Naltrexone

Treatment with VIVITROL should be part of a comprehensive management program that includes psychosocial support. VIVITROL contains naltrexone, an opioid antagonist, and 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 ( 1.1 ). VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification ( 1.2 ). VIVITROL should be part of a comprehensive management program that includes psychosocial support ( 1 ).

1.1 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.

1.2 Opioid Dependence VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification.

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). VIVITROL is an injectable suspension containing 380 mg of naltrexone in a microsphere formulation in a single-dose vial ( 3 ).

VIVITROL is contraindicated in: Patients receiving opioid analgesics [see Warnings and Precautions ( 5.3 )] . Patients with current physiologic opioid dependence [see Warnings and Precautions ( 5.3 )] . Patients in acute opioid withdrawal [see Warnings and Precautions ( 5.3 )] . Any individual who has failed the naloxone challenge test or has a positive urine screen for opioids [see Warnings and Precautions ( 5.3 )] . Patients who have previously exhibited hypersensitivity to naltrexone, PLG, carboxymethylcellulose, or any other components of the diluent [see Warnings and Precautions ( 5.8 )]. VIVITROL is contraindicated in: Patients receiving opioid analgesics ( 4 ). Patients with current physiologic opioid dependence ( 4 ). Patients in acute opioid withdrawal ( 4 ). Any individual who has failed the naloxone challenge test or has a positive urine screen for opioids ( 4 ). Patients who have previously exhibited hypersensitivity to naltrexone, polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other components of the diluent ( 4 ).

Vulnerability to Opioid Overdose : Following VIVITROL treatment, opioid tolerance is reduced from pretreatment baseline and patients are vulnerable to potentially fatal overdose at the end of a dosing interval, after missing a dose, or after discontinuing VIVITROL treatment. Attempts to overcome blockade may also lead to fatal overdose. Strongly consider recommending or prescribing an opioid reversal agent (e.g., naloxone, nalmefene) for the emergency treatment of opioid overdose ( 5.1 ). Injection Site Reactions : VIVITROL must be prepared and administered by a healthcare provider. In some cases, injection site reactions may be very severe. Some cases of injection site reactions required surgical intervention ( 5.2 ). Precipitation of Opioid Withdrawal : Opioid-dependent and opioid-using patients, including those being treated for alcohol dependence, should be opioid-free before starting VIVITROL treatment, and should notify healthcare providers of any recent opioid use. 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 ( 5.3 ). Hepatotoxicity : Cases of hepatitis and clinically significant liver dysfunction were observed in association with VIVITROL treatment during the clinical development program and in the postmarketing period. Discontinue use of VIVITROL in the event of symptoms or signs of acute hepatitis ( 5.4 ). Depression and Suicidality : Monitor patients for the development of depression or suicidal thinking ( 5.5 ). 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 ( 5.6 ). Eosinophilic Pneumonia: Patients who develop dyspnea and hypoxemia should seek medical attention immediately. Consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics ( 5.7 ). Hypersensitivity Reactions Including Anaphylaxis: Cases of urticaria, angioedema, and anaphylaxis have been observed with the use of VIVITROL ( 5.8 ).

5.1 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 ( 17 )]. 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 ( 17 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose At the initial VIVITROL injection and with each subsequent injection, inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because of the risks for opioid overdose described above, both at the initial VIVITROL injection and with each subsequent injection, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered.

