ADVERSE REACTIONS SECTION.

6 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 )] 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 orwww.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 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 ExposureARISTADA has been evaluated for safety in 1180 adult patients in clinical trials in schizophrenia.. Commonly Observed Adverse ReactionsThe 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 PatientsAdverse 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 TrialAdverse Reaction System Organ ClassPreferred TermPlacebo N=207(%)Aripiprazole Lauroxil441 mg N=207(%)882 mg N=208(%)General disorders and administration site conditionsInjection site pain234InvestigationsIncreased weight122Increased blood creatine phosphokinase021Nervous system disordersAkathisia41111Headache335Psychiatric disordersInsomnia234Restlessness131In an open label pharmacokinetic study, the adverse reactions associated with the use of 441 mg monthly, 882 mg every weeks, and 1064 mg every months were similar across the dose groups.. Injection Site ReactionsInjection 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 weeks, and 1064 mg every months, injection site reactions were similar across the dose groups.. Extrapyramidal SymptomsIn 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 PlaceboARISTADAAdverse Reaction TermPlaceboN=207(%)441 mgN=207(%)882 mgN=208(%)Akathisia41111Restlessness131Other EPS457 Dystonia122 Parkinsonism334. DystoniaSymptoms 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 StudiesThe following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which 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 rate equal to or less than placebo.Cardiac angina pectoris, tachycardia, palpitationsGastrointestinal disorders constipation, dry mouthGeneral disorders astheniaMusculoskeletal muscular weaknessNervous system disorders dizzinessPsychiatric disorders anxiety, suicide. Adverse Reactions Reported in Clinical Trials with Oral AripiprazoleThe following is 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: thrombocytopeniaCardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failureEye Disorders: photophobia, diplopiaGastrointestinal Disorders: gastroesophageal reflux diseaseGeneral Disorders and Administration Site Conditions: peripheral edema, chest pain, face edemaHepatobiliary Disorders: hepatitis, jaundiceImmune System Disorders: hypersensitivityInjury, Poisoning, and Procedural Complications: fall, heat strokeInvestigations: 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 increasedMetabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemiaMusculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis, mobility decreasedNervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia, akinesia, coordination abnormal, speech disorder, choreoathetosisPsychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walkingRenal and Urinary Disorders: urinary retention, nocturiaReproductive System and Breast Disorders: erectile dysfunction, gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapismRespiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspneaSkin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticariaVascular 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 population of uncertain size, it is not always possible to reliably estimate their frequency or to establish causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups, blood glucose fluctuation, oculogyric crisis, and drug reaction with eosinophilia and systemic symptoms (DRESS).

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Intramuscular administration of aripiprazole lauroxil to rats and dogs was associated with injection site tissue reactions at all doses in rats treated up to months at doses of 15, 29, and 103 mg/animal (which are approximately 0.3 to times and 0.5 to times the MRHD of 1064 mg on mg/m2 basis in males and females, respectively) and in dogs treated up to months at doses of 147, 662, and 2058 mg/animal (which are approximately 0.5 to times and 0.6 to times the MRHD in males and females, respectively on mg/m2 basis). These injection site tissue reactions consisted of localized granulomatous inflammation and granuloma formation. Transiently impaired limb function and swelling occurred in dogs. The granulomas did not completely resolve months following the last injection in the month rat study and months following the last injection in the month dog study (the low dose groups were not examined for reversibility in these studies).Orally administered aripiprazole produced retinal degeneration in albino rats in 26-week chronic toxicity study at dose of 60 mg/kg, which is 19 times the oral MRHD of 30 mg/day on mg/m2 basis, and in 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg, which are 13 and 19 times the oral MRHD on mg/m2 basis and to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

BOXED WARNING SECTION.

WARNING: 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. ARISTADA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSISSee full prescribing information for complete boxed warning.Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. (5.1)ARISTADA is not approved for the treatment of patients with dementia-related psychosis. (5.1). Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. (5.1). ARISTADA is not approved for the treatment of patients with dementia-related psychosis. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLifetime carcinogenicity studies have not been conducted with aripiprazole lauroxil.Lifetime carcinogenicity studies with oral aripiprazole have been conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to times and 0.3 to times the oral MRHD of 30 mg/day based on mg/m2, respectively). In addition, SD rats were dosed orally for years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the oral MRHD based on mg/m2). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses which are 0.1 to 0.9 times human exposure at the oral MRHD based on AUC and 0.5 to times the oral MRHD on mg/m2 basis. In female rats, the incidence of mammary gland fibroadenomas was increased at dietary dose which is 0.1 times human exposure at the oral MRHD based on AUC and times the oral MRHD on mg/m2 basis; and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose which is 14 times human exposure at oral MRHD based on AUC and 19 times the oral MRHD on mg/m2 basis.Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.. MutagenesisAripiprazole lauroxil was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosome aberration assay in human peripheral blood lymphocytes.Aripiprazole and its metabolite (2,3-DCPP) were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung (CHL) cells both in the presence and absence of metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. positive response was obtained in the oral in vivo micronucleus assay in mice; however, the response was due to mechanism not considered relevant to humans.. Impairment of Fertility. Animal Data for Aripiprazole LauroxilIn rat fertility study, aripiprazole lauroxil was administered intramuscularly. Males were treated with doses of 18, 49, or 144 mg /animal, which are approximately 0.4 to times the MRHD of 1064 mg on mg/m2 basis, on Days 1, 21, and 42 prior to and through mating; females were treated at these doses, which are approximately 0.6 to times the MRHD on mg/m2 basis, once 14 days prior to mating.In females, persistent diestrus was observed at all doses and the mean number of cycles was significantly decreased at the highest dose together with an increase in the copulatory interval (delay in mating). Additional changes at the high dose included slight increases in corpora lutea and pre-implantation loss, decline in mating, fertility, and fecundity indices in females and lower mating and fertility indices in males.. Animal Data for AripiprazoleFemale rats were treated with oral aripiprazole doses of 2, 6, and 20 mg/kg/day, which are 0.6 to times the oral MRHD of 30 mg/day on mg/m2 basis, from weeks prior to mating through day of gestation. Estrous cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was observed. Increased pre-implantation loss was found at and times the oral MRHD on mg/m2 basis and decreased fetal weight was noted at the highest dose which is times the oral MRHD on mg/m2 basis.Male rats were treated with oral aripiprazole doses of 20, 40, and 60 mg/kg/day, which are to 19 times the oral MRHD on mg/m2 basis, from weeks prior to and through mating. Disturbances in spermatogenesis at the highest dose and prostate atrophy at the mid and high doses were noted which are 13 and 19 times the oral MRHD on mg/m2 basis, but no impairment of fertility was observed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Aripiprazole lauroxil is prodrug of aripiprazole. Following intramuscular injection, aripiprazole lauroxil is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The mechanism of action of aripiprazole in schizophrenia is unknown. However, efficacy could be mediated through combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.. 