Naltrexoneside effects

The following clinically significant adverse reactions are described elsewhere in the labeling: Accidental Opioid Overdose Injection Site Reactions Precipitated Opioid Withdrawal Hepatotoxicity Depression and Suicidality Eosinophilic Pneumonia Hypersensitivity Reactions 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. 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. 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. All adverse events were assessed as having a maximum intensity of “mild” or “moderate.” Table 2: Treatment-emergent Clinical Adverse Events (Events in ≥2% of patients with opioid dependence treated with VIVITROL and occurring more frequently in the VIVITROL group than in the placebo group) Body System Adverse Event / Preferred Term Placebo N=124 VIVITROL 380 mg N=126 n % n % Investigations Alanine aminotransferase increased 7 6 16 13 Aspartate aminotransferase increased 3 2 13 10 Gamma-glutamyltransferase increased 4 3 9 7 Infections and Infestations Nasopharyngitis 3 2 9 7 Influenza 5 4 6 5 Psychiatric Disorders Insomnia 1 1 8 6 Vascular Disorders Hypertension 4 3 6 5 General Disorders and Administration Site Conditions Injection site pain 1 1 6 5 Gastrointestinal Disorders Toothache 2 2 5 4 Nervous System Disorders Headache 3 2 4 3 Laboratory Tests Eosinophil Count In clinical trials, subjects on VIVITROL had increases in eosinophil counts relative to subjects on placebo. With continued use of VIVITROL, eosinophil counts returned to normal over a period of several months. Platelet Count VIVITROL 380 mg was associated with a decrease in platelet count. In clinical trials, alcohol-dependent patients treated with VIVITROL experienced a mean maximal decrease in platelet count of 17.8 × 10 3 /μL, compared to 2.6 × 10 3 /μL in placebo patients. After 24 weeks of treatment, opioid-dependent patients treated with VIVITROL experienced a mean maximal decrease in platelet count of 62.8 × 10 3 /μL, compared to 39.9 × 10 3 /μL in placebo patients. In randomized controlled trials, VIVITROL was not associated with an increase in bleeding-related adverse events. Hepatic Enzyme Elevations In short-term, controlled trials, in alcohol-dependent patients, the incidence of AST elevations associated with VIVITROL treatment was similar to that observed with oral naltrexone treatment (1.5% each) and slightly higher than observed with placebo treatment (0.9%). In the 6-month controlled trial conducted in opioid-dependent subjects, 89% had a baseline diagnosis of hepatitis C infection, and 41% had a baseline diagnosis of HIV infection. There were frequently observed elevated liver enzyme levels (ALT, AST, and GGT); these were more commonly reported as adverse events in the VIVITROL 380 mg group than in the placebo group. Patients could not enroll in this trial if they had a baseline ALT or AST value that was more than three times the upper limit of normal. More patients treated with VIVITROL in this study experienced treatment-emergent elevations in transaminases to more than three times the upper limit of normal than patients treated with placebo. Shifts to more than three times the upper limit of normal occurred in 20% of patients treated with VIVITROL as compared with 13% of placebo patients. Shifts in values of AST to more than three times the upper limit were also more common in the VIVITROL (14%) arm compared with the placebo (11%) arm. Opioid-dependent patients treated with VIVITROL experienced a mean maximal increase from baseline ALT levels of 61 IU/L compared with 48 IU/L in placebo patients. Similarly for AST, opioid-dependent patients treated with VIVITROL experienced a mean maximal increase from baseline AST levels of 40 IU/L compared with 31 IU/L in placebo patients. Creatinine Phosphokinase In short-term controlled trials in alcohol-dependent patients, more patients treated with VIVITROL 380 mg (11%) and oral naltrexone (17%) shifted from normal creatinine phosphokinase (CPK) levels before treatment to abnormal CPK levels at the end of the trials, compared to placebo patients (8%). In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. For both the oral naltrexone and VIVITROL 380 mg groups, CPK abnormalities were most frequently in the range of 1–2 × ULN. However, there were reports of CPK abnormalities as high as 4x ULN for the oral naltrexone group, and 35 × ULN for the VIVITROL 380 mg group. Overall, there were no differences between the placebo and naltrexone (oral or injectable) groups with respect to the proportions of patients with a CPK value at least three times the upper limit of normal. No factors other than naltrexone exposure were associated with the CPK elevations. More opioid-dependent patients treated with VIVITROL 380 mg (39%) shifted from normal creatinine phosphokinase (CPK) levels before treatment to abnormal CPK levels during the study as compared to patients treated with placebo (32%). There were reports of CPK abnormalities as high as 41.8 × ULN for the placebo group, and 22.1 × ULN for the VIVITROL 380 mg group. Other Events Observed During the VIVITROL Clinical Studies The following is a list of treatment-emergent adverse reactions reported by alcohol- and/or opioid-dependent subjects treated with VIVITROL in all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events that were so general as to be uninformative, and those events reported only once that did not have a substantial probability of being acutely life-threatening. Blood and Lymphatic System Disorders – lymphadenopathy (including cervical adenitis), white blood cell count increased Cardiac Disorders – angina pectoris, angina unstable, atrial fibrillation, cardiac failure congestive, coronary artery atherosclerosis, myocardial infarction, palpitations Eye Disorders – conjunctivitis, vision blurred Gastrointestinal Disorders – abdominal discomfort, colitis, constipation, flatulence, gastroesophageal reflux disease, gastrointestinal hemorrhage, hemorrhoids, pancreatitis acute, paralytic ileus, perirectal abscess General Disorders and Administration Site Conditions – chest pain, chest tightness, chills, face edema, irritability, lethargy, pyrexia, rigors Hepatobiliary Disorders – cholecystitis acute, cholelithiasis Immune System Disorders – seasonal allergy, hypersensitivity reaction (including angioneurotic edema and urticaria) Infections and Infestations – bronchitis, gastroenteritis, laryngitis, pneumonia, sinusitis, tooth abscess, upper respiratory tract infection, urinary tract infection, advanced HIV disease in HIV-infected patients Investigations – weight decreased, weight increased Metabolism and Nutrition Disorders – appetite increased, dehydration, heat exhaustion, hypercholesterolemia Musculoskeletal and Connective Tissue Disorders – joint stiffness, muscle spasms, myalgia, pain in limb Nervous System Disorders – cerebral arterial aneurysm, convulsions, disturbance in attention, dysgeusia, mental impairment, migraine, ischemic stroke, paresthesia Pregnancy, Puerperium, and Perinatal Conditions – abortion missed Psychiatric Disorders – abnormal dreams, agitation, alcohol withdrawal syndrome, euphoric mood, delirium, libido decreased Respiratory, Thoracic, and Mediastinal Disorders – chronic obstructive pulmonary disease, dyspnea, pharyngolaryngeal pain, sinus congestion Skin and Subcutaneous Tissue Disorders – night sweats, pruritus, sweating increased Vascular Disorders – deep venous thrombosis, hot flushes, pulmonary embolism

6.2 Postmarketing

Experience Adverse Events Following Patient Self-Administration Adverse events including injection site reactions and precipitated opioid withdrawal resulting in serious outcomes, including hospitalization, have been reported following patient self-administration of VIVITROL. VIVITROL must be prepared and administered by a healthcare provider. Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been reported during postmarketing surveillance. Reports From Other Intramuscular Drug Products Containing Polylactide-co-glycolide (PLG) Microspheres Retinal Artery Occlusion Retinal artery occlusion after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres has been reported very rarely during postmarketing surveillance. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during VIVITROL clinical trials or postmarketing surveillance. VIVITROL should be administered by intramuscular (IM) injection into the gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel.