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Special Alerts
Naltrexone (Vivitrol™): Injection Site Reactions – August 2008
The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of reports of serious injection site reactions associated with naltrexone injectable suspension (Vivitrol™). The FDA has received 196 reports of reactions (including cellulitis, induration, hematoma, abscess, and necrosis) following administration. Surgical intervention was required for management of some of the reactions. Instruct patients to report injection site pain, swelling, bruising, pruritus, or redness at the injection site that does not improve (or worsens) within 2 weeks; consider surgical consult for worsening reactions. Naltrexone injectable suspension is for I.M. gluteal administration only, using the provided 1.5 inch 20-gauge administration needle. Alternate treatment should be considered in patients not able to receive an I.M. gluteal injection with the provided needle. Do not administer I.V., SubQ, or into fatty tissue (the risk of serious injection site reaction is increased if given SubQ or into fatty tissue). Patients with higher gluteal fat thickness may be at increased risk for injection site reactions.
Additional information may be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#naltrexone
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
Naltrexone may be confused with methylnaltrexone, naloxone
ReVia® may be confused with Revatio®, Revex®
Administration issues: Vivitrol™: For intramuscular (I.M.) gluteal injection only
Pronunciation
(nal TREKS one)
U.S. Brand Names
Index Terms
Generic Available
Yes: Tablet
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of ethanol dependence; blockade of the effects of exogenously administered opioids
Pregnancy Risk Factor
C
Pregnancy Considerations
Evidence of early fetal loss has been observed in animal studies with oral naltrexone. There are no adequate and well-controlled studies in pregnant women.
Lactation
Enters breast milk/not recommended
Contraindications
Hypersensitivity to naltrexone or any component of the formulation; narcotic dependence or current use of opioid analgesics; acute opioid withdrawal; failure to pass Narcan® challenge or positive urine screen for opioids; acute hepatitis; liver failure
Warnings/Precautions
Boxed warnings:
• Hepatocellular injury: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Accidental 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. Warn patients that attempts to overcome opioid blockade could lead to fatal overdose.
• 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; monitor for hypoxia and dyspnea.
• Hepatocellular injury: [U.S. Boxed Warning]: Dose-related hepatocellular injury is possible; the margin of separation between the apparent safe and hepatotoxic doses appears to be ? fivefold.
• Injection site reactions: Serious injection site reactions (eg, cellulitis, induration, hematoma, abscess, necrosis) have been reported with use. Patients should report injection site pain, swelling, bruising, pruritus, or redness that does not improve (or worsens) within 2 weeks; consider surgical consult for worsening reactions. For I.M. use only, do not administer I.V., SubQ, or into fatty tissue; may increase the risk of injection site reactions.
• Suicidal thoughts/depression: Suicidal thoughts and depression have been reported; monitor closely.
Disease-related concerns:
• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia) and/or patients on anticoagulant therapy; bleeding/hematoma may occur from I.M. administration.
• Hepatic impairment: Use with caution in patients with hepatic impairment; not studied in severe impairment.
• Renal impairment: Use with caution in patients with renal impairment; not studied in moderate-to-severe impairment.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Dosage form specific issues:
• Vehicle used in injectable (polylactide-co-glycolide microspheres): Has rarely been associated with retinal artery occlusion in patients with abnormal arteriovenous anastomosis (eg, patent foramen ovale).
Other warnings/precautions:
• Detoxified opioid addiction: Patients should be opioid-free for a minimum of 7-10 days; use naloxone challenge test to confirm. Use of naltrexone does not eliminate or diminish withdrawal symptoms.
Adverse Reactions
Combined reporting of adverse events from oral and injectable formulations:
>10%:
Cardiovascular: Syncope (13%)
Central nervous system: Headache (25%), insomnia (14%), dizziness (13%), anxiety (12%), somnolence (4%), nervousness, fatigue
Gastrointestinal: Nausea (33%), vomiting (14%), appetite decreased (14%), diarrhea (13%), abdominal pain (11%), abdominal cramping
Local: Injection site reaction (69%; includes bruising, induration, nodules, pain, pruritus, swelling, tenderness)
Neuromuscular & skeletal: Arthralgia (12%), CPK increased (11%)
Respiratory: Upper respiratory tract infection (13%), pharyngitis (11%)
1% to 10%:
Central nervous system: Depression (8%), suicidal thoughts (1%), energy increased, feeling down
Dermatologic: Rash (6%)
Endocrine & metabolic: Polydipsia
Gastrointestinal: Dry mouth (5%)
Genitourinary: Delayed ejaculation, impotency
Hepatic: AST increased (2%)
Neuromuscular & skeletal: Muscle cramps (8%), back pain (6%)
<1% (Limited to important or life-threatening): ALT increased, angina, atrial fibrillation, blood pressure increased, cerebral aneurysm, chest pain, chest tightness, CHF, cholecystitis, cholelithiasis, colitis, COPD, dehydration, delirium, disorientation, DVT, dyspnea, eosinophilic pneumonia, euphoria, GI hemorrhage, hallucinations, hypercholesterolemia, hypersensitivity reaction (includes angioedema and urticaria), hypertension, influenza, ischemic stroke, leukocytosis, lymphadenopathy, MI, narcotic withdrawal, palpitation, paralytic ileus, paranoia, PE, perirectal abscess, pneumonia, pyrexia, rigors, seizure, suicide attempts, tachycardia, thrombocytopenia, tooth abscess, UTI
Drug Interactions
There are no known significant interactions.
