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Vivitrol

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Vivitrol

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hepatotoxicity

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 (naltrexone xr inj) 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 (naltrexone xr inj) should be discontinued in the event of symptoms and/or signs of acute hepatitis.

Injection Site Reactions

VIVITROL (naltrexone xr inj) injections may be followed by pain, tenderness, induration, swelling, erythema, bruising, or pruritus; however, in some cases injection site reactions may be very severe. 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. In the postmarketing period, additional cases of injection site reaction with features including induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported. Some cases required surgical intervention, including debridement of necrotic tissue. Some cases resulted in significant scarring. The reported cases occurred primarily in female patients.

VIVITROL (naltrexone xr inj) is administered as an intramuscular gluteal injection, and inadvertent subcutaneous injection of VIVITROL (naltrexone xr inj) may increase the likelihood of severe injection site reactions. The needles provided in the carton are customized needles. VIVITROL (naltrexone xr inj) must not be injected using any other needle. The needle lengths (either 1.5 inches or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that the proper needle is selected and that the needle length is adequate for intramuscular administration. Healthcare professionals should ensure that the VIVITROL (naltrexone xr inj) injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the provided needles.

Patients should be informed that any concerning injection site reactions should be brought to the attention of the healthcare professional [see PATIENT INFORMATION]. Patients exhibiting signs of abscess, cellulitis, necrosis, or extensive swelling should be evaluated by a physician to determine if referral to a surgeon is warranted.

Eosinophilic Pneumonia

In clinical trials with VIVITROL (naltrexone xr inj) , there was one diagnosed case and one suspected case of eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with antibiotics and corticosteroids. Similar cases have been reported in postmarketing use. Should a person receiving VIVITROL (naltrexone xr inj) 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.

Hypersensitivity Reactions Including Anaphylaxis

Cases of urticaria, angioedema, and anaphylaxis have been observed with use of VIVITROL (naltrexone xr inj) in the clinical trial setting and in postmarketing use. Patients should be warned of the risk of hypersensitivity reactions, including anaphylaxis. In the event of a hypersensitivity reaction, patients should be advised to seek immediate medical attention in a healthcare setting prepared to treat anaphylaxis. The patient should not receive any further treatment with VIVITROL (naltrexone xr inj) .

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, opioid-dependent patients, including those being treated for alcohol dependence, must be opioid-free for a minimum of 7-10 days before starting VIVITROL (naltrexone xr inj) 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 (naltrexone xr inj) . Patients treated for alcohol dependence with VIVITROL (naltrexone xr inj) should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with VIVITROL (naltrexone xr inj) . Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or dependence on opioids.

Opioid Overdose at the End of a Dosing Interval, After Missing a Dose and Following an Attempt to Overcome Opioid Blockade

After opioid detoxification, patients are likely to have reduced tolerance to opioids. Although VIVITROL (naltrexone xr inj) blocks the effects of exogenous opioids for 28 days after administration, cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval or when missing a dose. Patients who have been treated with VIVITROL (naltrexone xr inj) may 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 (naltrexone xr inj) treatment is discontinued. Reduced tolerance is especially of concern at the end of a dosing interval, that is, near the end of the month after VIVITROL (naltrexone xr inj) was administered, or after a dose of VIVITROL (naltrexone xr inj) is missed. It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose, [see PATIENT INFORMATION].

There is also the possibility that a patient who is treated with VIVITROL (naltrexone xr inj) could overcome the opioid blockade effect of VIVITROL (naltrexone xr inj) . Although VIVITROL (naltrexone xr inj) is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL (naltrexone xr inj) 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. 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 PATIENT INFORMATION].

Depression and Suicidality

Alcohol- and opioid-dependent patients, including those taking VIVITROL (naltrexone xr inj) , should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with VIVITROL (naltrexone xr inj) 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 professional.

Alcohol Dependence

In controlled clinical trials of VIVITROL (naltrexone xr inj) administered to adults with alcohol dependence, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with VIVITROL (naltrexone xr inj) 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 (naltrexone xr inj) .

Depression-related events associated with premature discontinuation of study drug were also more common in patients treated with VIVITROL (naltrexone xr inj) (~1%) than in placebo-treated patients (0).

In the 24-week, placebo-controlled pivotal trial in 624 alcohol-dependent patients, adverse events involving depressed mood were reported by 10% of patients treated with VIVITROL (naltrexone xr inj) 380 mg, as compared to 5% of patients treated with placebo injections.