5.2 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. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Accidental Opioid Overdose [ see Warnings and Precautions ( 5.1 )] Injection Site Reactions [see Warnings and Precautions ( 5.2 )] Precipitated Opioid Withdrawal [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Depression and Suicidality [see Warnings and Precautions ( 5.5 )] Eosinophilic Pneumonia [see Warnings and Precautions ( 5.7 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )] The adverse events seen most frequently in association with VIVITROL therapy for alcohol dependence (i.e, those occurring in ≥5% and at least twice as frequently with VIVITROL than placebo) include nausea, vomiting, injection site reactions (including induration, pruritus, nodules and swelling), muscle cramps, dizziness or syncope, somnolence or sedation, anorexia, decreased appetite or other appetite disorders ( 6 ). The adverse events seen most frequently in association with VIVITROL therapy in opioid-dependent patients (i.e., those occurring in ≥2% of patients treated with VIVITROL and at least twice as frequently with VIVITROL than placebo) were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at 1-800-VIVITROL (1-800-848-4876) and/or email: usmedinfo@alkermes.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials during the premarketing development of VIVITROL, more than 1100 patients with alcohol and/or opioid dependence have been treated with VIVITROL. Approximately 700 patients have been treated for 6 months or more, and more than 400 for 1 year or longer. Adverse Events Leading to Discontinuation of Treatment Alcohol Dependence In controlled trials of 6 months or less in alcohol-dependent patients, 9% of alcohol-dependent patients treated with VIVITROL discontinued treatment due to an adverse event, as compared to 7% of the alcohol-dependent patients treated with placebo. Adverse events in the VIVITROL 380 mg group that led to more dropouts than in the placebo-treated group were injection site reactions (3%), nausea (2%), pregnancy (1%), headache (1%), and suicide-related events (0.3%). In the placebo group, 1% of patients withdrew due to injection site reactions, and 0% of patients withdrew due to the other adverse events. Opioid Dependence In a controlled trial of 6 months, 2% of opioid-dependent patients treated with VIVITROL discontinued treatment due to an adverse event, as compared to 2% of the opioid-dependent patients treated with placebo. Common Adverse Reactions Alcohol Dependence Table 1 lists all treatment-emergent clinical adverse reactions, regardless of causality, occurring in ≥5% of patients with alcohol dependence, for which the incidence was greater in the combined VIVITROL group than in the placebo group. A majority of patients treated with VIVITROL in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”. Table 1: Treatment-emergent Adverse Reactions (Reactions in ≥5% of patients with alcohol dependence treated with VIVITROL and occurring more frequently in the combined VIVITROL group than in the placebo group) Body System Adverse Reaction / Preferred Term Placebo Naltrexone for extended-release injectable suspension N=214 400 mg N=25 380 mg N=205 190 mg N=210 All N=440 N % N % N % N % N % a) Includes the preferred terms: diarrhea NOS; frequent bowel movements; gastrointestinal upset; loose stools b) Includes the preferred terms: abdominal pain NOS; abdominal pain upper; stomach discomfort; abdominal pain lower c) Includes the preferred terms: nasopharyngitis; pharyngitis streptococcal; pharyngitis NOS d) Includes the preferred terms: anxiety NEC; anxiety aggravated; agitation; obsessive compulsive disorder; panic attack; nervousness; posttraumatic stress e) Includes the preferred terms: malaise; fatigue (these two comprise the majority of cases); lethargy; sluggishness f) Includes the preferred terms: muscle cramps; spasms; tightness; twitching; stiffness; rigidity g) Includes the preferred terms: rash NOS; rash papular; heat rash h) Includes the preferred terms: headache NOS; sinus headache; migraine; frequent headaches Gastrointestinal Disorders Nausea 24 11 8 32 68 33 53 25 129 29 Vomiting NOS 12 6 3 12 28 14 22 10 53 12 Diarrhea a) 21 10 3 12 27 13 27 13 57 13 Abdominal pain b) 17 8 4 16 23 11 23 11 50 11 Dry Mouth 9 4 6 24 10 5 8 4 24 5 Infections & Infestations Pharyngitis c) 23 11 0 0 22 11 35 17 57 13 Psychiatric Disorders Insomnia, sleep disorder 25 12 2 8 29 14 27 13 58 13 Anxiety d) 17 8 2 8 24 12 16 8 42 10 Depression 9 4 0 0 17 8 7 3 24 5 General Disorders & Administration Site Conditions Any ISR 106 50 22 88 142 69 121 58 285 65 Injection site tenderness 83 39 18 72 92 45 89 42 199 45 Injection site induration 18 8 7 28 71 35 52 25 130 30 Injection site pain 16 7 0 0 34 17 22 10 56 13 Other ISR (primarily nodules, swelling) 8 4 8 32 30 15 16 8 54 12 Injection site pruritus 0 0 0 0 21 10 13 6 34 8 Injection site ecchymosis 11 5 0 0 14 7 9 4 23 5 Asthenic conditions e) 26 12 3 12 47 23 40 19 90 20 Musculoskeletal & Connective Tissue Disorders Arthralgia, arthritis, joint stiffness 11 5 1 4 24 12 12 6 37 9 Back pain, back stiffness 10 5 1 4 12 6 14 7 27 6 Muscle cramps f) 3 1 0 0 16 8 5 2 21 5 Skin & Subcutaneous Tissue Disorders Rash g) 8 4 3 12 12 6 10 5 25 6 Nervous System Disorders Headache h) 39 18 9 36 51 25 34 16 94 21 Dizziness, syncope 9 4 4 16 27 13 27 13 58 13 Somnolence, sedation 2 1 3 12 8 4 9 4 20 5 Metabolism & Nutrition Disorders Anorexia, appetite decreased NOS, appetite disorder NOS 6 3 5 20 30 14 13 6 48 11 Opioid Dependence In the open-label, long-term safety study conducted in the US, the commonly reported adverse reactions among the opioid-dependent patients in the study were similar to those commonly observed events in the alcohol-dependent populations in VIVITROL clinical trials as displayed in Table 1 , above. For example, injection site reactions of all types, nausea and diarrhea occurred in more than 5% of patients on VIVITROL in the open-label study. In contrast, 48% percent, of the opioid-dependent patients had at least one adverse event in the “Infections and Infestations” Body System. Adverse Reactions/Preferred Terms of nasopharyngitis, upper respiratory tract infection, urinary tract infection, and sinusitis were most commonly reported. In the placebo-controlled study in opioid-dependent patients conducted in Russia, the overall frequency of adverse events was lower than in the U.S. population described above. Table 2 lists treatment-emergent clinical adverse events, regardless of causality, occurring in ≥2% of patients with opioid dependence, for which the incidence was greater in the VIVITROL group than in the placebo group. […]

Patients taking VIVITROL may not benefit from opioid-containing medicines. Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations and opioid analgesics. Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations, and opioid analgesics ( 7 ).

Caution is recommended in administering VIVITROL to patients with moderate to severe renal impairment ( 8.6 ). VIVITROL pharmacokinetics have not been evaluated in subjects with severe hepatic impairment ( 8.7 ).

8.1 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).

8.2 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.

8.4 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.

8.5 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.

8.6 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 ( 12.3 )] .

8.7 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 ( 12.3 )] .

Naltrexone is an opioid antagonist with highest affinity for the mu opioid receptor. Naltrexone has little or no opioid agonist activity.