12.2 Pharmacodynamics. Aripiprazole exhibits high affinity for dopamine D2 and D3 (Kis 0.34 and 0.8 nM respectively), serotonin 5-HT1A and 5-HT2A receptors (Kis 1.7 and 3.4 nM respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Kis 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki 98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 1000 nM). Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).. 12.3 Pharmacokinetics. ARISTADA is prodrug of aripiprazole and its activity is primarily due to aripiprazole, and to lesser extent dehydro-aripiprazole (major metabolite of aripiprazole), which has been shown to have affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma.. AbsorptionAfter single intramuscular injection the appearance of aripiprazole in the systemic circulation starts from to days and continues to be released for an additional 36 days. Aripiprazole concentrations increase with consecutive doses of ARISTADA and reach steady-state four months following treatment initiation. The concentration-time course of dehydro-aripiprazole followed that of aripiprazole.With the addition of single intramuscular injection of ARISTADA INITIO and 30 mg oral aripiprazole at the time of the first ARISTADA dose, aripiprazole concentrations reach relevant levels within days. Similarly, with the addition of the oral supplementation for 21 days at the time of the first ARISTADA dose, aripiprazole concentrations reach relevant levels within days.Aripiprazole exposure was similar for deltoid and gluteal intramuscular injections of 441 mg ARISTADA, thus are interchangeable.Administration of 882 mg every weeks or 1064 mg every months results in plasma aripiprazole concentrations that were similar to exposure with 662 mg monthly and are within the range provided by doses of 441 mg monthly and 882 mg monthly. The doses of 441 mg monthly and 882 monthly showed similar clinical response to each other.. DistributionBased on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of ARISTADA was 268 L, indicating extensive extravascular distribution following absorption. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.. Elimination. MetabolismThe biotransformation of ARISTADA likely involves enzyme-mediated hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving CYP3A4 and CYP2D6. [see Dosage and Administration 2.4 )]. ExcretionThe mean aripiprazole terminal elimination half-life ranged from 53.9 days to 57.2 days after monthly, every 6-week and every month injections of ARISTADA. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following ARISTADA administration.. Drug Interaction StudiesNo specific drug interaction studies have been performed with ARISTADA. The drug interaction data provided below is obtained from studies with oral aripiprazole.Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure and Figure 2, respectively. Based on simulation, 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.Figure 1: The Effects of Other Drugs on Aripiprazole PharmacokineticsFigure 2: The Effects of Other Drugs on Dehydro-aripiprazole PharmacokineticsThe effects of aripiprazole on the exposures of other drugs are summarized in Figure 3.Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs. Figure 1. Figure 2. Figure 3. Specific Population StudiesA population pharmacokinetic analysis showed no effect of sex, race or smoking on ARISTADA pharmacokinetics [see Use in Specific Populations 8.8 )].Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in Figure and Figure 5, respectively.Figure 4: Effects of Intrinsic Factors on Aripiprazole PharmacokineticsFigure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics. Figure 4. Figure 5.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Efficacy of ARISTADA (441 mg monthly and 882 mg monthly)The efficacy of ARISTADA in the treatment of patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of ARISTADA was established in 12-week, randomized, double-blind, placebo-controlled, fixed-dose study in adult patients with schizophrenia meeting DSM-IV TR criteria [Study 1, = 622; 207 (ARISTADA 441 mg monthly), 208 (ARISTADA 882 mg monthly), and 207 (placebo)]. After establishing tolerability to oral aripiprazole, patients received oral aripiprazole or placebo daily for the first weeks. The intramuscular (IM) injections were administered on Days 1, 29 and 57.Efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I):The PANSS is 30-text scale that measures positive symptoms of schizophrenia (7 texts), negative symptoms of schizophrenia (7 texts), and general psychopathology (16 texts), each rated on scale of (absent) to (extreme). Total PANSS scores range from 30 to 210.The CGI-I rates improvement in mental illness on scale of (very much improved) to (very much worse) based on the change from baseline in clinical condition.Eligible patients were 18 to 70 years of age with PANSS total score of 70 to 120 and score of >=4 for at least of the selected Positive Scale texts. Patients were also required to have CGI-S score of >=4.The primary efficacy variable was the change from baseline to endpoint (Day 85) in PANSS total score. Statistically significant separation from placebo on PANSS total score change was observed in each ARISTADA dose group (Table 11).Table 11: Primary Efficacy ResultsStudy NumberTreatment GroupPrimary Efficacy Measure: PANSS Total ScoreMean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea(95% CI)SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons.a Difference (drug minus placebo) in least-squares mean change from baseline.b Doses that are demonstrated to be effective.Study 1ARISTADA 441 mg monthlyb 92.6 (10.2)-20.9 (1.4)-10.9 (-14.5, -7.3)ARISTADA 882 mg monthlyb 92.0 (10.8)-21.8 (1.4)-11.9 (-15.4, -8.3)Placebo93.9 (11.3)-9.8 (1.4)--The visit-wise mean change from baseline on PANSS total score change for each treatment group is shown in Figure 6.Figure 6: Change from Baseline in PANSS Total ScoreAbbreviations: AL= ARISTADA; PBO=placebo; PANSS=Positive and Negative Syndrome Scale.Vertical dotted line indicates end of oral supplementation.Subgroup analyses did not suggest any clear evidence of differential responsiveness in treatment outcome as function of age, gender, race, or weight.The secondary efficacy endpoint was defined as the CGI-I score at Day 85. Both ARISTADA treatment groups demonstrated statistically significantly better CGI-I scores versus placebo.. The PANSS is 30-text scale that measures positive symptoms of schizophrenia (7 texts), negative symptoms of schizophrenia (7 texts), and general psychopathology (16 texts), each rated on scale of (absent) to (extreme). Total PANSS scores range from 30 to 210.. The CGI-I rates improvement in mental illness on scale of (very much improved) to (very much worse) based on the change from baseline in clinical condition.. Figure 6. Efficacy of ARISTADA 662 mg Monthly, 882 mg Every Weeks and 1064 mg Every MonthsThe efficacy of ARISTADA 662 mg monthly, 882 mg every weeks, and 1064 mg every months in the treatment of adults with schizophrenia was established by pharmacokinetic bridging which demonstrated that these dosing regimens resulted in plasma aripiprazole concentrations that are within the range provided by doses of 441 mg monthly and 882 mg monthly. As depicted in Figure 6, the doses of 441 mg monthly and 882 mg monthly showed clinical responses similar to each other in the ARISTADA placebo-controlled trial.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. ARISTADA is contraindicated in patients with known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6)]. Known hypersensitivity to aripiprazole (4).

