether naltrexone and/or its metabolites cross the placenta.²¹⁷ Naltrexone and 6-β-naltrexol are distributed into human milk.²⁴⁷ ²⁵⁴

Plasma Protein Binding

Approximately 21–28%.¹ ² ⁷⁶ ⁷⁷ ¹⁰² ²⁴⁷

Elimination

Metabolism

Metabolized in the liver principally by reduction of the 6-keto group of naltrexone to an active metabolite, 6-β-naltrexol (6-β-hydroxynaltrexone); ¹ ² ³³ ⁶² ⁶⁷ ⁷² ⁸⁴ ¹⁰⁰ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁹ ¹¹² ¹¹³ ¹¹⁵ ¹¹⁶ ¹¹⁷ ¹¹⁸ other minor metabolites are formed.¹ ² ⁶² ⁶⁷ ⁷² ⁸⁴ ¹⁰⁰ ¹⁰¹ ¹⁰² ¹⁰³ ¹⁰⁵ ¹⁰⁷ ¹⁰⁸ ¹¹¹ ¹¹⁴ ¹¹⁷ ¹¹⁸

Because oral but not IM administration of naltrexone results in substantial first-pass hepatic metabolism, 6-β-naltrexol concentrations following IM administration are substantially lower than concentrations achieved following oral administration.²⁴⁷ ²⁵¹ ²⁵²

Naltrexone and its metabolites may undergo enterohepatic circulation.¹ ⁷¹

Elimination Route

Excreted principally in urine via glomerular filtration, mainly as metabolites (unconjugated and conjugated).¹ ² ³³ ⁶² ⁶⁷ ⁷² ¹⁰⁰ ¹⁰¹ ¹⁰² ¹⁰⁵ ¹⁰⁹ ¹¹⁰ ¹¹⁶ ²⁴⁷

Half-life

Following oral administration, biphasic.⁶⁷ ⁷² ¹⁰²

Initial phase, oral administration: 1.1–3.9 hours for naltrexone;¹ ⁷¹ ⁷² ¹⁰¹ ¹⁰² ¹⁰⁴ 2.3–3.1 hours for 6-β-naltrexol.⁷²

Terminal phase, oral administration: 9.7–10.3 hours for naltrexone;⁷² ⁷⁴ ¹⁰¹ 11.4–16.8 hours for 6-β-naltrexol.⁷¹ ⁷² ¹⁰¹ ¹⁰⁴

Following IM administration, half-life of naltrexone and 6-β-naltrexol is 5–10 days.²⁴⁷ ²⁵¹ ²⁵²

Special Populations

Following IM administration, pharmacokinetics not altered in patients with mild renal impairment (Cl_cr of 50–80 mL/minute).²⁴⁷

Stability

Storage

Oral

Tablets

20–25°C.¹

Parenteral

Extended-release Injection

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

After mixing with diluent, use immediately.²⁴⁷

Actions

Essentially a pure opiate antagonist.¹ ² ³ ⁷ ¹⁷ ²³ ¹⁰²
Opiate antagonist activity on a weight basis is reportedly 2–9 times that of naloxone.² ¹⁷ ²⁴ ²⁵ ²⁹ ¹³⁶ ¹⁷⁵
In usual doses in patients who have not recently received opiates, naloxone exerts little or no pharmacologic effect.⁷ ¹⁸ ²⁵ ⁴¹
In patients who have received single or repeated large doses of opiate agonists, naltrexone attenuates or produces a complete but reversible block of the pharmacologic effects (e.g., physical dependence, analgesia, euphoria, tolerance) of the opiate.¹ ³ ¹³ ¹⁴ ²² ²³ ²⁵ ³¹
Antagonizes most of the subjective and objective effects of opiates,³ ¹⁴ ²⁵ ¹⁰² ¹⁰³ including respiratory depression,⁷² ¹⁰² ¹⁰³ miosis,¹⁴ ²⁵ ⁷² ¹⁰² ¹⁰³ euphoria,¹⁴ ⁷² ¹⁰² ¹⁰³ and drug craving.³ ²⁵ ⁷² ¹⁰² ¹⁰³
Because the duration of action of naltrexone may be shorter than that of the opiate, the effects of the opiate may return as the effects of naltrexone dissipate.¹⁵ ³³ ³⁶ Degree of opiate antagonism produced by naltrexone depends on the dose and the time elapsed since the last dose of naltrexone and the dose of the opiate.¹ ¹¹ ³² ¹⁰² ¹²²
Does not produce physical or psychologic dependence, and tolerance to the drug’s opiate antagonist activity reportedly does not develop.¹ ⁷ ⁸ ¹¹ ¹³ ²² ²⁷ ³³ ³⁹ ⁴⁰ ⁷⁹ May precipitate mild to potentially severe withdrawal in individuals physically dependent on opiates¹ ² ⁷ ¹¹ ¹⁵ ³¹ ³⁵ ³⁸ ⁴² ⁸² or pentazocine.¹⁹⁶
Is thought to act as a competitive antagonist at µ, κ, and δ receptors in the CNS;¹ ⁷ ¹⁶ ²⁸ ³⁴ ⁷⁸ ¹⁰² ²¹⁸ appears to have the highest affinity for the μ receptor.⁷ ¹⁶ ¹⁹ ²¹⁸
Alcohol ingestion stimulates release of endogenous opiate agonists,¹ ²³⁵ ²³⁷ ²³⁸ ²³⁹ ²⁴² which may increase some of the rewarding effects associated with alcohol ingestion through agonist activity at opiate (e.g., μ) receptors.²³⁷ ²³⁸ By competitively binding to opiate receptors, naltrexone may reduce alcohol consumption by blocking the effects of endogenous opiates and thus making alcohol ingestion less pleasurable.¹ ²³² ²³³ ²³⁵ ²³⁶ ²³⁷ ²³⁸ ²⁴¹ ²⁴⁷
Does not cause disulfiram-like reactions following ingestion of alcohol.¹ ²³⁸ ²⁴² ²⁴⁷

