b'T:7.875" T:7.875"S:7" S:7"Generally, these risks are greatest at the beginning of treatment and during doseTable 2: Continued Renal and Urinary Disorders: urinary retention, nocturiadose (MRHD) of 1064 mg ARISTADA on mg/m2 basis and at doses of 241, 723, and escalation. Patients at increased risk of these adverse reactions or at increased risk ofRepro ductive System and Breast Disorders: erectile dysfunction, gynaecomastia,2893 mg/animal in pregnant rabbits which are approximately 1 to 15 times the MRHD37developing complications from hypotension include those with dehydration, hypovolemia,Aripiprazole Lauroxil menstruation irregular, amenorrhea, breast pain, priapismon mg/m2 basis. However, aripiprazole caused developmental toxicity and possible treatment with antihypertensive medication, history of cardiovascular disease (e.g., Placebo441 mg882 mgRespiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspneateratogenic effects in rats and rabbits.heart failure, myocardial infarction, ischemia, or conduction abnormalities), history ofAdverse Reaction System Organ Class N = 207N = 207N = 208Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivityAnimal Data for Aripiprazole: Pregnant rats were treated with oral doses of 3, 10, andcerebrovascular disease, as well as patients who are antipsychotic-nave. In such Preferred Term (%) (%) (%) reaction, alopecia, urticaria30 mg/kg/day, which are approximately 1 to 10 times the oral maximum recommended patients, consider using a lower starting dose, and monitor orthostatic vital signs.Vascular Disorders: hypotension, hypertension human dose (MRHD) of 30 mg/day on mg/m2 basis of aripiprazole during the periodOrthostatic hypotension was reported for 1 patient in the ARISTADA 882 mg group (0.5%)Psychiatric disorders Postmarketing Experience: The following adverse reactions have been identifiedof organogenesis. Treatment at the highest dose caused a slight prolongation of and no patients in the ARISTADA 441 mg and placebo groups in the 12-week schizophrenia Insomnia 2 3 4 during post-approval use of oral aripiprazole. Because these reactions are reportedgestation and delay in fetal development, as evidenced by decreased fetal weight, efficacy study. In the long-term open-label schizophrenia study, orthostatic hypotension wasvoluntarily from a population of uncertain size, it is not always possible to reliablyand undescended testes. Delayed skeletal ossification was observed at 3 andreported for 1 (0.2%) patient treated with ARISTADA. Orthostatic hypotension was defined Restlessness 1 3 1 estimate their frequency or to establish a causal relationship to drug exposure:10 times the oral MRHD on mg/m2 basis. as a decrease in systolic blood pressure 20 mmHg accompanied by an increase in heartIn an open-label pharmacokinetic study, the adverse reactions associated withoccurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm,At 3 and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased rate 25 bpm when comparing standing to supine values. the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 monthspruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups, bloodbody weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic Falls: Antipsychotics including ARISTADA may cause somnolence, postural hypotension, orwere similar across the dose groups. glucose fluctuation, oculogyric crisis, and drug reaction with eosinophilia andhernia were observed in offspring from the highest dose group (the other dose groups motor and sensory instability, which may lead to falls and, consequently, fractures or otherInjection-Site Reactions: Injection-site reactions were reported by 4% of patientssystemic symptoms (DRESS). were not examined for these findings). A low incidence of diaphragmatic hernia was also injuries. For patients with diseases, conditions, or medications that could exacerbate theseseen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening effects, complete fall risk assessments when initiating antipsychotic treatment andtreated with 441 mg ARISTADA and 5% of patients treated with 882 mg ARISTADADRUG INTERACTIONS was seen at 3 and 10 times the oral MRHD on mg/m2 basis and impaired reproductive recurrently for those patients on long-term antipsychotic therapy. compared to 2% of patients treated with placebo. Most of these were injection-siteDrugs Having Clinically Important Interactions With ARISTADA performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased Leukopenia, Neutropenia, and Agranulocytosis: In clinical trials and/or postmarketingpain (3%, 4%, and 2% in the 441 mg ARISTADA, 882 mg ARISTADA, and placebo groups,Table 4: Clinically Important Drug Interactions With ARISTADA post-implantation loss, likely mediated through effects on female offspring) along with experience, events of leukopenia and neutropenia have been reported temporally relatedrespectively), and most were associated with the first injection and decreased with eachStrong CYP3A4 Inhibitors and CYP2D6 Inhibitorssome maternal toxicity were seen at the highest dose; however, there was no evidence to antipsychotic agents. Agranulocytosis has also been reported. subsequent injection to less than or equal to 1% for both doses of ARISTADA andto suggest that these developmental effects were secondary to maternal toxicity. placebo. Other injection-site reactions (induration, swelling, and redness) occurred The concomitant use of oral aripiprazole with strong CYP3A4 In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day, which are 2Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cellat