DESCRIPTION SECTION.

11 DESCRIPTION. ARISTADA contains aripiprazole lauroxil, an atypical antipsychotic.The chemical name of aripiprazole lauroxil is 7-4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate. The empirical formula is C36H51Cl2N3O4 and its molecular weight is 660.7 g/mol. The chemical structure is: ARISTADA is available as white to off-white sterile aqueous extended-release injectable suspension for intramuscular injection in the following strengths of aripiprazole lauroxil (and deliverable volumes from single-dose pre-filled syringe): 441 mg (1.6 mL), 662 mg (2.4 mL), 882 mg (3.2 mL) and 1064 mg (3.9 mL). The inactive ingredients include sorbitan monolaurate (3.8 mg/mL), polysorbate 20 (1.5 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate dibasic anhydrous (0.62 mg/mL), sodium phosphate monobasic dihydrate (0.52 mg/mL) and water for injection.. Figure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer ARISTADA by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg, 882 mg or 1064 mg) muscle by healthcare professional (2.1).For patients naive to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA (2.1).There are two options for initiating treatment with ARISTADA:Option 1: Administer one injection of 675 mg of ARISTADA INITIO(R) and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection.(2.1).Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection(2.1). ARISTADA can be initiated at dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg dose every weeks, or 1064 mg dose every months (2.1).Dosing regimen adjustments may be required for missed doses (2.2).Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than weeks (2.4).. Administer ARISTADA by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg, 882 mg or 1064 mg) muscle by healthcare professional (2.1).. For patients naive to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA (2.1).. There are two options for initiating treatment with ARISTADA:Option 1: Administer one injection of 675 mg of ARISTADA INITIO(R) and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection.(2.1).Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection(2.1). Option 1: Administer one injection of 675 mg of ARISTADA INITIO(R) and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection.(2.1).. Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection(2.1).. ARISTADA can be initiated at dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg dose every weeks, or 1064 mg dose every months (2.1).. Dosing regimen adjustments may be required for missed doses (2.2).. Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than weeks (2.4).. 2.1 Recommended Dosage. ARISTADA is only to be administered as an intramuscular injection by healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.There are two ways to initiate treatment with ARISTADA:Option 1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle) and one dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.Depending on individual patients needs, treatment with ARISTADA can be initiated at dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every weeks or 1064 mg administered every months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively [see Clinical Pharmacology (12.3)]. Table 1: ARISTADA Dosing Frequency and Site of InjectionDoseDosing FrequencySite of Intramuscular Injection441 mgMonthlyDeltoid or Gluteal662 mgMonthlyGluteal882 mgMonthly or every weeksGluteal1064 mgEvery monthsGlutealUse the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily DoseOral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day441 mg every month15 mg per day662 mg every month882 mg every weeks1064 mg every months20 mg or higher per day882 mg every monthIn conjunction with the first ARISTADA injection, administer single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg, or continue treatment with oral aripiprazole for 21 consecutive days [see Recommended Dosage 2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA [see Clinical Pharmacology 12.3 )]. Option 1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle) and one dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.. Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.. Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.. 2.2 Missed Doses. When dose of ARISTADA is missed, administer the next injection of ARISTADA as soon as possible. Depending on the time elapsed since the last ARISTADA injection, supplement the next ARISTADA injection as recommended in Table below.Table 3: Recommendation for Concomitant Supplementation Following Missed Doses of ARISTADADose of Patients Last ARISTADA InjectionLength of Time Since Last Injectiona The patient should supplement with the same dose of oral aripiprazole as when the patient began ARISTADA (see Table 2).441 mg<= weeks> and <= weeks> weeks662 mg<= weeks> and <= 12 weeks> 12 weeks882 mg<= weeks> and <= 12 weeks> 12 weeks1064 mg<= 10 weeks> 10 and <= 12 weeks> 12 weeksDosage and Administration for Re-initiation of ARISTADANo Supplementation RequiredSupplement with Single Dose of ARISTADA INITIO OR Days of Oral Aripiprazolea Re-initiate with Single Dose of ARISTADA INITIO and Single Dose of Oral Aripiprazole 30 mg OR supplement with 21 Days of Oral Aripiprazolea 2.3 Early Dosing. The recommended ARISTADA dosing interval is monthly for the 441 mg, 662 mg and 882 mg doses, every weeks for the 882 mg dose, or every months for the 1064 mg dose and should be maintained. In the event of early dosing, an ARISTADA injection should not be given earlier than 14 days after the previous injection.. 2.4 Dose Adjustments for CYP450 Considerations. Refer to the prescribing information for oral aripiprazole for recommendations regarding dosage adjustments due to drug interactions, for the first 21 days when the patient is taking 21 days of oral aripiprazole concomitantly with the first dose of ARISTADA. Avoid initiating ARISTADA treatment with ARISTADA INITIO in patients requiring dose adjustments.Once stabilized on ARISTADA, refer to the dosing recommendations below for patients taking strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, or strong CYP3A4 inducers:No dosage changes recommended for ARISTADA, if CYP450 modulators are added for less than weeks.Make dose changes to ARISTADA if CYP450 modulators are added for greater than weeks (see Table 4).Table 4: ARISTADA Dose Adjustments with Concomitant CYP450 Modulator UseConcomitant MedicineDose Change for ARISTADAaa For the 882 mg dose administered every weeks and the 1064 mg administered every months, the next lower strength should be 441 mg administered monthly.Strong CYP3A4 InhibitorReduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated.Strong CYP2D6 InhibitorReduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: No dose adjustment required.Both Strong CYP3A4 Inhibitor and Strong CYP2D6 InhibitorAvoid use for patients at 662 mg, 882 mg, or 1064 mg dose. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated.CYP3A4 InducersNo dose adjustment for 662 mg, 882 mg, or 1064 mg dose; increase the 441 mg dose to 662 mg.. No dosage changes recommended for ARISTADA, if CYP450 modulators are added for less than weeks.. Make dose changes to ARISTADA if CYP450 modulators are added for greater than weeks (see Table 4).. 