Advice to Patients

Importance of patient reading the medication guide prior to initiating parenteral naltrexone therapy and before each injection of the drug.²⁵⁸ Importance of ensuring that patient understands risks.²⁶⁰
Importance of patients informing clinicians that they are taking naltrexone.¹ ²⁴⁷ ²⁵⁸ Advise patients to carry a medical identification card that can alert clinicians to this fact in an emergency situation.¹ ²⁴⁷ ²⁵⁸
Importance of contacting a clinician if manifestations of acute hepatitis (e.g., abdominal pain lasting more than a few days, light-colored [e.g., white] stools, dark urine, yellowing of the eyes) occur.¹ ²⁴⁷ ²⁵⁸ Discontinue oral naltrexone.¹
Importance of not self-administering opiates (e.g., heroin) during naltrexone therapy, since self-administration of small doses of opiates in an attempt to overcome the antagonist activity of naltrexone will not result in any pharmacologic effect and large doses may result in serious consequences (e.g., coma, death).¹ ¹⁰² ²⁴⁷ ²⁵⁸
Advise patients that they may be more sensitive to lower doses of opiate agonists following discontinuance of naltrexone therapy.¹ ²⁴⁷ ²⁵⁸
Advise patients receiving parenteral naltrexone to contact clinician if manifestations of pneumonia (shortness of breath, cough, wheezing) occur.²⁴⁷ ²⁵⁸
Advise patients receiving parenteral naltrexone to monitor the injection site and to contact clinician if injection site reactions (i.e., pain, swelling, tenderness, induration, bruising, pruritus, redness) worsen or if they do not improve within 2 weeks following injection.²⁵⁷ ²⁵⁸ Advise patients to notify clinician promptly if intense or prolonged pain, swelling, skin color changes, or signs of necrosis (e.g., hard nodule, blistering, open wound, dark scab) are present at the injection site.²⁴⁷ ²⁵⁸
Advise patients that they may need to be referred to a surgeon for worsening injection site reactions.²⁵⁷
Risk of dizziness; avoid driving or operating heavy machinery until effects on the individual are known.¹ ²⁴⁷ ²⁵⁸
Potential for depression and suicidality to occur;¹ ²⁴⁷ importance of contacting clinician immediately if new or worsening symptoms of depression or suicidal thoughts occur.¹ ²⁴⁷ ²⁵⁸
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g. liver disease).¹ ²⁴⁷ ²⁵⁸
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ²⁴⁷ ²⁵⁸
Importance of informing patients of other important precautionary information.¹ ²⁴⁷ ²⁵⁸ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Naltrexone
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injectable suspension, extended-release, for IM use	380 mg	Vivitrol (available as a dose pack containing naltrexone microspheres, diluent, needles)	Alkermes

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naltrexone Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	50 mg*	Naltrexone Hydrochloride
	Tablets, film-coated	50 mg*	Naltrexone Hydrochloride
			ReVia (scored)	Duramed

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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