less than 1%. In an open-label pharmacokinetic study evaluating 441 mg monthly, Clinical Impact:or CYP2D6 inhibitors increased the exposure of aripiprazoleto 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/ 882 mg every 6 weeks, and 1064 mg every 2 months, injection-site reactions werecompared to the use of oral aripiprazole alone. MRHD on mg/m2 basis of aripiprazole during the period of organogenesis, decreased neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-inducedsimilar across the dose groups.With concomitant use of ARISTADA with a strong CYP3A4maternal food consumption and increased abortions were seen at the highest dose as leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the firstExtrapyramidal Symptoms: In the 12-week schizophrenia efficacy study, forIntervention: inhibitor or CYP2D6 inhibitor for more than 2 weeks, reduce well as increased fetal mortality. Decreased fetal weight and increased incidence of few months of therapy. In such patients, consider discontinuation of ARISTADA at the firstARISTADA-treated patients, the incidence of other EPS-related events, excludingthe ARISTADA dose. fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC.sign of a clinical significant decline in WBC in the absence of other causative factors.akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, Examples: itraconazole, clarithromycin, quinidine, fluoxetine, paroxetineIn rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the Monitor patients with clinically significant neutropenia for fever or other symptoms orrespectively, versus 4% for placebo-treated patients (Table 3). oral MRHD on mg/m2 basis of aripiprazole perinatally and postnatally (from day 17 of signs of infection and treat promptly if such symptoms or signs occur. Discontinue3 Table 3: Incidence of EPS Compared to PlaceboStrong CYP3A4 Inducersgestation through day 21 postpartum), slight maternal toxicity and slightly prolonged ARISTADA in patients with severe neutropenia (absolute neutrophil count 1000/mm)The concomitant use of oral aripiprazole and carbamazepinegestation were seen at the highest dose. An increase in stillbirths and decreases in and follow their WBC until recovery. ARISTADA Clinical Impact:decreased the exposure of aripiprazole compared to the use of pup weight (persisting into adulthood) and survival were also seen at this dose. Seizures: As with other antipsychotic drugs, use ARISTADA cautiously in patients with Placebo441 mg882 mgoral aripiprazole alone. Lactation: Risk Summary: Aripiprazole is present in human breast milk; however, a history of seizures or with conditions that lower the seizure threshold. Conditions thatN = 207N = 207N = 208With concomitant use of ARISTADA with a strong CYP3A4 inducerthere are insufficient data to assess the amount in human milk, the effects on the lower the seizure threshold may be more prevalent in a population of 65 years or older. Adverse Reaction Term (%) (%) (%) Intervention: for more than 2 weeks consider increasing the ARISTADA dose. breastfed infant, or the effects on milk production. The development and health Potential for Cognitive and Motor Impairment: ARISTADA, like other antipsychotics, hasAkathisia 4 11 11 benefits of breastfeeding should be considered along with the mothers clinical needthe potential to impair judgment, thinking, or motor skills. Patients should be cautionedExamples: carbamazepine, rifampinfor ARISTADA and any potential adverse effects on the breastfed infant from ARISTADAabout operating hazardous machinery, including automobiles, until they are reasonablyRestlessness 1 3 1 Antihypertensive Drugsor from the underlying maternal condition. certain that therapy with ARISTADA does not affect them adversely. Other EPS 4 5 7 Due to its alpha adrenergic antagonism, aripiprazole has thePediatric Use: Safety and effectiveness of ARISTADA in patients 18 years of age have Body Temperature Regulation: Disruption of the bodys ability to reduce core bodyClinical Impact:potential to enhance the effect of certain antihypertensive agents. not been evaluated.temperature has been attributed to antipsychotic agents. Appropriate care is advised when Dystonia 1 2 2 Geriatric Use: Safety and effectiveness of ARISTADA in patients 65 years of age have prescribing ARISTADA for patients who will be experiencing conditions which may Parkinsonism 3 3 4 S:10" Intervention: T:10.75" Monitor blood pressure and adjust dose accordingly. not been evaluated. Elderly patients with dementia-related psychosis treated withS:10" T:10.75"contribute to an elevation in core body temperature (e.g., exercising strenuously, exposureExamples: carvedilol, lisinopril, prazosinantipsychotic drugs are at an increased risk of death. ARISTADA is not approved for to extreme heat, receiving concomitant medication with anticholinergic activity, or beingDystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups,treatment of patients with dementia-related psychosis.subject to dehydration). may occur in susceptible individuals during the first few days of treatment. DystonicBenzodiazepinesDysphagia: Esophageal dysmotility and aspiration have been associated with antipsychoticsymptoms include: spasm of the neck muscles, sometimes progressing to tightness ofThe intensity of sedation was greater with the combination of oralCYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known drug use. ARISTADA and other antipsychotic drugs should be used cautiously in patients atthe throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.aripiprazole