2.5 Important Administration Instructions. The kit contains syringe containing ARISTADA sterile aqueous extended-release injectable suspension and or safety needles depending on dose (a 2-inch 20 gauge needle with yellow needle hub, 1 1/2 -inch 20 gauge needle with yellow needle hub, and 1-inch 21 gauge needle with green needle hub (441 mg kit only)) for intramuscular injection. All materials should be stored at room temperature.A mL syringe containing ARISTADA sterile aqueous extended-release injectable suspensionB 20 gauge needle, 2-inch with yellow needle hubC 20 gauge needle, 1/2 -inch with yellow needle hubD 21 gauge needle, 1-inch with green needle hub1. TAP and vigorously SHAKE the syringe.1a. Tap the syringe at least 10 times to dislodge any material which may have settled.1b. Shake the syringe vigorously for minimum of 30 seconds to ensure uniform suspension. If the syringe is not used within 15 minutes, shake again for 30 seconds.2. SELECT the injection needle.2a. Select injection site.2b. Select needle length based on injection site. For patients with larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided.Table 5: Injection Site and Associated Needle LengthInjection SiteNeedle Length441 mg doseDeltoid21 gauge, 1-inch or 20 gauge, 1/2 -inchGluteal20 gauge, 1/2 -inch or 20 gauge, 2-inch662 mg doseGluteal20 gauge, 1/2 -inch or 20 gauge, 2-inch882 mg doseGluteal20 gauge, 1/2 -inch or 20 gauge, 2-inch1064 mg doseGluteal20 gauge, 1/2 -inch or 20 gauge, 2-inch[see Dosage and Administration(2.1)]3. ATTACH the injection needle.Attach the appropriate needle securely with clockwise twisting motion. Do NOT overtighten. Overtightening could lead to needle hub cracking.4. PRIME the syringe to remove air.4a. Bring the syringe into upright position and tap the syringe to bring air to the top.4b. Depress the plunger rod to remove air until few drops are released. It is normal to see small air bubbles remaining in the syringe.5. Inject in RAPID and CONTINUOUS manner. Product requires RAPID injection. Do not hesitate. Administer the entire content intramuscularly. Do not inject by any other route.6. DISPOSE of the needle. Cover the needle by pressing the safety device. Dispose of used and unused texts in proper waste container.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. ARISTADA is white to off-white aqueous extended-release injectable suspension provided in single-dose pre-filled syringe.ARISTADA is available as described in Table 6.Table 6: Presentations of ARISTADADose StrengthVolumeInject IntramuscularlyColor Label441 mg1.6 mLDeltoid or Gluteal MuscleLight Blue662 mg2.4 mLGluteal Muscle OnlyGreen882 mg3.2 mLGluteal Muscle OnlyBurgundy1064 mg3.9 mLGluteal Muscle OnlyDark Blue. Extended-release injectable suspension: 441 mg, 662 mg, 882 mg or 1064 mg single-dose pre-filled syringe (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Drugs Having Clinically Important Interactions with ARISTADA. Table 10: Clinically Important Drug Interactions with ARISTADAStrong CYP3A4 Inhibitors and CYP2D6 InhibitorsClinical Impact:The concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology 12.3 )]. Intervention:With concomitant use of ARISTADA with strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than weeks, reduce the ARISTADA dose [see Dosage and Administration 2.4 )]. Examples:itraconazole, clarithromycin, quinidine, fluoxetine, paroxetineStrong CYP3A4 InducersClinical Impact:The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology 12.3 )]. Intervention:With concomitant use of ARISTADA with strong CYP3A4 inducer for more than weeks consider increasing the ARISTADA dose [see Dosage and Administration 2.4 )]. Examples:carbamazepine, rifampinAntihypertensive DrugsClinical Impact:Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.Intervention:Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions 5.8 )].Examples:carvedilol, lisinopril, prazosinBenzodiazepinesClinical Impact:The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions 5.8 )]. Intervention:Monitor sedation and blood pressure. Adjust dose accordingly.Example:lorazepam. 7.2 Drugs Having No Clinically Important Interactions with ARISTADA. Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ARISTADA is required when administered concomitantly with famotidine, valproate, or lithium [see Clinical Pharmacology 12.3 )].In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with ARISTADA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with ARISTADA [see Clinical Pharmacology 12.3 )].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Safety and effectiveness of ARISTADA in patients >65 years of age have not been evaluated.Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ARISTADA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions 5.1 5.2 )].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/ STORAGE AND HANDLING. 16.1 How Supplied. ARISTADA extended-release injectable suspension is available in strengths of 441 mg in 1.6 mL, 662 mg in 2.4 mL, 882 mg in 3.2 mL and 1064 mg in 3.9 mL. The kit contains 5-mL pre-filled syringe containing ARISTADA as sterile white to off-white aqueous extended-release injectable suspension with safety needles.The 441 mg strength kit (NDC 65757-401-03; light blue label) contains three safety needles; 1-inch (25 mm) 21 gauge, 1 1/2 -inch (38 mm) 20 gauge, and 2-inch (50 mm) 20 gauge needle.The 662 mg strength kit (NDC 65757-402-03; green label) contains two safety needles; 1 1/2 -inch (38 mm) 20 gauge and 2-inch (50 mm) 20 gauge needle.The 882 mg strength kit (NDC 65757-403-03; burgundy label) contains two safety needles; 1 1/2 -inch (38 mm) 20 gauge and 2-inch (50 mm) 20 gauge needle.The 1064 mg strength kit (NDC 65757-404-03; dark blue label) contains two safety needles; 1 1/2 -inch (38 mm) 20 gauge and 2-inch (50 mm) 20 gauge needle.. The 441 mg strength kit (NDC 65757-401-03; light blue label) contains three safety needles; 1-inch (25 mm) 21 gauge, 1 1/2 -inch (38 mm) 20 gauge, and 2-inch (50 mm) 20 gauge needle.. The 662 mg strength kit (NDC 65757-402-03; green label) contains two safety needles; 1 1/2 -inch (38 mm) 20 gauge and 2-inch (50 mm) 20 gauge needle.. The 882 mg strength kit (NDC 65757-403-03; burgundy label) contains two safety needles; 1 1/2 -inch (38 mm) 20 gauge and 2-inch (50 mm) 20 gauge needle.. The 1064 mg strength kit (NDC 65757-404-03; dark blue label) contains two safety needles; 1 1/2 -inch (38 mm) 20 gauge and 2-inch (50 mm) 20 gauge needle.. 16.2 Storage. Store at room temperature 20C to 25C (68F to 77F) with excursions permitted between 15C and 30C (between 59F and 86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ARISTADA is indicated for the treatment of schizophrenia in adults [see Clinical Studies (14)]. ARISTADA is an atypical antipsychotic indicated for the treatment of schizophrenia in adults (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read FDA-approved patient labeling (Medication Guide).. Pathological Gambling and Other Compulsive BehaviorsAdvise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions 5.7 )].. Neuroleptic Malignant SyndromeCounsel patients about potentially fatal adverse reaction referred to as NMS that has been reported in association with administration of antipsychotic drugs. Advise patients to contact healthcare provider or report to the emergency room if they experience signs or symptoms of NMS [see Warnings and Precautions 5.4 )]. Tardive DyskinesiaAdvise patients that abnormal involuntary movements have been associated with administration of antipsychotic drugs. Counsel patients to notify their healthcare provider if they notice any movements which they cannot control in their face, tongue, or other body part [see Warnings and Precautions 5.5 )]. Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions 5.6 )]. Orthostatic HypotensionEducate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing), particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions 5.8 )]. FallsAdvise patients and their caregivers of the possibility that they may experience somnolence, postural hypotension, or motor and sensory instability, which may lead to the risk of falls, particularly in patients with diseases, conditions, or medications that could exacerbate these effects [see Warnings and Precautions (5.9 )].. Leukopenia/ NeutropeniaAdvise patients with pre-existing low WBC count or history of drug-induced leucopenia/neutropenia that they should have their CBC monitored while receiving ARISTADA [see Warnings and Precautions 5.10 )]. Interference with Cognitive and Motor PerformanceBecause ARISTADA may have the potential to impair judgment, thinking or motor skills, instruct patients to be cautious about operating hazardous machinery, including automobiles, until they are reasonably certain that ARISTADA therapy does not affect them adversely [see Warnings and Precautions 5.12 )]. Heat Exposure and DehydrationAdvise patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions 5.13 )]. Concomitant MedicationAdvise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is potential for interactions [see Drug Interactions (7)]. PregnancyAdvise patients that ARISTADA may cause extrapyramidal and/or withdrawal symptoms in neonate and to notify their healthcare provider with known or suspected pregnancy [see Use in Specific Populations 8.1 )]. Pregnancy RegistryAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA during pregnancy [see Use in Specific Populations 8.1 )]. For additional information, visit www.ARISTADA.com or call 1-866-274-7823Manufactured and marketed by:Alkermes, Inc.852 Winter StreetWaltham, MA 02451-1420Alkermes(C)2020 Alkermes, Inc. All rights reserved.ALKERMES(R) is registered trademark of Alkermes, Inc., ARISTADA(R) is registered trademark used by Alkermes, Inc. under license and ARISTADA INITIO(R) is registered trademark used by Alkermes, Inc. under license.Printed in U.S.A.

