b'USE IN SPECIFIC POPULATIONS CYP2D6 Poor Metabolizers: Approximately 8% of Caucasians and 3-8% of Black/ ARISTADA (aripiprazole lauroxil) extended-release injectable suspension, smallest dose and the shortest duration of treatment producing a satisfactory clinical Pregnancy African Americans cannot metabolize CYP2D6 substrates and are classified as poorfor intramuscular use response should be sought. The need for continued treatment should be reassessed Pregnancy Exposure Registry: There is a pregnancy exposure registry thatmetabolizers (PM). Avoid use of ARISTADA INITIO in these patients because dosageBRIEF SUMMARY OF PRESCRIBING INFORMATION periodically. monitors pregnancy outcomes in women exposed to ARISTADA INITIO duringadjustments are not possible (it is only available in one strength in a single-dose(For complete details, please see full Prescribing Information and Medication Guide.) If signs and symptoms of tardive dyskinesia appear in a patient treated with ARISTADA, pregnancy. For more information, contact the National Pregnancy Registry for pre-filled syringe). drug discontinuation should be considered. However, some patients may require Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/ Hepatic and Renal Impairment: No dosage adjustment for ARISTADA INITIO isWARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH treatment with ARISTADA despite the presence of the syndrome.clinical-and-research-programs/pregnancyregistry/. required based on a patients hepatic function (mild to severe hepatic impairment,DEMENTIA-RELATED PSYCHOSIS Metabolic Changes: Atypical antipsychotic drugs have been associated with Risk Summary: Neonates exposed to antipsychotic drugs during the third trimesterChild-Pugh score between 5 and 15), or renal function (mild to severe renalElderly patients with dementia-related psychosis treated with antipsychotic metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms followingimpairment, glomerular filtration rate between 15 and 90 mL/minute). drugs are at an increased risk of death weight gain. While all drugs in the class have been shown to produce some metabolic delivery. Limited published data on aripiprazole use in pregnant women are notOther Specific Populations: No dosage adjustment for ARISTADA INITIO is requiredARISTADA is not approved for the treatment of patients with changes, each drug has its own specific risk profile.sufficient to inform any drug-associated risks for birth defects or miscarriage. on the basis of a patients sex, race, or smoking status. dementia-related psychosis Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and No teratogenicity was observed in animal reproductive studies with intramuscularOVERDOSAGE associated with ketoacidosis or hyperosmolar coma or death, has been reported in administration of aripiprazole lauroxil to rats and rabbits during organogenesis atHuman Experience: Common adverse reactions (reported in at least 5% of allINDICATIONS AND USAGE: ARISTADA is an atypical antipsychotic indicated for thepatients treated with atypical antipsychotics. There have been reports of hyperglycemia doses up to 8 and 23 times, respectively, the maximum recommended human dosetreatment of schizophrenia in adults.2 overdose cases) reported with oral aripiprazole overdosage (alone or in combinationin patients treated with oral aripiprazole. Assessment of the relationship between atypical (MRHD) of 675 mg based on body surface area (mg/m ). However, aripiprazolewith other substances) include vomiting, somnolence, and tremor. Other clinicallyCONTRAINDICATIONS: ARISTADA is contraindicated in patients with a knownantipsychotic use and glucose abnormalities is complicated by the possibility of an caused developmental toxicity and possible teratogenic effects in rats and rabbits.important signs and symptoms observed in one or more patients with aripiprazolehypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged fromincreased background risk of diabetes mellitus in patients with schizophrenia andThe background risk of major birth defects and miscarriage for the indicatedoverdoses (alone or with other substances) include acidosis, aggression, aspartatepruritus/urticaria to anaphylaxis. the increasing incidence of diabetes mellitus in the general population. Given these population are unknown. In the U.S. general population, the estimated backgroundaminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state,WARNINGS AND PRECAUTIONS confounders, the relationship between atypical antipsychotic use and hyperglycemia-risk of major birth defects and miscarriage in clinically recognized pregnancies isconvulsion, blood creatine phosphokinase increased, depressed level ofIncreased