Opioid Dependence

In an open-label, long-term safety study conducted in the US, adverse events of a suicidal nature (depressed mood, suicidal ideation, suicide attempt) were reported by 5% of opioid-dependent patients treated with VIVITROL (naltrexone xr inj) 380 mg (n=101) and 10% of opioid-dependent patients treated with oral naltrexone (n=20). In the 24-week, placebo-controlled pivotal trial that was conducted in Russia in 250 opioid-dependent patients, adverse events involving depressed mood or suicidal thinking were not reported by any patient in either treatment group (VIVITROL (naltrexone xr inj) 380 mg or placebo).

Intramuscular Injections

As with any intramuscular injection, VIVITROL (naltrexone xr inj) should be administered with caution to patients with thrombocytopenia or any coagulation disorder (e.g., hemophilia and severe hepatic failure).

When Reversal of VIVITROL (naltrexone xr inj) Blockade Is Required for Pain Management

In an emergency situation in patients receiving VIVITROL (naltrexone xr inj) , suggestions for pain management include regional analgesia or use of non-opioid analgesics. If opioid therapy is required as part of anesthesia or analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy must be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

Irrespective of the drug chosen to reverse VIVITROL (naltrexone xr inj) blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

Alcohol Withdrawal

Use of VIVITROL (naltrexone xr inj) does not eliminate nor diminish alcohol withdrawal symptoms.

Interference with Laboratory Tests

VIVITROL (naltrexone xr inj) may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine. For further information, reference to the specific immunoassay instructions is recommended.

Patient Counseling Information

See FDA-Approved Medication Guide.

Patient Information

Physicians should include the following issues in discussions with patients for whom they prescribe VIVITROL (naltrexone xr inj) :

  • Advise patients that a reaction at the site of VIVITROL (naltrexone xr inj) injection may occur. Reactions include pain, tenderness, induration, swelling, erythema, bruising, or pruritus. Serious injection site reactions including necrosis may occur. Patients should receive their injection from a healthcare professional qualified to administer the injection. Patients should be advised to seek medical attention for worsening skin reactions.
  • Advise patients that they should be off all opioid-containing medicines (including methadone or buprenorphine) for 7-10 days before starting VIVITROL (naltrexone xr inj) in order to avoid precipitation of opioid withdrawal. Advise patients that they should not take VIVITROL (naltrexone xr inj) if they have any symptoms of opioid withdrawal. Advise patients with alcohol dependence that it is imperative to notify health care professionals of any recent use of opioids or any history of opioid dependence before starting VIVITROL (naltrexone xr inj) to avoid precipitation of opioid withdrawal.
  • Advise patients that if they previously used opioids, they may be more sensitive to lower doses of opioids after VIVITROL (naltrexone xr inj) treatment is discontinued. It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose.
  • Advise patients that administration of large doses of heroin or any other opioid while on VIVITROL (naltrexone xr inj) may lead to serious injury, coma, or death. In addition, administration of previously-tolerated doses of opioids at the end of the dosing interval or after missing a dose may lead to overdose.
  • Advise patients that because VIVITROL (naltrexone xr inj) 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 (naltrexone xr inj) . Also, patients on VIVITROL (naltrexone xr inj) may not experience the same effects from opioid-containing analgesic, antidiarrheal, or antitussive medications.
  • Advise patients that VIVITROL (naltrexone xr inj) 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.
  • Advise patients that they may experience depression while taking VIVITROL (naltrexone xr inj) . It is important that patients inform family members and the people closest to the patient that they are taking VIVITROL (naltrexone xr inj) and that they should call a doctor right away should they become depressed or experience symptoms of depression.
  • Advise patients that they should not take VIVITROL (naltrexone xr inj) if they are allergic to VIVITROL (naltrexone xr inj) or any of the microsphere or diluent components.
  • Advise patients that VIVITROL (naltrexone xr inj) may cause an allergic pneumonia. Patients should immediately notify their physician if they develop signs and symptoms of pneumonia, including dyspnea, coughing, or wheezing.
  • Advise patients 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 patients obtain adequate medical treatment in an emergency.
  • Advise patients that they may experience nausea following the initial injection of VIVITROL (naltrexone xr inj) . 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 they may also experience tiredness, headache, vomiting, decreased appetite, painful joints and muscle cramps.
  • Advise patients that because VIVITROL (naltrexone xr inj) is an intramuscular injection and not an implanted device, once VIVITROL (naltrexone xr inj) is injected, it is not possible to remove it from the body.
  • Advise patients that VIVITROL (naltrexone xr inj) has been shown to treat alcohol and opioid dependence only when used as part of a treatment program that includes counseling and support.
  • Advise patients that dizziness may occur with VIVITROL (naltrexone xr inj) treatment, and they should avoid driving or operating heavy machinery until they have determined how VIVITROL (naltrexone xr inj) affects them.
  • Advise patients to notify their physician if they:
    - become pregnant or intend to become pregnant during treatment with VIVITROL (naltrexone xr inj) .
    - are breast-feeding.
    - experience respiratory symptoms such as dyspnea, coughing, or wheezing when taking VIVITROL (naltrexone xr inj) .
    - experience any allergic reactions when taking VIVITROL (naltrexone xr inj) .
    - experience other unusual or significant side effects while on VIVITROL (naltrexone xr inj) therapy.
  • Patients should be advised of any other risks and information based on the clinical judgment of their physician.

