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Naltrexone

Pronunciation

Pronunciation

(nal TREKS one)

Index Terms

  • Naltrexone Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension Reconstituted, Intramuscular:

Vivitrol: 380 mg (1 ea)

Tablet, Oral, as hydrochloride:

ReVia: 50 mg [DSC] [scored]

Generic: 50 mg

Brand Names: U.S.

  • ReVia [DSC]
  • Vivitrol

Pharmacologic Category

  • Antidote
  • Opioid Antagonist

Pharmacology

Naltrexone (a pure opioid antagonist) is a cyclopropyl derivative of oxymorphone similar in structure to naloxone and nalorphine (a morphine derivative); it acts as a competitive antagonist at opioid receptor sites, showing the highest affinity for mu receptors.

Absorption

Oral: Almost complete

Distribution

Vd: ~1350 L; widely throughout the body but considerable interindividual variation exists

Metabolism

Extensively metabolized via noncytochrome-mediated dehydrogenase conversion to 6-beta-naltrexol (primary metabolite) and related minor metabolites; glucuronide conjugates are also formed from naltrexone and its metabolites

Oral: Extensive first-pass effect

Excretion

Primarily urine (as metabolites and small amounts of unchanged drug)

Time to Peak

Serum: Oral: ~60 minutes; IM: Biphasic: ~2 hours (first peak), ~2-3 days (second peak)

Duration of Action

Oral: 50 mg: 24 hours; 100 mg: 48 hours; 150 mg: 72 hours; IM: 4 weeks

Half-Life Elimination

Oral: 4 hours; 6-beta-naltrexol: 13 hours; IM: naltrexone and 6-beta-naltrexol: 5-10 days (dependent upon erosion of polymer)

Protein Binding

21%

Special Populations: Hepatic Function Impairment

An increase in naltrexone AUC of approximately 5- and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with healthy liver function has been reported.

Use: Labeled Indications

Alcohol dependence: Treatment of alcohol dependence.

Opioid dependence: For the blockade of the effects of exogenously administered opioids.

Contraindications

Hypersensitivity to naltrexone or any component of the formulation; opioid dependence or current use of opioid analgesics (including partial opioid agonists); acute opioid withdrawal; failure to pass naloxone challenge or positive urine screen for opioids

Dosing: Adult

Note: Do not initiate therapy until patient is opioid-free (including tramadol) for at least 7-10 days as determined by urinalysis; consider naloxone challenge test to confirm patient is opioid-free if there is any suspicion since urinary opioid screen may not be sufficient proof.

Alcohol dependence:

Oral: 50 mg daily; alternative maintenance regimens may be used and include: 50 mg on weekdays with a 100 mg dose on Saturday; 100 mg every other day; or 150 mg every 3 days (degree of blockade may be reduced with extended dosing interval regimens and doses >50 mg may increase risk of hepatocellular injury)

IM: 380 mg once every 4 weeks

Opioid dependence:

Oral: Initial: 25 mg; if no withdrawal signs occur, administer 50 mg/day thereafter; alternative maintenance regimens may be used and include: 50 mg on weekdays with a 100 mg dose on Saturday; 100 mg every other day; or 150 mg every 3 days (degree of blockade may be reduced with extended dosing interval regimens and doses >50 mg may increase risk of hepatocellular injury)

IM: 380 mg once every 4 weeks

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild impairment: No dosage adjustment necessary.

Moderate-to-severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); use with caution since naltrexone and its primary metabolite are primarily excreted in urine.

Dosing: Hepatic Impairment

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied); naltrexone AUC increased ~5- and 10-fold in patients with compensated or decompensated hepatic cirrhosis respectively.

Reconstitution

Injection: Prior to reconstitution, allow drug vial and provided diluent to reach room temperature (~45 minutes). Using the provided 1-inch preparation needle, reconstitute with 3.4 mL of the diluent and allow to dissolve by vigorously shaking the vial for ~1 minute. Mixed suspension will be milky white, free of clumps, and will move freely down the walls of the vial. Immediately after suspension, withdraw 4.2 mL of the suspension using the same preparation needle.

Prior to administration, replace the preparation needle with the appropriate size provided administration needle (use the 2-inch needle with the needle protection device for patients with a larger amount of subcutaneous tissue overlying the gluteal muscle; for very lean patients, the 1.5-inch needle may be appropriate; either needle may be used for patients with average body habitus). Prior to injection, remove any air bubbles and push on the plunger until 4 mL of the suspension remains in the syringe. Following reconstitution of the suspension, administer immediately.

