Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses.
Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects.
The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only five-fold or less. VIVITROL does not appear to be a hepatotoxin at the recommended doses.
Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of VIVITROL should be discontinued in the event of symptoms and/or signs of acute hepatitis.
In clinical trials with VIVITROL, there was one diagnosed case and one suspected case of eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with antibiotics and corticosteroids. Should a person receiving VIVITROL develop progressive dyspnea and hypoxemia, the diagnosis of eosinophilic pneumonia should be considered (see ADVERSE REACTIONS ). Patients should be warned of the risk of eosinophilic pneumonia, and advised to seek medical attention should they develop symptoms of pneumonia. Clinicians should consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics.
Unintended Precipitation of Opioid Withdrawal
To prevent occurrence of an acute abstinence syndrome (withdrawal) in patients dependent on opioids, or exacerbation of a pre-existing subclinical abstinence syndrome, patients must be opioid-free for a minimum of 7-10 days before starting VIVITROL treatment . Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge test should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of VIVITROL .
Opioid Overdose F ollowing an Attempt to Overcome Opiate Blockade
VIVITROL is not indicated for the purpose of opioid blockade or the treatment of opiate dependence. Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Indeed, any attempt by a patient to overcome the antagonism by taking opioids is very dangerous and may lead to fatal overdose. Injury may arise because the plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. As a consequence, the patient may be in immediate danger of suffering life-endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of trying to overcome the opioid blockade (see INFORMATION FOR PATIENTS ).
There is also the possibility that a patient who had been treated with VIVITROL will respond to lower doses of opioids than previously used. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.). Patients should be aware that they may be more sensitive to lower doses of opioids after VIVITROL treatment is discontinued (see INFORMATION FOR PATIENTS ).
When Reversal of VIVITROL Blockade Is Required for Pain Management
In an emergency situation in patients receiving VIVITROL, a suggested plan for pain management is regional analgesia, conscious sedation with a benzodiazepine, and use of non-opioid analgesics or general anesthesia.
In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.
A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction), presumably due to histamine release.
Irrespective of the drug chosen to reverse VIVITROL blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.
Depression and Suicidality
In controlled clinical trials of VIVITROL, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with VIVITROL than in patients treated with placebo (1% vs. 0). In some cases, the suicidal thoughts or behavior occurred after study discontinuation, but were in the context of an episode of depression which began while the patient was on study drug. Two completed suicides occurred, both involving patients treated with VIVITROL.
Depression-related events associated with premature discontinuation of study drug were also more common in patients treated with VIVITROL (~1%) than in placebo-treated patients (0).
In the 24-week, placebo-controlled pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with VIVITROL 380 mg, as compared to 5% of patients treated with placebo injections.
Alcohol dependent patients, including those taking VIVITROL, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with VIVITROL should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.
Injection Site Reactions
VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema or pruritus. In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision. Additional cases of injection site reaction with features including abscess, sterile abscess, induration, and necrosis, some of which resulted in surgical intervention, have been reported during postmarketing surveillance. Patients should be informed that any concerning injection site reactions should be brought to the attention of the physician (see INFORMATION FOR PATIENTS ).
VIVITROL pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency. Because naltrexone and its primary metabolite are excreted primarily in the urine, caution is recommended in administering VIVITROL to patients with moderate to severe renal impairment.
Use of VIVITROL does not eliminate nor diminish alcohol withdrawal symptoms.
As with any intramuscular injection, VIVITROL should be administered with caution to patients with thrombocytopenia or any coagulation disorder (e.g., hemophilia and severe hepatic failure).
Information for Patients
Physicians should discuss the following issues with patients for whom they prescribe VIVITROL:
- Patients should be advised to carry documentation to alert medical personnel to the fact that they are taking VIVITROL (naltrexone for extended-release injectable suspension). This will help to ensure that the patients obtain adequate medical treatment in an emergency.
- Patients should be advised that administration of large doses of heroin or any other opioid while on VIVITROL may lead to serious injury, coma, or death.
