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Naltrexone

Medically reviewed by Drugs.com. Last updated on Mar 29, 2020.

Pronunciation

(nal TREKS one)

Index Terms

  • Naltrexone Hydrochloride

Dosage Forms

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

Brand Names: U.S.

  • 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. 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).

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 to 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 to 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 use disorder: Treatment of alcohol use disorder.

Opioid use disorder: 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 2018).

Off Label Uses

Cholestatic pruritus

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 [Terg 2002], [Wolfhagen 1997].

American Association for the Study of Liver Diseases (AASLD) practice guidelines for primary biliary cholangitis recommend the use of oral naltrexone for cholestatic pruritus refractory to treatment with bile acid sequestrants [AASLD [Lindor 2019]].

Pathological gambling disorder

Data from 2 small controlled trials, in which naltrexone resulted in improvement on gambling assessment scales, suggest that it may be beneficial for the treatment of pathologic gambling disorder [Grant 2008], [Kim 2001].

Contraindications

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

Canadian labeling: Additional contraindications (not in the US labeling): Acute hepatitis; hepatic failure

Dosing: Adult

Note: Do not initiate therapy until patient 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) (Kampman [ASAM 2015]; SAMHSA 2018). 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 use disorder:

Oral: 50 mg daily; some patients may require doses up to 100 mg/day (APA [Reus 2018]). 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 use disorder:

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). Note: Oral naltrexone tablets have not been shown to be more effective than placebo for opioid use disorder due to poor patient adherence (SAMHSA 2018).

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).

Dosing: Geriatric

Refer to adult dosing.

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

Bremelanotide: May decrease the serum concentration of Naltrexone. Avoid combination

Lofexidine: May decrease the serum concentration of Naltrexone. Monitor therapy

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

Sibutramine: May enhance the adverse/toxic effect of Centrally Acting Weight Loss Agents. Avoid combination

Test Interactions

May cause cross-reactivity with some opioid immunoassay methods.

Adverse Reactions

>10%:

Cardiovascular: Syncope (≤13%)

Central nervous system: Headache (25%), insomnia (≤14%), sleep disorder (≤14%), dizziness (≤13%), anxiety (12%)

Gastrointestinal: Nausea (33%), vomiting (14%), anorexia (≤14%), change in appetite (≤14%), decreased appetite (≤14%), diarrhea (13%), abdominal pain (11%)

Hepatic: Increased serum transaminases (20%), increased serum aspartate aminotransferase (2% to 14%)

Local: Injection site reaction (69%), tenderness at injection site (45%), induration at injection site (35%), pain at injection site (17%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (11% to 39%), asthenia (23%), arthralgia (≤12%), arthritis (≤12%), joint stiffness (≤12%)

Respiratory: Pharyngitis (11%)

1% to 10%:

Central nervous system: Depression (8% to 10%), drowsiness (≤4%), sedated state (≤4%), suicidal ideation (≤1%), suicidal tendencies (≤1%)

Dermatologic: Skin rash (6%)

Gastrointestinal: Xerostomia (5%)

Local: Itching at injection site (10%), bruising at injection site (7%)

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

Frequency not defined:

Cardiovascular: Acute ischemic stroke, acute myocardial infarction, angina pectoris, atrial fibrillation, cardiac failure, cerebral aneurysm, chest pain, chest tightness, coronary arteriosclerosis, deep vein thrombosis, facial edema, palpitations, pulmonary embolism, unstable angina pectoris

Central nervous system: Abnormal dreams, agitation, alcohol withdrawal syndrome, chills, decreased mental acuity, delirium, disturbance in attention, euphoria, heat exhaustion, irritability, lethargy, migraine, paresthesia, peripheral pain, rigors, seizure

Dermatologic: Diaphoresis, night sweats, pruritus

Endocrine & metabolic: Decreased libido, dehydration, hot flash, hypercholesterolemia, weight gain, weight loss

Gastrointestinal: Abdominal discomfort, acute pancreatitis, cholecystitis, cholelithiasis, colitis, constipation, dysgeusia, flatulence, gastroenteritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, hemorrhoids, increased appetite, paralytic ileus

Genitourinary: Abscess of rectum and/or peri-rectal area, urinary tract infection

Hematologic & oncologic: Decreased platelet count, eosinophilia, leukocytosis, lymphadenopathy

Hepatic: Increased serum alanine aminotransferase

Hypersensitivity: Seasonal allergy

Infection: Tooth abscess

Neuromuscular & skeletal: Muscle spasm, myalgia

Ophthalmic: Blurred vision, conjunctivitis

Respiratory: Bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, nasal congestion, pharyngolaryngeal pain, pneumonia, sinusitis, upper respiratory tract infection

Miscellaneous: Fever

Postmarketing: Anaphylaxis, angioedema, eosinophilic pneumonitis, hepatic insufficiency, hepatitis, hypersensitivity reaction, opioid withdrawal syndrome, retinal artery occlusion, urticaria

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 patients with opioid use disorder, 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 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:

• 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 2018).

• 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 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) (Kampman [ASAM 2015]).

Monitoring Parameters

Liver function tests (baseline and periodic); monitor for 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 2018); and depression and/or suicidal thinking

Reproductive Considerations

Pregnancy testing is recommended prior to initiating naltrexone therapy for opioid use disorder (SAMHSA 2018).

Pregnancy Considerations

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).

Clinical practice guidelines recommend that if a woman 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]). Pharmacological agents should not be used for the treatment of alcohol use disorder in pregnant women 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]).

Patient Education

What is this drug used for?

• It is used to help keep you alcohol-free.

• It is used to keep a drug-free state.

• It may be given for other reasons.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Anxiety

• Abdominal pain

• Muscle cramps

• Constipation

• Trouble sleeping

• Nausea

• Vomiting

• Joint pain

• Muscle pain

• Lack of appetite

• Fatigue

• Loss of strength and energy

• Common cold symptoms

• Tooth pain

• Dry mouth

• Increased thirst

• Nose irritation

• Throat irritation

• Back pain

• Diarrhea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Severe dizziness

• Passing out

• Severe headache

• Vision changes

• Sexual dysfunction (males)

• Confusion

• Trouble breathing

• Slow breathing

• Shallow breathing

• Lung problems like shortness of breath or other trouble breathing, cough that is new or worse

• Severe injection site blisters, scabs, pain, swelling, lumps, or irritation

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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