Can Aripiprazole Lauroxil cause product administered at inappropriate site?

ADVERSE REACTIONS The following are discussed in more details in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke [see Boxed Warning , Warnings and Precautions ( 5.2 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Metabolic Changes [see Warnings and Precautions ( 5.6 )] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions ( 5.7 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.8 )] Falls [see Warnings and Precautions ( 5.9 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.12 )] Body Temperature Regulation [see Warnings and Precautions ( 5.13 )] Dysphagia [see Warnings and Precautions ( 5.14 )] Most commonly observed adverse reaction with ARISTADA (incidence ≥5% and at least twice that for placebo) was akathisia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at 1-866-274-7823 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies 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. ARISTADA Patient Exposure ARISTADA has been evaluated for safety in 1180 adult patients in clinical trials in schizophrenia. Commonly Observed Adverse Reactions The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia. Adverse Reactions Occurring at an Incidence of 2% or More in ARISTADA-Treated Patients Adverse reactions associated with the use of ARISTADA (incidence of 2% or greater, rounded to the nearest percent and ARISTADA incidence greater than placebo) that occurred are shown in Table 8 . Table 8: Adverse Reaction in 2% or More of ARISTADA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial Adverse Reaction System Organ Class Preferred Term Placebo N=207 (%) Aripiprazole Lauroxil 441 mg N=207 (%) 882 mg N=208 (%) General disorders and administration site conditions Injection site pain 2 3 4 Investigations Increased weight 1 2 2 Increased blood creatine phosphokinase 0 2 1 Nervous system disorders Akathisia 4 11 11 Headache 3 3 5 Psychiatric disorders Insomnia 2 3 4 Restlessness 1 3 1 In an open label pharmacokinetic study, the adverse reactions associated with the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months were similar across the dose groups. Injection Site Reactions Injection site reactions were reported by 4% of patients treated with 441 mg ARISTADA and 5% of patients treated with 882 mg ARISTADA compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg ARISTADA, 882 mg ARISTADA and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of ARISTADA and placebo. Other injection site reactions (induration, swelling and redness) occurred at less than 1%. In an open label pharmacokinetic study evaluating 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months, injection site reactions were similar across the dose groups. Extrapyramidal Symptoms In the 12-week schizophrenia efficacy study [see Clinical Studies ( 14 )] , for ARISTADA-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patient ( Table 9 ). Table 9: Incidence of EPS Compared to Placebo ARISTADA Adverse Reaction Term Placebo N=207 (%) 441 mg N=207 (%) 882 mg N=208 (%) Akathisia 4 11 11 Restlessness 1 3 1 Other EPS 4 5 7 Dystonia 1 2 2 Parkinsonism 3 3 4 Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Cardiac – angina pectoris, tachycardia, palpitations Gastrointestinal disorders – constipation, dry mouth General disorders – asthenia Musculoskeletal – muscular weakness Nervous system disorders – dizziness Psychiatric disorders – anxiety, suicide Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for ARISTADA. Blood and Lymphatic System Disorders: thrombocytopenia Cardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failure Eye Disorders: photophobia, diplopia Gastrointestinal Disorders: gastroesophageal reflux disease General Disorders and Administration Site Conditions: peripheral edema, chest pain, face edema Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: fall, heat stroke Investigations: blood prolactin decreased, weight decreased, hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased, blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis, mobility decreased Nervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia, akinesia, coordination abnormal, speech disorder, choreoathetosis Psychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking Renal and Urinary Disorders: urinary retention, nocturia Reproductive System and Breast Disorders: erectile dysfunction, gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticaria Vascular Disorders: hypotension, hypertension 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure: occurrences of allerg

WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemia attack, including fatalities) ( 5.2 ). Potential for Dosing and Medication Errors : Substitution and dispensing errors between ARISTADA and ARISTADA INITIO could occur. Do not substitute ARISTADA INITIO for ARISTADA ( 5.3 ). Neuroleptic Malignant Syndrome : Manage with immediate discontinuation and close monitoring ( 5.4 ). Tardive Dyskinesia : Discontinue if clinically appropriate ( 5.5 ). Metabolic Changes : Monitor for hyperglycemia, dyslipidemia, and weight gain ( 5.6 ). Pathological Gambling and Other Compulsive Behaviors : Consider dose reduction or discontinuation ( 5.7 ). Orthostatic Hypotension : Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.8 ). Leukopenia, Neutropenia, and Agranulocytosis : Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors ( 5.10 ). Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.11 ). Potential for Cognitive and Motor Impairment : Use caution when operating machinery ( 5.12 ). 5.1 Increased Mortality in Elderly Patients with Dementia-related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ARISTADA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.2 )]. 5.2 Cerebrovascular Adverse Reactions, Including Stroke In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. ARISTADA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )]. 5.3 Potential for Dosing and Medication Errors Medication errors, including substitution and dispensing errors, between ARISTADA and ARISTADA INITIO could occur. ARISTADA INITIO is for single administration in contrast to ARISTADA which is administered monthly, every 6 weeks, or every 8 weeks [see Dosage and Administration ( 2.1 )] . Do not substitute ARISTADA INITIO for ARISTADA because of differing pharmacokinetic profiles [see Clinical Pharmacology ( 12.3 )]. 5.4 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur in association with antipsychotic drugs, including ARISTADA. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported. 5.5 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, ARISTADA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with ARISTADA drug discontinuation should be considered. However, some patients may require treatment with ARISTADA despite the presence of the syndrome. 5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia/ Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with oral aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patien