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Naltrexone

Pronunciation

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

Warning(s)

  • Hepatic Effects
  • 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.)

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, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

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

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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

  • Flexible Naltrexone Hydrochloride Dosing Schedules for Maintenance Therapy for Opiate Cessation
  • 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 (Clcr 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 (Clcr 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 mc, 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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Embeda 20-0.8MG Controlled-release Capsules (KING PHARMA): 20/$96.99 or 30/$144.98

Embeda 50-2MG Controlled-release Capsules (KING PHARMA): 30/$239.98 or 90/$699.99

Naltrexone HCl 50MG Tablets (MALLINCKRODT PHARM): 30/$103.99 or 90/$308.95

ReVia 50MG Tablets (TEVA/WOMENS HEALTH): 30/$275.32 or 90/$794.22

Vivitrol 380MG Suspension (ALKERMES): 1/$1,101.94 or 3/$3,263.83

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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