Administration

Oral: May be administered with or without food. Administration with food or after meals may minimize adverse gastrointestinal effects. Advise patient not to self-administer opioids while receiving naltrexone therapy.

IM: Vivitrol: Administer IM into the upper outer quadrant of the gluteal area; must inject dose using one of the provided needles for administration. Use either the 1.5-inch needle (for very lean patients) or the 2-inch needle (for patients with a larger amount of subcutaneous tissue overlying the gluteal muscle). Either needle may be used for patients with average body habitus. Avoid inadvertent injection into a blood vessel; do not administer IV, SubQ, or into fatty tissue (the risk of serious injection site reaction is increased if given incorrectly as a SubQ injection or into fatty tissue instead of the gluteal muscle). Injection should alternate between the 2 buttocks. Do not substitute any components of the dose-pack.

Storage

Injection: Store unopened kit at 2°C to 8°C (36°F to 46°F). Kit may be kept at room temperature of ≤25°C (77°F) for ≤7 days prior to use; do not freeze. Following reconstitution of the suspension, administer immediately.

Tablet: Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Analgesics (Opioid): Naltrexone may diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Test Interactions

May cause cross-reactivity with some opioid immunoassay methods.

Adverse Reactions

Combined reporting of adverse events from oral and injectable formulations:

>10%:

Cardiovascular: Syncope (13%)

Central nervous system: Headache (3% to 25%), insomnia (3% to 14%), dizziness (4% to 13%), anxiety (2% to 12%), decreased energy (>10%), nervousness (4% to >10%)

Gastrointestinal: Nausea (10% to 33%), vomiting (3% to 14%), appetite decreased (14%), diarrhea (13%), abdominal pain (11%), abdominal cramping

Hepatic: ALT increased (13%)

Local: Injection site reaction (≤69%; includes bruising, induration, nodules, pain, pruritus, swelling, tenderness)

Neuromuscular & skeletal: CPK increased (11% to 39%), arthralgia (12%), myalgia (>10%)

Respiratory: Pharyngitis (7% to 11%)

1% to 10%:

Cardiovascular: Hypertension (5%)

Central nervous system: Suicidal ideation (≤10%), depression (8%), somnolence (2% to 4%), fatigue (4%), chills, energy increased, feeling down, irritability

Dermatologic: Skin rash (6% to 10%)

Endocrine & metabolic: Increased thirst, polydipsia

Gastrointestinal: Dry mouth (5%), toothache (4%), constipation

Genitourinary: Delayed ejaculation (<10%), impotency (<10%)

Hepatic: AST increased (2% to 10%), GGT increased (7%)

Neuromuscular & skeletal: Muscle cramps (8%), back pain (6%)

Miscellaneous: Influenza (5%)

<1% (Limited to important or life-threatening): Abnormality in thinking, acne vulgaris, alopecia, angina, anorexia, atrial fibrillation, blood pressure increased, cerebral aneurysm, chest tightness, cholecystitis, colitis, COPD, dehydration, delirium, depression, DVT, dysuria, ECG changes, edema, eosinophilia (transient), eosinophilic pneumonia, epistaxis, GI hemorrhage, hemorrhoids, hepatic insufficiency, hepatitis, HF, hypercholesterolemia, hyperkinesia, hypersensitivity reaction (includes anaphylaxis, angioedema, and urticaria), ischemic stroke, leukocytosis, lymphadenopathy, MI, opioid withdrawal, palpitation, pancreatitis, paralytic ileus, paranoia, PE, perirectal abscess, photophobia, pneumonia, rhinorrhea, rigors, seizure, shortness of breath, swelling of eye, tachycardia, thrombocytopenia, ulcer

Warnings/Precautions

Concerns related to adverse effects:

• Accidental opioid overdose: Patients who had been treated with naltrexone may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Patients should be aware that they may be more sensitive to lower doses of opioids after naltrexone treatment is discontinued, after a missed dose, or near the end of the dosing interval. Warn patients that any attempt to overcome opioid blockade during naltrexone therapy, could potentially lead to fatal opioid overdose; the opioid competitive receptor blockade produced by naltrexone is potentially surmountable in the presence of large amounts of opioids.