LACTATION SECTION.

8.2 Lactation. Risk SummaryAripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mothers clinical need for ARISTADA and any potential adverse effects on the breastfed infant from ARISTADA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Aripiprazole lauroxil is prodrug of aripiprazole. Following intramuscular injection, aripiprazole lauroxil is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The mechanism of action of aripiprazole in schizophrenia is unknown. However, efficacy could be mediated through combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLifetime carcinogenicity studies have not been conducted with aripiprazole lauroxil.Lifetime carcinogenicity studies with oral aripiprazole have been conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to times and 0.3 to times the oral MRHD of 30 mg/day based on mg/m2, respectively). In addition, SD rats were dosed orally for years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the oral MRHD based on mg/m2). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses which are 0.1 to 0.9 times human exposure at the oral MRHD based on AUC and 0.5 to times the oral MRHD on mg/m2 basis. In female rats, the incidence of mammary gland fibroadenomas was increased at dietary dose which is 0.1 times human exposure at the oral MRHD based on AUC and times the oral MRHD on mg/m2 basis; and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose which is 14 times human exposure at oral MRHD based on AUC and 19 times the oral MRHD on mg/m2 basis.Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.. MutagenesisAripiprazole lauroxil was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosome aberration assay in human peripheral blood lymphocytes.Aripiprazole and its metabolite (2,3-DCPP) were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung (CHL) cells both in the presence and absence of metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. positive response was obtained in the oral in vivo micronucleus assay in mice; however, the response was due to mechanism not considered relevant to humans.. Impairment of Fertility. Animal Data for Aripiprazole LauroxilIn rat fertility study, aripiprazole lauroxil was administered intramuscularly. Males were treated with doses of 18, 49, or 144 mg /animal, which are approximately 0.4 to times the MRHD of 1064 mg on mg/m2 basis, on Days 1, 21, and 42 prior to and through mating; females were treated at these doses, which are approximately 0.6 to times the MRHD on mg/m2 basis, once 14 days prior to mating.In females, persistent diestrus was observed at all doses and the mean number of cycles was significantly decreased at the highest dose together with an increase in the copulatory interval (delay in mating). Additional changes at the high dose included slight increases in corpora lutea and pre-implantation loss, decline in mating, fertility, and fecundity indices in females and lower mating and fertility indices in males.. Animal Data for AripiprazoleFemale rats were treated with oral aripiprazole doses of 2, 6, and 20 mg/kg/day, which are 0.6 to times the oral MRHD of 30 mg/day on mg/m2 basis, from weeks prior to mating through day of gestation. Estrous cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was observed. Increased pre-implantation loss was found at and times the oral MRHD on mg/m2 basis and decreased fetal weight was noted at the highest dose which is times the oral MRHD on mg/m2 basis.Male rats were treated with oral aripiprazole doses of 20, 40, and 60 mg/kg/day, which are to 19 times the oral MRHD on mg/m2 basis, from weeks prior to and through mating. Disturbances in spermatogenesis at the highest dose and prostate atrophy at the mid and high doses were noted which are 13 and 19 times the oral MRHD on mg/m2 basis, but no impairment of fertility was observed.. 13.2 Animal Toxicology and/or Pharmacology. Intramuscular administration of aripiprazole lauroxil to rats and dogs was associated with injection site tissue reactions at all doses in rats treated up to months at doses of 15, 29, and 103 mg/animal (which are approximately 0.3 to times and 0.5 to times the MRHD of 1064 mg on mg/m2 basis in males and females, respectively) and in dogs treated up to months at doses of 147, 662, and 2058 mg/animal (which are approximately 0.5 to times and 0.6 to times the MRHD in males and females, respectively on mg/m2 basis). These injection site tissue reactions consisted of localized granulomatous inflammation and granuloma formation. Transiently impaired limb function and swelling occurred in dogs. The granulomas did not completely resolve months following the last injection in the month rat study and months following the last injection in the month dog study (the low dose groups were not examined for reversibility in these studies).Orally administered aripiprazole produced retinal degeneration in albino rats in 26-week chronic toxicity study at dose of 60 mg/kg, which is 19 times the oral MRHD of 30 mg/day on mg/m2 basis, and in 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg, which are 13 and 19 times the oral MRHD on mg/m2 basis and to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 10.1 Human Experience. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.. 10.2 Management of Overdosage. In case of overdosage, call the Poison control center immediately at 1-800-222-1222.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel 441 mg/1.6 mL Carton LabelNDC: 65757-401-03Rx onlyAristada(R)aripiprazole lauroxilextended-release injectable suspension441 mgFor deltoid or gluteal intramuscular injection onlySingle-dose injection Entire Content of Syringe Must BeAdministered by Healthcare Professional Only441 mg/1.6 mL administered monthly.For dosing and administration instructions, pleasesee accompanying full prescribing information.Dispense enclosed Medication Guide to Patient.Store at room temperature 20C to 25C (68F to 77F)with excursions permitted between 15C to 30C (59F to 86F)Keep out of reach of children. Principal Display Panel 441 mg/1.6 mL Carton Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of ARISTADA in patients <18 years of age have not been evaluated.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Aripiprazole exhibits high affinity for dopamine D2 and D3 (Kis 0.34 and 0.8 nM respectively), serotonin 5-HT1A and 5-HT2A receptors (Kis 1.7 and 3.4 nM respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Kis 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki 98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 1000 nM). Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. ARISTADA is prodrug of aripiprazole and its activity is primarily due to aripiprazole, and to lesser extent dehydro-aripiprazole (major metabolite of aripiprazole), which has been shown to have affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma.. AbsorptionAfter single intramuscular injection the appearance of aripiprazole in the systemic circulation starts from to days and continues to be released for an additional 36 days. Aripiprazole concentrations increase with consecutive doses of ARISTADA and reach steady-state four months following treatment initiation. The concentration-time course of dehydro-aripiprazole followed that of aripiprazole.With the addition of single intramuscular injection of ARISTADA INITIO and 30 mg oral aripiprazole at the time of the first ARISTADA dose, aripiprazole concentrations reach relevant levels within days. Similarly, with the addition of the oral supplementation for 21 days at the time of the first ARISTADA dose, aripiprazole concentrations reach relevant levels within days.Aripiprazole exposure was similar for deltoid and gluteal intramuscular injections of 441 mg ARISTADA, thus are interchangeable.Administration of 882 mg every weeks or 1064 mg every months results in plasma aripiprazole concentrations that were similar to exposure with 662 mg monthly and are within the range provided by doses of 441 mg monthly and 882 mg monthly. The doses of 441 mg monthly and 882 monthly showed similar clinical response to each other.. DistributionBased on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of ARISTADA was 268 L, indicating extensive extravascular distribution following absorption. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.. Elimination. MetabolismThe biotransformation of ARISTADA likely involves enzyme-mediated hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving CYP3A4 and CYP2D6. [see Dosage and Administration 2.4 )]. ExcretionThe mean aripiprazole terminal elimination half-life ranged from 53.9 days to 57.2 days after monthly, every 6-week and every month injections of ARISTADA. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following ARISTADA administration.. Drug Interaction StudiesNo specific drug interaction studies have been performed with ARISTADA. The drug interaction data provided below is obtained from studies with oral aripiprazole.Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure and Figure 2, respectively. Based on simulation, 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.Figure 1: The Effects of Other Drugs on Aripiprazole PharmacokineticsFigure 2: The Effects of Other Drugs on Dehydro-aripiprazole PharmacokineticsThe effects of aripiprazole on the exposures of other drugs are summarized in Figure 3.Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs. Figure 1. Figure 2. Figure 3. Specific Population StudiesA population pharmacokinetic analysis showed no effect of sex, race or smoking on ARISTADA pharmacokinetics [see Use in Specific Populations 8.8 )].Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in Figure and Figure 5, respectively.Figure 4: Effects of Intrinsic Factors on Aripiprazole PharmacokineticsFigure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics. Figure 4. Figure 5.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visithttp://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Risk SummaryNeonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage. No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to and 15 times, respectively, the maximum recommended human dose (MRHD) of 1064 mg based on body surface area (mg/m2). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data]. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to fetus.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsExtrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.. Data. Animal Data for Aripiprazole LauroxilAripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.6 to times the MRHD of 1064 mg on mg/m2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately to 15 times the MRHD on mg/m2 basis. However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data below].. Animal Data for AripiprazolePregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately to 10 times the oral MRHD of 30 mg/day on mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal ossification was observed at and 10 times the oral MRHD on mg/m2 basis.At and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are to 11 times human exposure at the oral MRHD based on AUC and to 65 times the oral MRHD on mg/m2 basis of aripiprazole during the period of organogenesis decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at and 11 times the oral MRHD based on AUC.In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are to 10 times the oral MRHD on mg/m2 basis of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised 03/2021MEDICATION GUIDEARISTADA(R)(air-is-TAH-dah)(aripiprazole lauroxil)extended-release injectable suspension, for intramuscular useWhat is the most important information should know about ARISTADAEach injection of ARISTADA must be administered by healthcare professional only.ARISTADA may cause serious side effects, including:Increased risk of death in elderly people with dementia-related psychosis. ARISTADA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ARISTADA is not for the treatment of people with dementia-related psychosis.What is ARISTADAARISTADA is prescription medicine used to treat schizophrenia in adults.It is not known if ARISTADA is safe and effective in children under 18 years of age.Do not receive ARISTADA if you are allergic to aripiprazole or any of the ingredients in ARISTADA. See the end of this Medication Guide for complete list of ingredients in ARISTADA.Before receiving ARISTADA, tell your healthcare provider about all of your medical conditions, including if you:have never taken ABILIFY(R), ABILIFY MAINTENA(R) or any aripiprazole product beforehave or had heart problems or strokehave diabetes or high blood sugar or family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start receiving ARISTADA and during your treatment.have or had low or high blood pressurehave or had seizures (convulsions)have or had low white blood cell counthave problems that may affect you receiving an injection in your buttocks or your armare pregnant or plan to become pregnant. It is not known if ARISTADA will harm your unborn baby.If you become pregnant while receiving ARISTADA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ are breastfeeding or plan to breastfeed. ARISTADA can pass into your breast milk and it is not known if it may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you receive ARISTADA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.ARISTADA and other medicines may affect each other causing possible serious side effects. ARISTADA may affect the way other medicines work, and other medicines may affect how ARISTADA works.Your healthcare provider can tell you if it is safe to receive ARISTADA with your other medicines. Do not start or stop any medicines while receiving ARISTADA without talking to your healthcare provider first.How should receive ARISTADAFollow your ARISTADA treatment schedule exactly as your healthcare provider tells you to.Each ARISTADA is an injection given by your healthcare provider into the muscle (intramuscular) of your arm or buttock.There are ways to start treatment with ARISTADA:Option 1: You will receive dose of ARISTADA INITIO in combination with single dose of oral aripiprazole. You may also receive your first injection of ARISTADA on the same day you receive ARISTADA INITIO or up to 10 days after you receive ARISTADA INITIO.Option 2: After your first injection of ARISTADA, you will take oral aripiprazole for 21 days in row (consecutive). You should not miss dose of ARISTADA. If you miss dose for some reason, call your healthcare provider right away to discuss what you should do next.What should avoid while receiving ARISTADADo not drive car, operate hazardous machinery, or do other dangerous activities until you know how ARISTADA affects you. ARISTADA may affect your judgment, thinking or motor skills.Avoid becoming too hot or dehydrated while you receive ARISTADA.Do not exercise too much.In hot weather, stay inside in cool place if possible.Stay out of the sun.Do not wear too much clothing or heavy clothing.Drink plenty of water. What are the possible side effects of ARISTADAARISTADA may cause serious side effects, including:See What is the most important information should know about ARISTADA Cerebrovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death.Neuroleptic malignant syndrome (NMS), serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs symptoms of NMS:high feverstiff musclesconfusionsweatingchanges in pulse, heart rate, and blood pressureUncontrolled body movements (tardive dyskinesia). ARISTADA may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving ARISTADA. Tardive dyskinesia may also start after you stop receiving ARISTADA.Problems with your metabolism such as:high blood sugar (hyperglycemia). Increases in blood sugar can happen in some people who receive ARISTADA. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or family history of diabetes), your healthcare provider should check your blood sugar before you start receiving ARISTADA and during your treatment.Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving ARISTADA:Feel very thirstyFeel very hungryFeel sick to your stomachNeed to urinate more than usualFeel weak or tiredFeel confused, or your breath smells fruityincreased fat levels (cholesterol and triglycerides) in your blood.weight gain. You and your healthcare provider should check your weight regularly.Unusual and uncontrollable (compulsive) urges. Some people taking aripiprazole products have had strong unusual urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges include increased sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having unusual urges, talk to your healthcare provider.Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from sitting or lying position.Falls. ARISTADA may make you sleepy or dizzy, may cause decrease in your blood pressure when changing position and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.Low white blood cell countSeizures (convulsions)Problems controlling your body temperature. See What should avoid while receiving ARISTADADifficulty swallowingThe most common side effects of ARISTADA include restlessness or feeling like you need to move (akathisia).These are not all the possible side effects of ARISTADA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about ARISTADAIf you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ARISTADA that is written for health professionals.What are the ingredients in ARISTADAActive ingredient: aripiprazole lauroxil Inactive ingredients: sorbitan monolaurate, polysorbate 20, sodium chloride, sodium phosphate dibasic anhydrous, sodium phosphate monobasic dihydrate and water for injection Manufactured and marketed by: Alkermes, Inc., 852 Winter Street, Waltham, MA 02451-1420For more information, go to www.ARISTADA.com or call 1-866-274-7823.. Increased risk of death in elderly people with dementia-related psychosis. ARISTADA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ARISTADA is not for the treatment of people with dementia-related psychosis.. have never taken ABILIFY(R), ABILIFY MAINTENA(R) or any aripiprazole product before. have or had heart problems or stroke. have diabetes or high blood sugar or family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start receiving ARISTADA and during your treatment.. have or had low or high blood pressure. have or had seizures (convulsions). have or had low white blood cell count. have problems that may affect you receiving an injection in your buttocks or your arm. are pregnant or plan to become pregnant. It is not known if ARISTADA will harm your unborn baby.If you become pregnant while receiving ARISTADA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ If you become pregnant while receiving ARISTADA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. are breastfeeding or plan to breastfeed. ARISTADA can pass into your breast milk and it is not known if it may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you receive ARISTADA.. Follow your ARISTADA treatment schedule exactly as your healthcare provider tells you to.. Each ARISTADA is an injection given by your healthcare provider into the muscle (intramuscular) of your arm or buttock.. There are ways to start treatment with ARISTADA:Option 1: You will receive dose of ARISTADA INITIO in combination with single dose of oral aripiprazole. You may also receive your first injection of ARISTADA on the same day you receive ARISTADA INITIO or up to 10 days after you receive ARISTADA INITIO.Option 2: After your first injection of ARISTADA, you will take oral aripiprazole for 21 days in row (consecutive). Option 1: You will receive dose of ARISTADA INITIO in combination with single dose of oral aripiprazole. You may also receive your first injection of ARISTADA on the same day you receive ARISTADA INITIO or up to 10 days after you receive ARISTADA INITIO.. Option 2: After your first injection of ARISTADA, you will take oral aripiprazole for 21 days in row (consecutive).. You should not miss dose of ARISTADA. If you miss dose for some reason, call your healthcare provider right away to discuss what you should do next.. Do not drive car, operate hazardous machinery, or do other dangerous activities until you know how ARISTADA affects you. ARISTADA may affect your judgment, thinking or motor skills.. Avoid becoming too hot or dehydrated while you receive ARISTADA.Do not exercise too much.In hot weather, stay inside in cool place if possible.Stay out of the sun.Do not wear too much clothing or heavy clothing.Drink plenty of water. Do not exercise too much.. In hot weather, stay inside in cool place if possible.. Stay out of the sun.. Do not wear too much clothing or heavy clothing.. Drink plenty of water.. See What is the most important information should know about ARISTADA Cerebrovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death.. Neuroleptic malignant syndrome (NMS), serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs symptoms of NMS:. high fever. stiff muscles. confusion. sweating. changes in pulse, heart rate, and blood pressure. Uncontrolled body movements (tardive dyskinesia). ARISTADA may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving ARISTADA. Tardive dyskinesia may also start after you stop receiving ARISTADA.. Problems with your metabolism such as:high blood sugar (hyperglycemia). Increases in blood sugar can happen in some people who receive ARISTADA. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or family history of diabetes), your healthcare provider should check your blood sugar before you start receiving ARISTADA and during your treatment.. high blood sugar (hyperglycemia). Increases in blood sugar can happen in some people who receive ARISTADA. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or family history of diabetes), your healthcare provider should check your blood sugar before you start receiving ARISTADA and during your treatment.. Feel very thirsty. Feel very hungry. Feel sick to your stomach. Need to urinate more than usual. Feel weak or tired. Feel confused, or your breath smells fruity. increased fat levels (cholesterol and triglycerides) in your blood.. weight gain. You and your healthcare provider should check your weight regularly.. Unusual and uncontrollable (compulsive) urges. Some people taking aripiprazole products have had strong unusual urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges include increased sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having unusual urges, talk to your healthcare provider.. Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from sitting or lying position.. Falls. ARISTADA may make you sleepy or dizzy, may cause decrease in your blood pressure when changing position and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.. Low white blood cell count. Seizures (convulsions). Problems controlling your body temperature. See What should avoid while receiving ARISTADA. Difficulty swallowing.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. ARISTADA is only to be administered as an intramuscular injection by healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.There are two ways to initiate treatment with ARISTADA:Option 1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle) and one dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.Depending on individual patients needs, treatment with ARISTADA can be initiated at dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every weeks or 1064 mg administered every months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively [see Clinical Pharmacology (12.3)]. Table 1: ARISTADA Dosing Frequency and Site of InjectionDoseDosing FrequencySite of Intramuscular Injection441 mgMonthlyDeltoid or Gluteal662 mgMonthlyGluteal882 mgMonthly or every weeksGluteal1064 mgEvery monthsGlutealUse the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily DoseOral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day441 mg every month15 mg per day662 mg every month882 mg every weeks1064 mg every months20 mg or higher per day882 mg every monthIn conjunction with the first ARISTADA injection, administer single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg, or continue treatment with oral aripiprazole for 21 consecutive days [see Recommended Dosage 2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA [see Clinical Pharmacology 12.3 )]. Option 1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle) and one dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.. Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.. Option 2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.

