Version October 2024
Dosage guidance:
Clinical considerations: Do not initiate therapy until patient has passed a naloxone challenge test or is opioid-free (including tramadol) for at least 7 to 10 days after last opioid use; up to 14 days may be necessary for patients on long-acting opioids (eg, methadone, buprenorphine) (Ref). If need for opioid pain management is anticipated during treatment (eg, for elective surgery), discontinue oral naltrexone ≥3 days prior to surgery or IM naltrexone ≥30 days prior to surgery (Ref).
Alcohol use disorder, moderate to severe:
Note: Not recommended for patients currently taking opioids or with acute hepatitis, liver enzymes ≥3 to 5 times normal, or liver failure (Ref). May be initiated while the patient is actively drinking (Ref). Some experts consider alternative therapy if goals are not met within 6 months of treatment (Ref).
Oral: 50 mg once daily; may increase to 100 mg once daily after 1 week based on response and tolerability. Some experts initiate with 25 mg once daily for several days before increasing to 50 mg once daily (Ref).
IM: 380 mg once every 4 weeks.
Opioid use disorder, mild to severe (alternative agent for moderate to severe):
Note: Treatment initiation should be medically supervised due to risk for precipitated withdrawal. Some experts consider switching to alternative therapy if goals are not met within 3 to 6 months of treatment (Ref).
Oral (alternative route): Initial: 25 mg once daily for 1 to 3 days; if no withdrawal signs occur, administer 50 mg once daily thereafter. Note: Use only for patients who are highly motivated or able to comply with techniques such as observed dosing to enhance adherence; efficacy is limited when patient adherence is poor (Ref).
IM: 380 mg once every 4 weeks. Note: Patients who experience a reduction in efficacy prior to 4 weeks (eg, breakthrough cravings, ability to overcome opioid receptor blockade), may benefit from dosing every 3 weeks; however, no clinical trials have evaluated dosing frequencies <4 weeks (Ref).
Switching from buprenorphine to naltrexone: Taper the buprenorphine dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone. A naloxone challenge may be used to demonstrate an absence of physical dependence (Ref).
Switching from methadone to naltrexone: Taper the methadone dose gradually and discontinue. Wait 7 to 14 days before initiating treatment with naltrexone. A naloxone challenge may be used to demonstrate an absence of physical dependence (Ref).
Switching from naltrexone to methadone or buprenorphine: Begin methadone or buprenorphine ~1 day following last dose of oral naltrexone and ~28 days following last dose of IM naltrexone (Ref).
Pruritus (off-label use):
Opioid-induced, associated with neuraxial opioid administration:
Oral: 6 mg once; generally, doses >6 mg may reverse analgesia (Ref).
Nonopioid-induced (eg, from cholestasis) (alternative agent): Note: Studies of naltrexone for uremic pruritus have mixed results (Ref).
Oral: 12.5 mg to 50 mg once daily (Ref).
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.
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. Use is not recommended in acute hepatitis or hepatic failure (Ref).
Refer to adult dosing.
Naltrexone may result in accidental opioid overdose in patients with opioid dependence or opioid use disorder. Risk of opioid overdose with naltrexone use may be higher than other opioid agonist treatments (Ref). Opioid overdose related to naltrexone use may result in life-threatening and fatal events (Ref).
Mechanism: Related to the pharmacologic action; naltrexone is an opioid receptor-antagonist, reducing or blocking the effects of opioids and potentially leading to secondary up-regulation of opioid receptors. Patients may be hypersensitive to opioid effects and susceptible to overdose at lower opioid doses than previously tolerated (Ref). In addition, the opioid competitive receptor blockade produced by naltrexone is potentially surmountable in the presence of large amounts of opioids.
Onset: Varied; overdose occurred within 2 weeks after discontinuation in one study (Ref). In another study, overdose occurred within a 12-month period (Ref).
Risk factors:
• Naltrexone discontinuation
• Missed doses of naltrexone
• Near the end of the naltrexone dosing interval
• Opioid dose (Ref)
• Time since opioid administration (Ref)
• Patient metabolism (Ref)
Naltrexone may cause transient, mildly increased serum transaminases (Ref). Most increases in serum transaminases resolve (some with continued therapy) (Ref). Hepatitis has been reported.