• Acute opioid withdrawal: May precipitate symptoms of acute withdrawal in opioid-dependent patients, including pain, hypertension, sweating, agitation, and irritability; in neonates: shrill cry, failure to feed.

• Eosinophilic pneumonia: Cases of eosinophilic pneumonia have been reported and should be considered in patients presenting with progressive hypoxia and dyspnea.

• Hepatocellular injury: Dose-related hepatocellular injury is possible; the margin of separation between the apparent safe and hepatotoxic doses appears to be ≤5-fold. Discontinue therapy if signs/symptoms of acute hepatitis develop. Clinicians should note that elevated transaminases may be a result of pre-existing alcoholic liver disease, hepatitis B and/or C infection, or concomitant use of other hepatotoxic drugs; abrupt opioid withdrawal may also lead to acute liver injury.

• Hypersensitivity reactions: Hypersensitivity, including urticaria, angioedema, and anaphylaxis, have been reported.

• Injection site reactions: Serious injection site reactions (eg, cellulitis, induration, hematoma, abscess, necrosis) have been reported with use, including severe cases requiring surgical debridement. Females appear to be at a higher risk. Patients should report any injection site pain, swelling, bruising, pruritus, or redness that does not improve (or worsens). For IM use only in the gluteal muscle, do not administer IV, SubQ, or into fatty tissue; incorrect administration may increase the risk of injection site reactions.

• Suicidal thoughts/depression: Suicidal thoughts, attempted suicide, and depression have been reported postmarketing; monitor closely.

Disease-related concerns:

• Bleeding disorders: Use IM injection with caution in patients thrombocytopenia or any bleeding disorder (including hemophilia and severe hepatic failure), or patients on anticoagulant therapy; bleeding/hematoma may occur from IM administration.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment (has not been studied; if coagulopathy presents, IM injection may cause hematoma formation).

• Renal impairment: Use with caution in patients with moderate-to-severe renal impairment (has not been studied).

Dosage form specific issues:

• Injection: Vehicle used in the injectable naltrexone formulation (polylactide-co-glycolide microspheres) has rarely been associated with retinal artery occlusion in patients with abnormal arteriovenous anastomosis following injection of other drug products that also use the polylactide-co-glycolide microspheres vehicle.

Other warnings/precautions:

• Detoxified opioid addiction: Patients should be opioid-free (including tramadol) for a minimum of 7-10 days; a naloxone challenge test may be helpful to confirm patient is opioid-free prior to therapy if there is any suspicion since urinary opioid screen may not be sufficient proof. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Use of naltrexone does not eliminate or diminish withdrawal symptoms.

• Emergency pain management: In naltrexone-treated patients requiring emergency pain management, consider alternatives to opioid therapy (eg, regional analgesia, nonopioid analgesics, general anesthesia). If opioid therapy is required for pain therapy, patients should be under the direct care of a trained anesthesia provider.

• Surgery: In patients treated with naltrexone for opioid addiction who requiring surgery, discontinue oral naltrexone at least 72 hours before scheduled elective surgery if opioid use is anticipated; extended-release IM naltrexone should be discontinued at least 30 days prior to scheduled surgery (oral naltrexone may be used temporarily) (Kampman [ASAM 2015]).

Monitoring Parameters

Liver function tests (baseline and periodic); monitor for opioid withdrawal, injection site reactions with IM administration, and depression and/or suicidal thinking

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Information related to the use of naltrexone during pregnancy is limited (Farid 2008). Clinical practice guidelines recommend that if a women being treated with naltrexone for the treatment of opioid use disorder becomes pregnant, naltrexone should be discontinued if the patient and physician agree that the risk of relapse if low. If patient is concerned about relapse and wishes to continue naltrexone, the patient should be informed of the potential risks of continuing treatment and consent for ongoing treatment should be obtained. If naltrexone is discontinued and the patient subsequently relapses, consideration should be given for treatment with methadone or buprenorphine (Kampman [ASAM 2015]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience anxiety, headache, abdominal pain, cramps, insomnia, nausea, vomiting, fatigue, joint pain, muscle pain, lack of appetite, loss of strength and energy, dry mouth, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), severe dizziness, passing out, tachycardia, blurred vision, arrhythmia, confusion, hallucinations, dyspnea, difficulty breathing, cough or severe injection site blisters, scabs, pain, edema, lumps, or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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