STORAGE AND HANDLING SECTION.

16.2 Storage. Store at room temperature 20C to 25C (68F to 77F) with excursions permitted between 15C and 30C (between 59F and 86F).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates in women exposed during the third trimester of pregnancy (8.1).. Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates in women exposed during the third trimester of pregnancy (8.1).. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visithttp://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.. Risk SummaryNeonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage. No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to and 15 times, respectively, the maximum recommended human dose (MRHD) of 1064 mg based on body surface area (mg/m2). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data]. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to fetus.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsExtrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.. Data. Animal Data for Aripiprazole LauroxilAripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.6 to times the MRHD of 1064 mg on mg/m2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately to 15 times the MRHD on mg/m2 basis. However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data below].. Animal Data for AripiprazolePregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately to 10 times the oral MRHD of 30 mg/day on mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal ossification was observed at and 10 times the oral MRHD on mg/m2 basis.At and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are to 11 times human exposure at the oral MRHD based on AUC and to 65 times the oral MRHD on mg/m2 basis of aripiprazole during the period of organogenesis decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at and 11 times the oral MRHD based on AUC.In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are to 10 times the oral MRHD on mg/m2 basis of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.. 8.2 Lactation. Risk SummaryAripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mothers clinical need for ARISTADA and any potential adverse effects on the breastfed infant from ARISTADA or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of ARISTADA in patients <18 years of age have not been evaluated.. 8.5 Geriatric Use. Safety and effectiveness of ARISTADA in patients >65 years of age have not been evaluated.Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ARISTADA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions 5.1 5.2 )]. 8.6 CYP2D6 Poor Metabolizers. Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration 2.4 ),Clinical Pharmacology 12.3 )].. 8.7 Hepatic and Renal Impairment. No dosage adjustment for ARISTADA is required based on patients hepatic function (mild to severe hepatic impairment, Child-Pugh score between and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology 12.3 )].. 8.8 Other Specific Populations. No dosage adjustment for ARISTADA is required on the basis of patients sex, race, or smoking status [see Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5 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 history of 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 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).. 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 history of 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 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 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 typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to 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 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 weeks, or every 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. 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 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 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. 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 manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from 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 satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.If signs and symptoms of tardive dyskinesia appear in 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 MellitusHyperglycemia, 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 patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.In the long-term, open-label schizophrenia study with ARISTADA, 14% of patients with normal hemoglobin A1c (<5.7%) at baseline developed elevated levels (>=5.7%) post-baseline.. DyslipidemiaUndesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.In the long-term, open-label schizophrenia study with ARISTADA, shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (>=240 mg/dL) were reported in 1% of patients; shifts in baseline fasting LDL cholesterol from normal (<100 mg/dL) to high (>=160 mg/dL) were reported in 1% of patients; and shifts in baseline fasting triglycerides from normal (<150 mg/dL) to high (>=200 mg/dL) were reported in 8% of patients. In the same study, shifts in baseline fasting total cholesterol from borderline (>= 200 mg/dL and <240 mg/dL) to high (>=240 mg/dL) were reported in 15% of patients; shifts in baseline fasting LDL cholesterol from borderline (>=100 mg/dL and <160 mg/dL) to high (>=160 mg/dL) were reported in 8% of patients; and shifts in baseline fasting triglycerides from borderline (>=150 mg/dL and <200 mg/dL) to high (>=200 mg/dL) were reported in 35% of patients. In addition, the proportion of patients with shifts in fasting HDL cholesterol from normal (>=40 mg/dL) to low (<40 mg/dL) was reported in 15% of patients.. Weight GainWeight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.The proportion of adult patients with weight gain >=7% of body weight is presented in Table 7.Table 7: Proportion of Adult Patients with Shifts in Weight in the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia TrialPlaceboN 207(%)ARISTADA441 mgN 207(%)882 mgN 208(%)Weight Gain>=7% increase from baseline6109. 5.7 Pathological Gambling and Other Compulsive Behaviors. Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm for the patient and others if not recognized. Consider dose reduction or stopping the medication if patient develops such urges.. 5.8 Orthostatic Hypotension. Aripiprazole may cause orthostatic hypotension, perhaps due to its 1-adrenergic receptor antagonism. Associated adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naive. In such patients, consider using lower starting dose, and monitor orthostatic vital signs.Orthostatic hypotension was reported for one patient in the ARISTADA 882 mg group (0.5%) and no patients in the ARISTADA 441 mg and placebo groups in the 12-week schizophrenia efficacy study [see Clinical Studies (14)]. In the long-term open-label schizophrenia study, orthostatic hypotension was reported for (0.2%) patient treated with ARISTADA. Orthostatic hypotension was defined as decrease in systolic blood pressure >=20 mmHg accompanied by an increase in heart rate >=25 bpm when comparing standing to supine values.. 5.9 Falls. Antipsychotics including ARISTADA may cause somnolence, postural hypotension, or motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for those patients on long-term antipsychotic therapy.. 5.10 Leukopenia, Neutropenia, and Agranulocytosis. In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis has also been reported.Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with history of clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ARISTADA at the first sign of clinical significant decline in WBC in the absence of other causative factors.Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ARISTADA in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.. 5.11 Seizures. As with other antipsychotic drugs, use ARISTADA cautiously in patients with history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in population of 65 years or older.. 5.12 Potential for Cognitive and Motor Impairment. ARISTADA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ARISTADA does not affect them adversely.. 5.13 Body Temperature Regulation. Disruption of the bodys ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ARISTADA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).. 5.14 Dysphagia. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. ARISTADA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.