Mechanism: Dose-related; exact mechanism unknown. (Ref).
Onset: Varied; most increased serum alanine aminotransferase and increased serum aspartate aminotransferase occur in the first 30 days of therapy, but may occur later (Ref).
Risk factors:
• Higher oral doses (Ref)
• Concurrent NSAIDs (Ref)
• Older patients (>50 years) (Ref)
Naltrexone IM administration may cause injection site reaction, pain at injection site, tenderness at injection site, bruising at injection site, swelling at injection site, injection site nodule, and itching at injection site. Serious reactions, including abscess at injection site, cellulitis at injection site, hematoma at injection site, induration at injection site, sterile abscess at injection site, and tissue necrosis at injection site have been reported; some requiring surgical intervention (Ref). Nicolau syndrome or embolia cutis medicamentosa has been reported, characterized by blanching and pain around the injection site, followed by erythema and tissue necrosis (Ref).
Mechanism: Most injection site reactions may be related to improper administration. Nicolau syndrome may occur due to direct damage to the end artery or cytotoxic effects of naltrexone and/or additives in the preparation (Ref).
Onset: Varied; most injection site reactions occur within 1 to 3 days but may occur more than 10 days after injection (Ref). Nicolau syndrome may occur after 1 week (Ref).
Risk factors:
• Improper administration (eg, inadvertent SUBQ administration) (Ref)
• Patients with HIV (Ref)
Naltrexone may precipitate opioid withdrawal syndrome in patients with opioid dependence or opioid use disorder. Symptoms may be severe and include abdominal pain, agitation, altered level of consciousness, confusion, diaphoresis, diarrhea, dilated pupils, dizziness, irritability, nausea, pain, tachycardia, and vomiting (Ref). Naltrexone-precipitated opioid withdrawal symptoms may last 48 to 72 hours (Ref). Withdrawal symptoms may require hospitalization but are rarely life-threatening (Ref).
Mechanism: Related to the pharmacologic action; naltrexone displaces opioids from opioid receptors, precipitating withdrawal (Ref).
Onset: Rapid; within 5 minutes, peaking between 1 to 3 hours (Ref).
Risk Factors:
• Dose and timing of opioid use (Ref)
• Naltrexone administration prior to adequate opioid-free period
• Accidental or deliberate naltrexone administration (Ref)
• Transitioning from methadone or buprenorphine to naltrexone
• Peri-operative pain management (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are as reported with the IM formulation.
>10%:
Cardiovascular: Syncope (≤13%)
Gastrointestinal: Abdominal pain (11%), anorexia (≤14%), change in appetite (≤14%), decreased appetite (≤14%), diarrhea (13%), nausea (33%), vomiting (14%)
Hepatic: Increased serum aspartate aminotransferase (2% to 14%) (table 1), increased serum transaminases (20%) (table 2)
|
Drug (Naltrexone) |
Placebo |
Dosage Form |
Indication |
|---|---|---|---|
|
14% |
11% |
IM |
Opioid dependence |
|
2% |
0.9% |
IM |
Alcohol dependence |
|
Drug (Naltrexone) |
Placebo |
Dosage Form |
Indication |
|---|---|---|---|
|
20% |
13% |
IM |
Opioid dependence |
Local: Induration at injection site (35%) (table 3), injection-site reaction (69%, including injection-site nodule and swelling at injection site) (table 4), pain at injection site (17%) (table 5), tenderness at injection site (45%) (table 6)
|
Drug (Naltrexone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Naltrexone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
35% |
8% |
380 mg every 4 weeks |
IM |
Alcohol dependence |
205 |
214 |
|
Drug (Naltrexone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Naltrexone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
69% |
50% |
380 mg every 4 weeks |
IM |
Alcohol dependence |
205 |
214 |
|
Drug (Naltrexone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Naltrexone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
17% |
7% |
380 mg every 4 weeks |
IM |
Alcohol dependence |
205 |
214 |
|
Drug (Naltrexone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Naltrexone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
