b'T:7.875"S:7"Generally, these risks are greatest at the beginning of treatment and during doseTable 2:Continued36 escalation. Patients at increased risk of these adverse reactions or at increased risk ofAripiprazole Lauroxildeveloping complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., Placebo441 mg882 mg heart failure, myocardial infarction, ischemia, or conduction abnormalities), history ofAdverse Reaction System Organ Class N = 207N = 207N = 208 cerebrovascular disease, as well as patients who are antipsychotic-nave. In such Preferred Term (%) (%) (%)patients, consider using a lower starting dose, and monitor orthostatic vital signs. Orthostatic hypotension was reported for 1 patient in the ARISTADA 882 mg group (0.5%)Psychiatric disordersand no patients in the ARISTADA 441 mg and placebo groups in the 12-week schizophrenia Insomnia 2 3 4efficacy study. In the long-term open-label schizophrenia study, orthostatic hypotension was reported for 1 (0.2%) patient treated with ARISTADA. Orthostatic hypotension was defined Restlessness 1 3 1as a decrease in systolic blood pressure 20 mmHg accompanied by an increase in heartIn an open-label pharmacokinetic study, the adverse reactions associated with rate 25 bpm when comparing standing to supine values. the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months Falls: Antipsychotics including ARISTADA may cause somnolence, postural hypotension, orwere similar across the dose groups.motor and sensory instability, which may lead to falls and, consequently, fractures or otherInjection-Site Reactions: Injection-site reactions were reported by 4% of patients injuries. For patients with diseases, conditions, or medications that could exacerbate thesetreated with 441 mg ARISTADA and 5% of patients treated with 882 mg ARISTADA effects, complete fall risk assessments when initiating antipsychotic treatment andcompared to 2% of patients treated with placebo. Most of these were injection-site recurrently for those patients on long-term antipsychotic therapy. pain (3%, 4%, and 2% in the 441 mg ARISTADA, 882 mg ARISTADA, and placebo groups, Leukopenia, Neutropenia, and Agranulocytosis: In clinical trials and/or postmarketingrespectively), and most were associated with the first injection and decreased with each experience, events of leukopenia and neutropenia have been reported temporally relatedsubsequent injection to less than or equal to 1% for both doses of ARISTADA and to antipsychotic agents. Agranulocytosis has also been reported. placebo. Other injection-site reactions (induration, swelling, and redness) occurredPossible risk factors for leukopenia/neutropenia include pre-existing low white blood cellat less than 1%. In an open-label pharmacokinetic study evaluating 441 mg monthly,count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/ 882 mg every 6 weeks, and 1064 mg every 2 months, injection-site reactions were neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-inducedsimilar across the dose groups. leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the firstExtrapyramidal Symptoms: In the 12-week schizophrenia efficacy study, for few months of therapy. In such patients, consider discontinuation of ARISTADA at the firstARISTADA-treated patients, the incidence of other EPS-related events, excluding sign of a clinical significant decline in WBC in the absence of other causative factors.akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, Monitor patients with clinically significant neutropenia for fever or other symptoms orrespectively, versus 4% for placebo-treated patients (Table 3).signs of infection and treat promptly if such symptoms or signs occur. Discontinue3 Table 3: Incidence of EPS Compared to Placebo ARISTADA in patients with severe neutropenia (absolute neutrophil count 1000/mm) and follow their WBC until recovery. ARISTADASeizures: As with other antipsychotic drugs, use ARISTADA cautiously in patients with Placebo441 mg882 mg a history of seizures or with conditions that lower the seizure threshold. Conditions thatN = 207N = 207N = 208 lower the seizure threshold may be more prevalent in a population of 65 years or older. Adverse Reaction Term (%) (%) (%)Potential for Cognitive and Motor Impairment: ARISTADA, like other antipsychotics, hasAkathisia 4 11 11the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonablyRestlessness 1 3 1certain that therapy with ARISTADA does not affect them adversely. Other EPS 4 5 7Body Temperature Regulation: Disruption of the bodys ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when Dystonia 1 2 2prescribing ARISTADA for patients who will be experiencing conditions which may Parkinsonism 3 3 4 S:10" T:10.75"contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or beingDystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, subject to dehydration). may occur in susceptible individuals during the first few days of treatment. Dystonic Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychoticsymptoms include: spasm of the neck muscles, sometimes progressing to tightness of drug use. ARISTADA and other antipsychotic drugs should be used cautiously in patients atthe throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. risk for aspiration pneumonia. While these symptoms can occur at low doses, they occur more frequently and with ADVERSE REACTIONS greater severity with high potency and at higher doses of first-generation antipsychotic Clinical Studies Experience: Because clinical trials are conducted under widely varyingdrugs. An elevated risk of acute dystonia is observed in males and younger age groups.conditions, adverse reaction rates observed in the clinical trials of a drug cannot beOther Adverse Reactions Observed in Clinical Studies: The following listing doesdirectly compared to rates in the clinical trials of another drug and may not reflect thenot include reactions: 1) already listed in previous tables or elsewhere in labeling,rates observed in practice. 2) for which a drug cause was remote, 3) which were so general as to be Patient Exposure: ARISTADA has been evaluated for safety in 1180 adult patients in clinicaluninformative, 4) which were not considered to have significant clinical implications, trials in schizophrenia. or 5) which occurred at a rate equal to or less than placebo.Commonly Observed Adverse Reactions: The most common adverse reaction (incidenceCardiacangina pectoris, tachycardia, palpitations5% and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia.Gastrointestinal disordersconstipation, dry mouth General disordersastheniaAdverse Reactions Occurring at an Incidence of 2% or More in ARISTADA-Treated Patients.Musculoskeletalmuscular weakness Adverse reactions associated with the use of ARISTADA (incidence of 2% or greater,Nervous system disordersdizzinessrounded to the nearest percent and ARISTADA incidence greater than placebo) thatPsychiatric disordersanxiety, suicideoccurred are shown in Table 2. Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole: The Table 2:Adverse Reaction in 2% or More of ARISTADA-Treated Patients and That following is a list of additional adverse reactions that have been reported in clinical Occurred at Greater Incidence Than in the Placebo-Treated Patients intrials with oral aripiprazole and not reported above for ARISTADA. the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial Blood and Lymphatic System Disorders: thrombocytopenia Cardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block, Aripiprazole Lauroxil atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failure Placebo441 mg882 mgEye Disorders: photophobia, diplopia Adverse Reaction System Organ Class N = 207N = 207N = 208Gastrointestinal Disorders: gastroesophageal reflux diseasePreferred Term (%) (%) (%) General Disorders and Administration-Site Conditions: peripheral edema, chest pain, face edema General disorders and administration site conditions Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivityInjection site pain 2 3 4 Injury, Poisoning, and Procedural Complications: fall, heat strokeInvestigations Investigations: weight decreased, hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased, bloodIncreased weight 1 2 2 prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Increased blood creatine0 2 1 Metabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemia phosphokinase Musculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis, Nervous system disorders mobility decreased Nervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia,Akathisia 4 11 11 myoclonus, bradykinesia, akinesia, coordination abnormal, speech disorder,Headache 3 3 5 choreoathetosis Psychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking'