(nal TREKS one)
- Naltrexone Hydrochloride
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]
ReVia: 50 mg [DSC] [scored]
Generic: 50 mg
Brand Names: U.S.
- ReVia [DSC]
- Opioid Antagonist
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. Endogenous opioids are involved in modulating the expression of alcohol's reinforcing effects (Hemby 1997; Lee 2005). Naltrexone also modifies the hypothalamic-pituitary-adrenal axis to suppress ethanol consumption (Williams 2004).
Oral: Almost complete
Vd: ~1350 L; widely throughout the body but considerable interindividual variation exists
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
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
Oral: 4 hours; 6-beta-naltrexol: 13 hours; IM: naltrexone and 6-beta-naltrexol: 5-10 days (dependent upon erosion of polymer)
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.
Off Label Uses
Cholestatic pruritus (adults)
Data from small controlled trials support the use of oral naltrexone in the management of cholestatic pruritus, with an onset of action as early as the first day in some patients. Additional trials may be necessary to further define the role of naltrexone in this condition.
American Association for the Study of Liver Diseases practice guidelines for primary biliary cirrhosis recommend the use of oral naltrexone for cholestatic pruritus refractory to treatment with bile acid sequestrants. The limiting factor to naltrexone use in the management of cholestatic pruritus is the possibility of an opioid withdrawal–like reaction, which may be avoided by starting the drug at a lower dose and titrating upward.
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
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.
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
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
Cholestatic pruritus (off-label use): Oral: Initial: 12.5 mg once daily; increase dose by 12.5 mg every 3 to 7 days until clinical benefits are achieved (AASLD [Lindor 2009]). Doses of 50 mg daily have been reportedly used for up to 28 weeks (Carson 1996; Terg 2002; Wolfhagen 1997).
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.
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.
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.
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).
Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination
Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. 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
Opioid Analgesics: Naltrexone may diminish the therapeutic effect of Opioid Analgesics. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification
May cause cross-reactivity with some opioid immunoassay methods.
Combined reporting of adverse events from oral and injectable formulations.
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%), decreased appetite (14%), diarrhea (13%), abdominal pain (11%), abdominal cramps
Hepatic: Increased serum ALT (13%)
Local: Injection site reaction (≤69%; includes bruise, induration, nodules, pain, pruritus, swelling, tenderness)
Neuromuscular & skeletal: Increased creatine phosphokinase (11% to 39%), arthralgia (12%), myalgia (>10%)
Respiratory: Pharyngitis (7% to 11%)
1% to 10%:
Cardiovascular: Hypertension (5%)
Central nervous system: Suicidal ideation (≤10%), delayed ejaculation (<10%), depression (8%), drowsiness (2% to 4%), fatigue (4%), chills, depressed mood, increased energy, irritability
Dermatologic: Skin rash (6% to 10%)
Endocrine & metabolic: Increased gamma-glutamyl transferase (7%), increased thirst, polydipsia
Gastrointestinal: Xerostomia (5%), toothache (4%), constipation
Genitourinary: Impotence (<10%)
Hepatic: Increased serum AST (2% to 10%)
Infection: Influenza (5%)
Neuromuscular & skeletal: Muscle cramps (8%), back pain (6%)
<1%, postmarketing, and/or case reports: Abnormality in thinking, acne vulgaris, acute ischemic stroke, agitation, alopecia, altered blood pressure, angina pectoris, anorexia, atrial fibrillation, blurred vision, burning sensation of eyes, cardiac failure, cerebral aneurysm, chest pain, chest tightness, cholecystitis, cholelithiasis, chronic obstructive pulmonary disease, cold extremities, colitis, confusion, cough, decreased libido, deep vein thrombosis, dehydration, delirium, diaphoresis, disorientation, dyspnea, dysuria, ECG changes, edema, eosinophilia (transient), eosinophilic pneumonitis, epistaxis, euphoria, eye pain, fever, flatulence, gastrointestinal hemorrhage, groin pain, hallucination, hemorrhoids, hepatic insufficiency, hepatitis, herpes labialis, hoarseness, hot flash, hypercholesterolemia, hyperkinesia, hypersensitivity reaction (includes anaphylaxis, angioedema, and urticaria), increased appetite, increased bronchial secretions, increased libido, knee pain, leg pain, leukocytosis, lymphadenopathy, malaise, myocardial infarction, nasal congestion, nightmares, oily skin, opioid withdrawal syndrome, otalgia, palpitations, pancreatitis, paralytic ileus, paranoia, perirectal abscess, photophobia, pneumonia, pulmonary embolism, restlessness, rhinorrhea, rigors, seizure, shoulder pain, sinusitis, sneezing, sore throat, swelling of eye, tachycardia, thrombocytopenia, tinea pedis, tinnitus, tremor, twitching, ulcer, urinary frequency, urinary tract infection, visual disturbance, weakness, weight gain, weight loss, yawning
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.
• 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.
• 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]).
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
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]).
• 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, abdominal pain, cramps, constipation, insomnia, nausea, vomiting, joint pain, muscle pain, lack of appetite, loss of strength and energy, dry mouth, increased thirst, rhinitis, pharyngitis, back pain, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), severe dizziness, passing out, severe headache, severe fatigue, sexual dysfunction (males), confusion, difficulty breathing, slow breathing, shallow breathing, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), 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.
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