- Patients should be advised that because VIVITROL can block the effects of opiates and opiate-like drugs, patients will not perceive any effect if they attempt to self-administer heroin or any other opioid drug in small doses while on VIVITROL. Also, patients on VIVITROL may not experience the same effects from opioid containing analgesic, antidiarrheal, or antitussive medications.
- Patients should be advised that if they previously used opioids, they may be more sensitive to lower doses of opioids after VIVITROL treatment is discontinued.
- Patients should be advised that VIVITROL may cause liver injury in people who develop liver disease from other causes. Patients should immediately notify their physician if they develop symptoms and/or signs of liver disease.
- Patients should be advised that VIVITROL may cause an allergic pneumonia. Patients should immediately notify their physician if they develop signs and symptoms of pneumonia, including dyspnea, coughing or wheezing.
- Patients should be advised that a reaction at the site of VIVITROL injection may occur. Reactions include pain, tenderness, induration, swelling, erythema, and pruritus. Rarely, serious injection site reactions may occur. Patients should be advised to seek medical attention for worsening skin reactions, particularly if the reaction does not improve one month following the injection.
- Patients should be advised that they may experience nausea following the initial injection of VIVITROL. These episodes of nausea tend to be mild and subside within a few days post-injection. Patients are less likely to experience nausea in subsequent injections.
- Patients should be advised that because VIVITROL is an intramuscular injection and not an implanted device, once VIVITROL is injected, it is not possible to remove it from the body.
- Patients should be advised that VIVITROL has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.
- Patients should be advised to notify their physician if they:
- become pregnant or intend to become pregnant during treatment with VIVITROL.
- are breast-feeding.
- experience respiratory symptoms such as dyspnea, coughing, or wheezing when taking VIVITROL.
- experience significant pain or redness at the site of injection, particularly if the reaction does not improve one month following the injection.
- experience other unusual or significant side effects while on VIVITROL therapy.
Patients taking VIVITROL may not benefit from opioid-containing medicines (see PRECAUTIONS, Pain Management ).
Because naltrexone is not a substrate for CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes are unlikely to change the clearance of VIVITROL. No clinical drug interaction studies have been performed with VIVITROL to evaluate drug interactions, therefore prescribers should weigh the risks and benefits of concomitant drug use.
The safety profile of patients treated with VIVITROL concomitantly with antidepressants was similar to that of patients taking VIVITROL without antidepressants.
Carcinogen e sis, mutagen e sis , impairment of fertility
Carcinogenicity studies have not been conducted with VIVITROL.
Carcinogenicity studies of oral naltrexone hydrochloride (administered via the diet) have been conducted in rats and mice. In rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The clinical significance of these findings is not known.
Naltrexone was negative in the following in vitro genotoxicity studies: bacterial reverse mutation assay (Ames test), the heritable translocation assay, CHO cell sister chromatid exchange assay, and the mouse lymphoma gene mutation assay. Naltrexone was also negative in an in vivo mouse micronucleus assay. In contrast, naltrexone tested positive in the following assays: Drosophila recessive lethal frequency assay, non-specific DNA damage in repair tests with E. coli and WI-38 cells, and urinalysis for methylated histidine residues.
Naltrexone given orally caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (600 mg/m2/day). There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.
Pregnancy Category C
Reproduction and developmental studies have not been conducted for VIVITROL. Studies with naltrexone administered via the oral route have been conducted in pregnant rats and rabbits.
Teratogenic Effects: Oral naltrexone has been shown to increase the incidence of early fetal loss in rats administered ≥ 30 mg/kg/day (180 mg/m2/day) and rabbits administered ≥ 60 mg/kg/day (720 mg/m2/day).
There are no adequate and well-controlled studies of either naltrexone or VIVITROL in pregnant women. VIVITROL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The potential effect of VIVITROL on duration of labor and delivery in humans is unknown.
Transfer of naltrexone and 6β-naltrexol into human milk has been reported with oral naltrexone. Because of the potential for tumorigenicity shown for naltrexone in animal studies, and because of the potential for serious adverse reactions in nursing infants from VIVITROL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and efficacy of VIVITROL have not been established in the pediatric population.
In trials of alcohol dependent subjects, 2.6% (n=26) of subjects were >65 years of age, and one patient was >75 years of age. Clinical studies of VIVITROL did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.