Vivitrol
(naltrexone)Dosage & Administration
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Vivitrol Prescribing Information
Treatment with VIVITROL should be part of a comprehensive management program that includes psychosocial support.
Alcohol Dependence
VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. Patients should not be actively drinking at the time of initial VIVITROL administration.
Opioid Dependence
VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification.
Important Dosage and Administration Information
VIVITROL must be prepared and administered by a healthcare provider.
VIVITROL must ONLY be administered as a deep intramuscular gluteal injection.
Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial [see Dosage and Administration ].
Prior to initiating VIVITROL, an opioid-free duration of a minimum of 7–10 days is recommended for patients, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization [see Warnings and Precautions ].
The recommended dose of VIVITROL is 380 mg delivered intramuscularly (deep) as a gluteal injection every 4 weeks or once a month, alternating buttocks for each subsequent injection, using the carton components provided [see How Supplied/Storage and Handling ]. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1 1/2 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 needle length is adequate for intramuscular administration. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1 1/2-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. Healthcare providers should ensure that the VIVITROL 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.
If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible.
Pretreatment with oral naltrexone is not required before using VIVITROL.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver, at the initial VIVITROL injection and with each subsequent injection. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose after VIVITROL treatment is discontinued, at the end of the VIVITROL dosing interval (i.e., near the end of the month that VIVITROL was administered), or after a dose of VIVITROL is missed, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Warnings and Precautions ].
Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information ].
Reinitiation of Treatment in Patients Previously Discontinued
There are no data to specifically address reinitiation of treatment. Patients reinitiating treatment with VIVITROL should be opioid-free at the time of dose administration [see Indications and Usage , Contraindications , and Warnings and Precautions ].
Switching From Oral Naltrexone
There are no systematically collected data that specifically address the switch from oral naltrexone to VIVITROL.
Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone
There are no systematically collected data that specifically address the switch from buprenorphine or methadone to VIVITROL; however, review of postmarketing case reports have indicated that some patients may experience severe manifestations of precipitated withdrawal when being switched from opioid agonist therapy to opioid antagonist therapy [see Warnings and Precautions ]. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers should be prepared to manage withdrawal symptomatically with non-opioid medications.
Directions for Use
VIVITROL must be prepared and administered by a healthcare provider.
VIVITROL must ONLY be administered as a deep intramuscular gluteal injection.
To ensure proper dosing, it is important that you follow the preparation and administration instructions outlined in this document.
VIVITROL must be suspended only in the diluent supplied in the carton and must be administered only with one of the administration needles supplied in the carton. The microspheres, diluent, preparation needle, and an administration needle with needle protection device are required for preparation and administration. Two thin-walled 1 1/2-inch needles with needle protection device and two 2-inch thin-walled needles with needle protection device have been provided to accommodate varying patient body habitus. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1 1/2-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. A spare administration needle of each size is provided in case of clogging [see How Supplied/Storage and Handling ]. Do not substitute any other components for the components of the carton.
Prior to preparation, allow drug to reach room temperature (approximately 45 minutes).
Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial [see Directions for Use, illustration below].
Keep out of reach of children.
Prepare and administer the VIVITROL suspension using aseptic technique.
WARNING: To reduce the risk of a needlestick:
- Do not intentionally disengage the needle protection device.
- Discard bent or damaged needle into a sharps container and use the spare needle provided. Do not attempt to straighten the needle or engage needle protection device if the needle is bent or damaged.
- Do not mishandle the needle protection device in a way that could lead to protrusion of the needle.
- Do not use free hand to press sheath over needle.
THE CARTON SHOULD NOT BE EXPOSED TO TEMPERATURES EXCEEDING 25 °C (77 °F).
The entire carton should be stored in the refrigerator (2 °C to 8 °C, 36 °F to 46 °F). Unrefrigerated, VIVITROL microspheres can be stored at temperatures not exceeding 25 °C (77 °F) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25 °C (77 °F). VIVITROL should not be frozen.
Parenteral products should be visually inspected for particulate matter and discoloration prior to administration. | |
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 | Inject the 3.4 mL of diluent into the VIVITROL microsphere vial. (see Figure C) |
 | Mix the powder and diluent by vigorously shaking the vial for approximately 1 minute. (see Figure D) Ensure that the dose is thoroughly suspended prior to proceeding to Step E. A PROPERLY MIXED SUSPENSION WILL BE MILKY WHITE, WILL NOT CONTAIN CLUMPS, AND WILL MOVE FREELY DOWN THE WALLS OF THE VIAL. |
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 | After the injection is administered, cover the needle by pressing the needle protection device against a flat surface using a one-handed technique to activate the safety mechanism away from self and others. (see Figure I) |
 | Visually confirm needle is fully engaged into the needle protection device. (see Figure J) DISPOSE OF USED AND UNUSED ITEMS IN PROPER WASTE CONTAINERS. |
VIVITROL is an off-white to light tan powder for injectable suspension in a 5 mL single-dose vial.
VIVITROL contains 380 mg of naltrexone in a microsphere formulation per vial (337 mg of naltrexone per gram of microspheres).
Pregnancy
Risk Summary
The available data from published case series with VIVITROL use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are clinical considerations (see Clinical Considerations). Reproduction and developmental animal studies have not been conducted for VIVITROL. Daily oral administration of naltrexone to female rats and rabbits increased the incidence of early fetal loss at exposures ≥ 11 times and ≥ 2 times the human exposure, respectively. Daily oral administration of naltrexone to pregnant rats and rabbits during the period of organogenesis did not induce malformation at exposures up to 175 times and 14 times the human exposure, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated maternal and embryo-fetal risk
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.