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.
Tablet: Store at 20°C to 25°C (68°F to 77°F).
Mechanism of Action
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.
Pharmacodynamics/Kinetics
Duration: Oral: 50 mg: 24 hours; 100 mg: 48 hours; 150 mg: 72 hours; I.M.: 4 weeks
Absorption: Oral: Almost complete
Distribution: Vd: 19 L/kg; widely throughout the body but considerable interindividual variation exists
Protein binding: 21%
Metabolism: Noncytochrome-mediated dehydrogenase conversion to 6-beta-naltrexol and related minor metabolites; Oral: Extensive first-pass effect
Half-life elimination: Oral: 4 hours; 6-beta-naltrexol: 13 hours; I.M.: naltrexone and 6-beta-naltrexol: 5-10 days
Time to peak, serum: Oral: ~60 minutes; I.M.: Biphasic: 2 hours (first peak), 2-3 days (second peak)
Excretion: Primarily urine (as metabolites and unchanged drug)
Dosage
Adults: Do not give until patient is opioid-free for 7-10 days as determined by urinalysis
Oral: Alcohol dependence, opioid antidote: 25 mg; if no withdrawal signs within 1 hour give another 25 mg; maintenance regimen is flexible, variable and individualized (50 mg/day to 100-150 mg 3 times/week for 12 weeks); up to 800 mg/day has been tolerated in a small number of healthy adults without an adverse effect
I.M.: Alcohol dependence: 380 mg once every 4 weeks
Dosage adjustment in renal impairment: Use caution. No adjustment needed in mild impairment. Not adequately studied in moderate-to-severe renal impairment.
Dosage adjustment in hepatic impairment: Use caution. An increase in naltrexone AUC of approximately five- and 10-fold in patients with compensated or decompensated liver cirrhosis respectively, compared with normal liver function has been reported No adjustment required with mild-to-moderate hepatic impairment. Not adequately studied in severe hepatic impairment.
Administration: Oral
To minimize adverse gastrointestinal effects, administer with food or antacids or after meals; advise patient not to self-administer opiates while receiving naltrexone therapy.
Administration: I.M.
Vivitrol™ should be administered I.M. into the upper outer quadrant of the gluteal area; use provided 1.5 inch 20-gauge needle for administration. Avoid inadvertent injection into a blood vessel; do not administer I.V., SubQ, or into fatty tissue (the risk of serious injection site reaction is increased if given SubQ or into fatty tissue. Injection should alternate between the two buttocks. Do not substitute any components of the dose-pack.
Monitoring Parameters
For narcotic withdrawal; liver function tests; injection site reactions
Test Interactions
May cause cross-reactivity with some opioid immunoassay methods.
Patient Education
This medication will help you achieve abstinence from opiates if taken as directed. Do not increase or change dose. Do not use opiates or any medications not approved by your prescriber during naltrexone therapy. Carry documentation to alert medical personnel you are taking medication in the event of an emergency. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); trouble sleeping; decreased appetite; abdominal cramping, nausea or vomiting (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); low energy; or decreased sexual function (reversible when drug is discontinued). Report yellowing of skin or eyes, change in color of stool or urine, thoughts of suicide, increased perspiration or chills, acute headache, palpitations, unusual joint pain, or signs and symptoms of pneumonia (trouble breathing, coughing, or wheezing). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Anesthesia and Critical Care Concerns/Other Considerations
May also be used in detoxification with special guidelines
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Dry mouth.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Nursing: Physical Assessment/Monitoring
Do not use until patient has been opioid-free for 7-10 days. Assess carefully for several days following start of therapy for narcotic withdrawal symptoms or severe adverse reactions. Use non-narcotic analgesics for pain. Monitor for suicide ideation. Assess results of laboratory tests. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, microspheres for suspension, extended release:
Vivitrol™: 380 mg [contains polylactide-co-glycolide; packaged with diluent, syringe, needles, and safety device]
Tablet, as hydrochloride: 50 mg
Depade®: 25 mg, 50 mg, 100 mg
ReVia®: 50 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Naltrexone HCl)
50 mg (30): $103.99
Tablets (ReVia)
50 mg (30): $248.19
References
Kleber HD, “Naltrexone,” J Subst Abuse Treat, 1985, 2(2):117-22.
Mitchell JE, “Naltrexone and Hepatotoxicity,” Lancet, 1986, 1(8491):1215.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
O'Connor PG and Kosten TR, “Rapid and Ultrarapid Opioid Detoxification Techniques,” JAMA, 1998, 279(3):229-34.
Tang J, and Weiter JJ, “Branch Retinal Artery Occlusion After Injection of a Long-Acting Risperidone Preparation,” Annals Intern Med, 2007, 147(4): 283-3.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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