Mortality in Elderly Patients With Dementia-related Psychosis: Elderlyrelated adverse events is not completely understood. However, epidemiological studies 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to consciousness, hypertension, hypokalemia, hypotension, lethargy, loss ofpatients with dementia-related psychosis treated with antipsychotic drugs are at suggest an increased risk of hyperglycemia-related adverse reactions in patients treated a fetus.consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration,an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration with the atypical antipsychotics.Clinical Considerations: Fetal/Neonatal Adverse Reactions: Extrapyramidal and/orrespiratory arrest, status epilepticus, and tachycardia. of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk Patients with an established diagnosis of diabetes mellitus who are started on atypical withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor,Management of Overdosage: In case of overdosage, call the Poison control centerof death in drug-treated patients of between 1.6 to 1.7 times the risk of death inantipsychotics should be monitored regularly for worsening of glucose control. Patients somnolence, respiratory distress and feeding disorder have been reported inimmediately at 1-800-222-1222.placebo-treated patients. Over the course of a typical 10-week controlled trial, thewith risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are neonates who were exposed to antipsychotic drugs during the third trimester ofrate of death in drug-treated patients was about 4.5%, compared to a rate of about pregnancy. These symptoms have varied in severity. Monitor neonates forTo report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at 2.6% in the placebo group.starting treatment with atypical antipsychotics should undergo fasting blood glucose extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.1-866-274-7823 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. testing at the beginning of treatment and periodically during treatment. Any patient Some neonates recover within hours or days without specific treatment; othersAlthough the causes of death were varied, most of the deaths appeared to be eithertreated with atypical antipsychotics should be monitored for symptoms of hyperglycemia required prolonged hospitalization. PATIENT COUNSELING INFORMATION cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) inincluding polydipsia, polyuria, polyphagia, and weakness. Patients who develop Physicians are advised to discuss the FDA-approved patient labeling (Medicationnature. Observational studies suggest that, similar to atypical antipsychotic drugs,symptoms of hyperglycemia during treatment with atypical antipsychotics should Data: Animal Data for ARISTADA (Aripiprazole Lauroxil): Aripiprazole lauroxil did notGuide) with patients for whom they prescribe ARISTADA INITIO. treatment with conventional antipsychotic drugs may increase mortality. The extent toundergo fasting blood glucose testing. In some cases, hyperglycemia has resolvedcause adverse developmental or maternal effects in rats or rabbits whenwhich the findings of increased mortality in observational studies may be attributed towhen the atypical antipsychotic was discontinued; however, some patients require administered intramuscularly during the period of organogenesis at doses of 18, 49,This Brief Summary is based on ARISTADA INITIO Full Prescribing Information the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.continuation of anti-diabetic treatment despite discontinuation of the suspect drug.or 144 mg/animal in pregnant rats which are approximately 1 to 8 times the MRHD of 675 mg based on mg/m2, and at doses of 241, 723, and 2893 mg/animal inRev February 2020.ARISTADA is not approved for the treatment of patients with dementia-related psychosis. In the long-term, open-label schizophrenia study with ARISTADA, 14% of patients pregnant rabbits which are approximately 2 to 23 times the MRHD based on mg/m2.Cerebrovascular Adverse Reactions, Including Stroke: In placebo-controlled trialswith normal hemoglobin A1c (5.7%) at baseline developed elevated levels (5.7%) However, aripiprazole caused developmental toxicity and possible teratogenic effectsManufactured and marketed by Alkermes, Inc., Waltham, MA 02451-1420. with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, therepost-baseline.in rats and rabbits [see Data below].was a higher incidence of cerebrovascular adverse reactions (cerebrovascular ALKERMESis a registered trademark of Alkermes, Inc. ARISTADAand logo, andaccidents and transient ischemic attacks) including fatalities compared to placebo- Dyslipidemia: Undesirable alterations in lipids have been observed in patients Animal Data for Aripiprazole: Pregnant rats were treated with oral doses of 3, 10, and ARISTADA INITIO, are registered trademarks of Alkermes Pharma Ireland Limited,treated patients. ARISTADA is not approved for the treatment of patients with dementia- treated with atypical antipsychotics. 30 mg/kg/day which are approximately 1 to 10 times the oral MRHD of 30 mg/day based on mg/m2 of aripiprazole during the period of organogenesis. Treatment at theused by Alkermes, Inc., under license. related psychosis. In the long-term, open-label schizophrenia study with ARISTADA, shifts in baseline highest dose caused a slight prolongation of gestation and delay in fetalPotential for Dosing and Medication Errors: Medication errors, including fasting total cholesterol from normal (200 mg/dL) to high (240 mg/dL) were development, as evidenced by decreased fetal weight, and undescended testes.2020 Alkermes, Inc. All rights reserved. ARI-004119 substitution and dispensing errors, between ARISTADA and ARISTADA INITIO reported in 1% of patients; shifts in baseline fasting LDL cholesterol from normal Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD based(aripiprazole lauroxil) could occur. ARISTADA INITIO is for single administration (100 mg/dL) to high (160 mg/dL) were reported in 1% of patients; and shifts in on mg/m2.in contrast to ARISTADA which is administered monthly, every 6 weeks, or every baseline fasting triglycerides from normal (150 mg/dL) to high (200 mg/dL) At 3 and 10 times the oral MRHD based on mg/m2, delivered offspring had decreased8 weeks. Do not substitute ARISTADA INITIO for ARISTADA because of differingwere reported in 8% of patients. In the same study, shifts in baseline fasting total body weights. Increased incidences of hepatodiaphragmatic nodules andpharmacokinetic profiles. cholesterol from borderline (200 mg/dL and 240 mg/dL) to high (240 mg/dL) diaphragmatic hernia were observed in offspring from the highest dose group (theNeuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimeswere reported in 15% of patients; shifts in baseline fasting LDL cholesterol from other dose groups were not examined for these findings). A low incidence ofreferred to as Neuroleptic Malignant Syndrome (NMS) may occur in association withborderline (100 mg/dL and 160 mg/dL) to high (160 mg/dL) were reported in diaphragmatic hernia was also seen in the fetuses exposed to the highest dose.antipsychotic drugs, including ARISTADA. Clinical manifestations of NMS are hyperpyrexia,8% of patients; and shifts in baseline fasting triglycerides from borderlinePostnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHDmuscle rigidity, altered mental status, and evidence of autonomic instability (irregular(150 mg/dL and 200 mg/dL) to high (200mg/dL) were reported in 35% of based on mg/m2 and impaired reproductive performance (decreased fertility rate,pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additionalpatients. In addition, the proportion of patients with shifts in fasting HDL cholesterol corpora lutea, implants, live fetuses, and increased post-implantation loss, likelysigns may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), from normal (40 mg/dL) to low (40 mg/dL) was reported in 15% of patients.mediated through effects on female offspring) along with some maternal toxicityand acute renal failure. Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical were seen at the highest dose; however, there was no evidence to suggest that theseThe diagnostic evaluation of patients with this syndrome is complicated. In arriving at monitoring of weight is recommended.developmental effects were secondary to maternal toxicity.a diagnosis, it is important to identify cases in which the clinical presentation includesThe proportion of adult patients with weight gain 7% of body weight is presented In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated in Table 1.2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times theor inadequately treated extrapyramidal signs and symptoms (EPS). Other important oral MRHD based on mg/m2 of aripiprazole during the period of organogenesisconsiderations in the differential diagnosis include central anticholinergic toxicity, heatTable 1:Proportion of Adult Patients With Shifts in Weight in the 12-Week, decreased maternal food consumption and increased abortions were seen at thestroke, drug fever, and primary central nervous system pathology. Placebo-Controlled, Fixed-Dose Schizophrenia Trialhighest dose as well as increased fetal mortality. Decreased fetal weight andThe management of NMS should include (1) immediate discontinuation of