45% |
39% |
380 mg every 4 weeks |
IM |
Alcohol dependence |
205 |
214 |
Nervous system: Anxiety (12%), asthenia (23%), dizziness (≤13%), headache (25%), insomnia (≤14%), sleep disorder (≤14%)
Neuromuscular & skeletal: Arthralgia (≤12%), arthritis (≤12%), increased creatine phosphokinase in blood specimen (11% to 39%), joint stiffness (≤12%)
Respiratory: Pharyngitis (11%)
1% to 10%:
Dermatologic: Skin rash (6%)
Gastrointestinal: Xerostomia (5%)
Local: Bruising at injection site (7%) (table 7), injection-site pruritus (10%) (table 8)
|
Drug (Naltrexone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Naltrexone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
7% |
5% |
380 mg every 4 weeks |
IM |
Alcohol dependence |
205 |
214 |
|
Drug (Naltrexone) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Naltrexone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
10% |
0% |
380 mg every 4 weeks |
IM |
Alcohol dependence |
205 |
214 |
Nervous system: Depression (8% to 10%), drowsiness (≤4%), sedated state (≤4%), suicidal ideation (≤1%), suicidal tendencies (≤1%)
Neuromuscular & skeletal: Back pain (≤6%), back stiffness (≤6%), muscle cramps (8%)
Frequency not defined:
Cardiovascular: , Angina pectoris, atrial fibrillation, chest pain, chest tightness, coronary artery disease, deep vein thrombosis, heart failure, palpitations, pulmonary embolism
Dermatologic: Diaphoresis, night sweats, pruritus
Endocrine & metabolic: Decreased libido, dehydration, heat exhaustion, hot flash, hypercholesterolemia, weight gain, weight loss
Gastrointestinal: Abdominal distress, cholecystitis, cholelithiasis, colitis, constipation, dysgeusia, flatulence, gastroenteritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, hemorrhoids, increased appetite, paralytic ileus
Hematologic & oncologic: Decreased platelet count, eosinophilia, leukocytosis, lymphadenopathy
Hypersensitivity: Facial edema
Nervous system: Abnormal dreams, acute ischemic stroke, agitation, alcohol withdrawal syndrome, cerebral aneurysm, chills, decreased mental acuity, disturbance in attention, euphoria, irritability, lethargy, migraine, paresthesia, rigors, seizure
Neuromuscular & skeletal: Limb pain, muscle spasm, myalgia
Ophthalmic: Blurred vision, conjunctivitis
Respiratory: Bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, nasal congestion, pharyngolaryngeal pain, sinusitis
Miscellaneous: Fever
Postmarketing:
Cardiovascular: Acute myocardial infarction (Ref)
Dermatologic: Urticaria
Gastrointestinal: Acute pancreatitis (Ref)
Hepatic: Hepatitis, increased serum alanine aminotransferase (Ref)
Hypersensitivity: Anaphylaxis, angioedema
Local: Abscess at injection site, cellulitis at injection site, hematoma at injection site, sterile abscess at injection site, tissue necrosis at injection site
Nervous system: Delirium (Ref), opioid withdrawal syndrome (Ref)
Respiratory: Eosinophilic pneumonitis (Ref), pneumonia (including interstitial pneumonia) (Ref)
Hypersensitivity to naltrexone or any component of the formulation; current physiological 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
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in the US labeling): Acute hepatitis; hepatic failure
Concerns related to adverse effects:
• 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 is not recommended in acute hepatitis or hepatic failure (APA [Reus 2018]).
• 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:
• Discontinuation of therapy: There is no maximum recommended duration for maintenance treatment of opioid use disorder; patients may require treatment indefinitely. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid use disorder treatment (SAMHSA 2021).
• Opioid use disorder: Patients should be opioid-free (including tramadol) for a minimum of 7 to 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. Oral naltrexone tablets have not been shown to be more effective than placebo for opioid use disorder due to poor patient adherence (SAMHSA 2021).
• 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.