Frequently Asked Questions

1. Can I prepare the suspension prior to my patient's arrival?

No. You may remove the carton from the refrigerator prior to the patient's arrival, but once the diluent is added to the VIVITROL (naltrexone xr inj) Microspheres, the dose should be mixed and the suspension administered immediately. It is very important to use proper aseptic technique when preparing the suspension [see DOSAGE AND ADMINISTRATION].

2. How much time do I have between preparing and administering the dose?

It is recommended that the suspension be administered immediately once the product has been suspended and transferred into the syringe. If a few minutes' delay occurs after suspension but before transfer into the syringe [see DOSAGE AND ADMINISTRATION (Figure D)], the vial can be inverted a few times to resuspend and then transferred into the syringe for immediate use [see DOSAGE AND ADMINISTRATION].

3. Can I use needles other than those provided in the carton?

No. The needles in the carton are specially designed for administration of VIVITROL (naltrexone xr inj) . Do not make any substitutions for components of the carton [see DOSAGE AND ADMINISTRATION].

4. The suspension is milky white upon mixing with the diluent. Is this normal?

Yes. VIVITROL (naltrexone xr inj) Microspheres will form a milky suspension when mixed with the provided diluent [see DOSAGE AND ADMINISTRATION].

5. What if a needle clog occurs during administration of the product?

If a clog occurs during administration, the needle should be withdrawn from the patient, capped with the attached needle protection device, and replaced with the spare administration needle. Gently push on the plunger until a bead of the suspension appears at the tip of the needle. The remainder of the suspension should then be administered into an adjacent site in the same gluteal region [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: 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 a two-year Carcinogenicity study in rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of testicular mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (3-times the human exposure based on an AUC(0-28d) comparison) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day was 4% but only the incidence in females was increased compared with a maximum historical control incidence of 2% (3- and 32-times the human exposure based on an AUC(0-28d) comparison in males and females, respectively). There was no evidence of Carcinogenicity in a two-year dietary study with naltrexone in male and female mice (12- and 3-times the human exposure based on an AUC(0-28d) comparison, respectively). The clinical significance of these findings is not known.

Mutagenesis: 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.

Impairment of Fertility: Naltrexone given via oral gavage caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (75-times the human exposure based on an AUC(0-28d) comparison). There was no effect on male fertility at this dose level (6-times the human exposure based on an AUC(0-28d) comparison). The relevance of these observations to human fertility is not known.

Use In Specific Populations

Pregnancy

There are no adequate and well-controlled studies of either naltrexone or VIVITROL (naltrexone xr inj) in pregnant women. VIVITROL (naltrexone xr inj) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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: Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥ 30 mg/kg/day (11-times the human exposure based on an AU(0-28d) comparison) and to rabbits at oral doses ≥ 60 mg/kg/day (2-times the human exposure based on an AUC(0-28d) comparison).

There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (175- and 14-times the human exposure based on an AUC(0-28d) comparison, respectively).

Labor and Delivery

The potential effect of VIVITROL (naltrexone xr inj) on duration of labor and delivery in humans is unknown.

Nursing Mothers

Transfer of naltrexone and 6p-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 (naltrexone xr inj) , 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.

Pediatric Use

The safety and efficacy of VIVITROL (naltrexone xr inj) have not been established in the pediatric population. The pharmacokinetics of VIVITROL (naltrexone xr inj) have not been evaluated in a pediatric population.

Geriatric Use

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 (naltrexone xr inj) did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. No subjects over age 65 were included in studies of opioid-dependent subjects. The pharmacokinetics of VIVITROL (naltrexone xr inj) have not been evaluated in the geriatric population.

Renal Impairment

Pharmacokinetics of VIVITROL (naltrexone xr inj) are not altered in subjects with mild renal insufficiency (creatinine clearance of 50-80 mL/min). Dose adjustment is not required in patients with mild renal impairment. VIVITROL (naltrexone xr inj) 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 (naltrexone xr inj) to patients with moderate to severe renal impairment [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

The pharmacokinetics of VIVITROL (naltrexone xr inj) are not altered in subjects with mild to moderate hepatic impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required in subjects with mild or moderate hepatic impairment. VIVITROL (naltrexone xr inj) pharmacokinetics were not evaluated in subjects with severe hepatic impairment [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 11/8/2010
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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