Published studies have demonstrated that alcohol is associated with fetal harm including growth restriction, facial abnormalities, central nervous system abnormalities, behavioral disorders, and impaired intellectual development.
Data
Animal Data
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.
Daily oral administration of 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 AUC(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).
Daily oral administration of naltrexone to rats and rabbits during the period of organogenesis did not induce malformations at doses up to 200 mg/kg/day (175- and 14-times the human exposure based on an AUC(0-28d) comparison, respectively).
Lactation
Risk Summary
Naltrexone and its major metabolite, 6β-naltrexol, are present in human milk. There are no data on the effects on the breastfed infant or the effects on milk production. The developmental health benefits of breastfeeding should be considered along with the mother's clinical need for naltrexone and any potential adverse effects on the breastfed infant from naltrexone or the mother's underlying maternal condition.
Pediatric Use
The safety and efficacy of VIVITROL have not been established in the pediatric population. The pharmacokinetics of VIVITROL 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 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 have not been evaluated in the geriatric population.
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Renal Impairment
Pharmacokinetics of VIVITROL 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 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 [see Clinical Pharmacology ].
Hepatic Impairment
The pharmacokinetics of VIVITROL 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 pharmacokinetics were not evaluated in subjects with severe hepatic impairment [see Clinical Pharmacology ].
VIVITROL is contraindicated in:
- Patients receiving opioid analgesics [see Warnings and Precautions ].
- Patients with current physiologic opioid dependence [see Warnings and Precautions ].
- Patients in acute opioid withdrawal [see Warnings and Precautions ].
- Any individual who has failed the naloxone challenge test or has a positive urine screen for opioids [see Warnings and Precautions ].
- Patients who have previously exhibited hypersensitivity to naltrexone, PLG, carboxymethylcellulose, or any other components of the diluent [see Warnings and Precautions ].
Vulnerability to Opioid Overdose
After opioid detoxification, patients are likely to have reduced tolerance to opioids. VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration. However, as the blockade wanes and eventually dissipates completely, patients who have been treated with VIVITROL may respond to lower doses of opioids than previously used, just as they would have shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment.
Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after VIVITROL treatment is discontinued, especially at the end of a dosing interval (i.e., near the end of the month that VIVITROL was administered), or after a dose of VIVITROL 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 Counseling Information ].
There is also the possibility that a patient who is treated with VIVITROL could overcome the opioid blockade effect of VIVITROL. Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. 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 especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade[see Patient Counseling Information ].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver, at the initial VIVITROL injection and with each subsequent injection. Because of the risks for opioid overdose described above, discuss with the patient and caregiver the importance of having access to naloxone for the emergency treatment of opioid overdose. Inform patients and caregivers of the options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Strongly consider prescribing naloxone for the emergency treatment of opioid overdose.
Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help in all cases of known or suspected opioid overdose, even if naloxone is administered [see Patient Counseling Information ].
Injection Site Reactions
VIVITROL must be prepared and administered by a healthcare provider.
VIVITROL must ONLY be administered as a deep intramuscular gluteal injection.
VIVITROL 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 is administered as a deep intramuscular gluteal injection, and inadvertent subcutaneous injection of VIVITROL may increase the likelihood of severe injection site reactions. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1 1/2 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. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1 1/2-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. Healthcare providers should ensure that the VIVITROL 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 provider [see Patient Counseling 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.
Precipitation of Opioid Withdrawal
The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal syndrome can be severe enough to require hospitalization. Review of postmarketing cases of precipitated opioid withdrawal in association with naltrexone treatment has identified cases with symptoms of withdrawal severe enough to require hospital admission, and in some cases, management in the intensive care unit.
To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or exacerbation of a pre-existing subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting VIVITROL treatment. An opioid-free interval of a minimum of 7–10 days is recommended for patients previously dependent on short-acting opioids. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks.
If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed.
In every case, healthcare providers should always be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use. Patients treated for alcohol dependence with VIVITROL should also be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with VIVITROL. 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 co-dependence on opioids.
Hepatotoxicity
Cases of hepatitis and clinically significant liver dysfunction were observed in association with VIVITROL exposure during the clinical development program and in the postmarketing period. Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials and postmarketing period. Although patients with clinically significant liver disease were not systematically studied, clinical trials did include patients with asymptomatic viral hepatitis infections. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae including acute liver injury.
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.
Depression and Suicidality
Alcohol- and opioid-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.
Alcohol Dependence
In controlled clinical trials of VIVITROL 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 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 that 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 in 624 alcohol-dependent patients, 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.
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 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 380 mg or placebo).
When Reversal of VIVITROL Blockade Is Required for Pain Management
In an emergency situation in patients receiving VIVITROL, 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 blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.
Eosinophilic Pneumonia
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. Similar cases have been reported in postmarketing use. 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.
Hypersensitivity Reactions Including Anaphylaxis
Cases of urticaria, angioedema, and anaphylaxis have been observed with use of VIVITROL 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.
Intramuscular Injections
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).
Alcohol Withdrawal
Use of VIVITROL does not eliminate nor diminish alcohol withdrawal symptoms.
Interference with Laboratory Tests
VIVITROL 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.