antipsychoticARISTADAincreased incidence of fused sternebrae were observed at 3 and 11 times the oraldrugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic MRHD based on AUC.treatment and medical monitoring; and (3) treatment of any concomitant serious medicalPlacebo441 mg882 mg In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 timesproblems for which specific treatments are available. There is no general agreementN = 207N = 207N = 208 the oral MRHD based on mg/m2 of aripiprazole perinatally and postnatally (from dayabout specific pharmacological treatment regimens for uncomplicated NMS. (%) (%) (%)17 of gestation through day 21 postpartum), slight maternal toxicity and slightlyIf a patient appears to require antipsychotic drug treatment after recovery from NMS,Weight gainprolonged gestation were seen at the highest dose. An increase in stillbirths andreintroduction of drug therapy should be closely monitored, since recurrences of NMS decreases in pup weight (persisting into adulthood) and survival were also seen athave been reported. 7% increase from baseline 6 10 9this dose.Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic Lactation: Risk Summary: Aripiprazole is present in human breast milk; however,movements may develop in patients treated with antipsychotic drugs. Although thePathological Gambling and Other Compulsive Behaviors: Post-marketing case there are insufficient data to assess the amount in human milk, the effects on theprevalence of the syndrome appears to be highest among the elderly, especially elderlyreports suggest that patients can experience intense urges, particularly for gambling, breastfed infant, or the effects on milk production. The development and healthwomen, it is impossible to predict which patients will develop the syndrome. Whetherand the inability to control these urges while taking aripiprazole. Other compulsive benefits of breastfeeding should be considered along with the mothers clinical needantipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. urges, reported less frequently include: sexual urges, shopping, eating or binge for ARISTADA INITIO and any potential adverse effects on the breastfed infant fromThe risk of developing tardive dyskinesia and the likelihood that it will become irreversibleeating, and other impulsive or compulsive behaviors. Because patients may not ARISTADA INITIO or from the underlying maternal condition.appear to increase as the duration of treatment and the total cumulative dose ofrecognize these behaviors as abnormal, it is important for prescribers to ask patients Pediatric Use: Safety and effectiveness of ARISTADA INITIO in pediatric patients haveantipsychotic drugs administered to the patient increase, but the syndrome can developor their caregivers specifically about the development of new or intense gambling not been established. after relatively brief treatment periods at low doses, although this is uncommon. urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or Geriatric Use: Safety and effectiveness of ARISTADA INITIO in patients 65 years ofTardive dyskinesia may remit, partially or completely, if antipsychotic treatment isother urges while being treated with aripiprazole. It should be noted that impulse-age have not been evaluated. withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) thecontrol symptoms can be associated with the underlying disorder. In some cases, Elderly patients with dementia-related psychosis treated with antipsychotic drugs aresigns and symptoms of the syndrome and may thus mask the underlying process.although not all, urges were reported to have stopped when the dose was reduced or at an increased risk of death. ARISTADA INITIO is not approved for the treatment ofThe effect of symptomatic suppression on the long-term course of the syndrome the medication was discontinued. Compulsive behaviors may result in harm for the patients with dementia-related psychosis. is unknown.patient and others if not recognized. Consider dose reduction or stopping the Given these considerations, ARISTADA should be prescribed in a manner that is mostmedication if a patient develops such urges.likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatmentOrthostatic Hypotension: Aripiprazole may cause orthostatic hypotension, perhapsshould generally be reserved for patients who suffer from a chronic illness that is knowndue to its a 1 -adrenergic receptor antagonism. Associated adverse reactions relatedto respond to antipsychotic drugs. In patients who do require chronic treatment, theto orthostatic hypotension can include dizziness, lightheadedness, and tachycardia. 20-ARI-2760_HCP_NPP_VANF_JournalAd_Med-Directory-fi3.indd 6 8/21/20 8:59 AM'