• Naloxone access: Discuss the availability of naloxone with all patients, as well as their caregivers, at initial treatment and regularly during therapy (eg, with each subsequent naltrexone injection). Patients being treated for an opioid use disorder have the potential for relapse and are at risk for opioid overdose; this risk may be increased in patients treated with naltrexone near the end of the naltrexone dosing interval (particularly if using naltrexone injection), if a dose of naltrexone is missed, or when naltrexone treatment is discontinued. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.
• Surgery: In patients treated with naltrexone for opioid use disorder who are 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) (ASAM 2020).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Reconstituted, Intramuscular:
Vivitrol: 380 mg (1 ea)
Tablet, Oral, as hydrochloride:
Generic: 50 mg
May be product dependent
Suspension (reconstituted) (Vivitrol Intramuscular)
380 mg (per each): $1,969.33
Tablets (Naltrexone HCl Oral)
50 mg (per each): $1.35 - $4.28
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
ReVia: 50 mg
Generic: 50 mg
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 deep IM into the gluteal muscle; 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.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Vivitrol: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021897s052lbl.pdf#page=33
Alcohol use disorder: Treatment of alcohol use disorder.
Opioid use disorder, mild to severe: For the blockade of the effects of exogenously administered opioids.
Limitation of use: Oral naltrexone tablets have not been shown to be more effective than placebo for opioid use disorder due to poor patient adherence (SAMHSA 2021).
Pruritus
Naltrexone may be confused with methylnaltrexone, naloxone
ReVia may be confused with Revatio
Vivitrol: For deep intramuscular (IM) gluteal injection only
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Bremelanotide: May decrease the serum concentration of Naltrexone. Risk X: Avoid combination
Lofexidine: May decrease the serum concentration of Naltrexone. Risk C: Monitor therapy
Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Opioid Agonists: Naltrexone may diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Sibutramine: May enhance the adverse/toxic effect of Centrally Acting Weight Loss Agents. Risk X: Avoid combination
Naltrexone is not the preferred treatment for opioid use disorder during pregnancy; pregnancy testing is recommended prior to initiating naltrexone therapy (SAMHSA 2021).
Naltrexone and the 6-beta-naltrexol metabolite cross the placenta (Towers 2020).
Alcohol use and opioid use disorder are associated with adverse fetal and obstetrical outcomes. Information related to the use of naltrexone during pregnancy is limited (ACOG 711 2017; Farid 2008; Towers 2020; Tran 2017).
Information related to the use of naltrexone for the treatment of opioid use disorder during pregnancy is limited. Consider transitioning to a preferred agent or discontinue treatment if the patient and health care provider agree the risk of relapse is low. If treatment with naltrexone continues, the risks and benefits should be discussed (ASAM 2020; SAMHSA 2021). Pregnant patients are not appropriate candidates for the ER injection (SAMHSA 2021).
Pharmacological agents should not be used for the treatment of alcohol use disorder in pregnant patients unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder; agents other than naltrexone are recommended for acute alcohol withdrawal (APA [Reus 2018]).
Naltrexone and the 6-beta-naltrexol metabolite are present in breast milk (Chan 2004).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Pharmacological agents should not be used for the treatment of alcohol use disorder in breastfeeding patients unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder; agents other than naltrexone are recommended for acute alcohol withdrawal (APA [Reus 2018]).
Liver function tests (baseline and periodic); signs or symptoms of opioid withdrawal, injection-site reactions with IM administration; pregnancy test (baseline); hepatitis and HIV testing, particularly for patients with opioid use disorder (prior to initiation) (SAMHSA 2021); and depression and/or suicidal thinking
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 alcohol consumption (Williams 2004).
Duration: Oral: 50 mg: 24 hours; 100 mg: 48 hours; 150 mg: 72 hours; IM: 4 weeks
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
Protein binding: 21%
Bioavailability: Oral: Variable range (5% to 40%)
Half-life elimination: Oral: 4 hours; 6-beta-naltrexol: 13 hours; IM: Naltrexone and 6-beta-naltrexol: 5 to 10 days (dependent upon erosion of polymer)
Time to peak, serum: Oral: ~60 minutes; IM: Biphasic: ~2 hours (first peak), ~2 to 3 days (second peak)
Excretion: Primarily urine (as metabolites and small amounts of unchanged drug)
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.
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