and lorazepam as compared to that observed withCYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately risk for aspiration pneumonia. While these symptoms can occur at low doses, they occur more frequently and withClinical Impact:aripiprazole alone. The orthostatic hypotension observed was8% of Caucasians and 3-8% of Black/African Americans cannot metabolize ADVERSE REACTIONS greater severity with high potency and at higher doses of first-generation antipsychoticgreater with the combination as compared to that observed withCYP2D6 substrates and are classified as poor metabolizers (PM).drugs. An elevated risk of acute dystonia is observed in males and younger age groups. lorazepam alone. Hepatic and Renal Impairment: No dosage adjustment for ARISTADA is required based Clinical Studies Experience: Because clinical trials are conducted under widely varyingon a patients hepatic function (mild to severe hepatic impairment, Child-Pugh score conditions, adverse reaction rates observed in the clinical trials of a drug cannot beOther Adverse Reactions Observed in Clinical Studies: The following listing does Intervention: Monitor sedation and blood pressure. Adjust dose accordingly. between 5 and 15), or renal function (mild to severe renal impairment, glomerular directly compared to rates in the clinical trials of another drug and may not reflect thenot include reactions: 1) already listed in previous tables or elsewhere in labeling, Example: lorazepam filtration rate between 15 and 90 mL/minute). rates observed in practice. 2) for which a drug cause was remote, 3) which were so general as to beOther Specific Populations: No dosage adjustment for ARISTADA is required on the Patient Exposure: ARISTADA has been evaluated for safety in 1180 adult patients in clinicaluninformative, 4) which were not considered to have significant clinical implications,USE IN SPECIFIC POPULATIONS basis of a patients sex, race, or smoking status.trials in schizophrenia. or 5) which occurred at a rate equal to or less than placebo. Pregnancy OVERDOSAGECommonly Observed Adverse Reactions: The most common adverse reaction (incidenceCardiacangina pectoris, tachycardia, palpitations Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitorsHuman Experience: Common adverse reactions (reported in at least 5% of all 5% and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia.Gastrointestinal disordersconstipation, dry mouthpregnancy outcomes in women exposed to ARISTADA during pregnancy. For moreoverdose cases) reported with oral aripiprazole overdosage (alone or in General disordersasthenia information, contact the National Pregnancy Registry for Atypical Antipsychotics at Adverse Reactions Occurring at an Incidence of 2% or More in ARISTADA-Treated Patients.Musculoskeletalmuscular weakness1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research- combination with other substances) include vomiting, somnolence, and tremor. Adverse reactions associated with the use of ARISTADA (incidence of 2% or greater,Nervous system disordersdizziness programs/pregnancyregistry/. Other clinically important signs and symptoms observed in one or more patients rounded to the nearest percent and ARISTADA incidence greater than placebo) thatPsychiatric disordersanxiety, suicide with aripiprazole overdoses (alone or with other substances) include acidosis, occurred are shown in Table 2. Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole: TheRisk Summary: Neonates exposed to antipsychotic drugs during the third trimester aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, Table 2: Adverse Reaction in 2% or More of ARISTADA-Treated Patients and That following is a list of additional adverse reactions that have been reported in clinicalof pregnancy are at risk for extrapyramidal and/or withdrawal symptoms followingcoma, confusional state, convulsion, blood creatine phosphokinase increased, Occurred at Greater Incidence Than in the Placebo-Treated Patients intrials with oral aripiprazole and not reported above for ARISTADA.delivery. Limited published data on aripiprazole use in pregnant women are notdepressed level of consciousness, hypertension, hypokalemia, hypotension, the 12-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trial Blood and Lymphatic System Disorders: thrombocytopeniasufficient to inform any drug-associated risks for birth defects or miscarriage. lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia Cardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block,No teratogenicity was observed in animal reproductive studies with intramuscularaspiration, respiratory arrest, status epilepticus, and tachycardia.Aripiprazole Lauroxil atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failureadministration of aripiprazole lauroxil to rats and rabbits during organogenesis atManagement of Overdosage: In case of overdosage, call the Poison control center doses up to 5 and 15 times, respectively, the maximum recommended human doseimmediately at 1-800-222-1222. Placebo441 mg882 mgEye Disorders: photophobia, diplopia(MRHD) of 1064 mg based on body surface area (mg/m2). However, aripiprazole Adverse Reaction System Organ Class N = 207N = 207N = 208Gastrointestinal Disorders: gastroesophageal reflux diseasecaused developmental toxicity and possible teratogenic effects in rats and rabbitsTo report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at Preferred Term (%) (%) (%) General Disorders and Administration-Site Conditions: peripheral edema, chest pain,[see Data]. The background risk of major birth defects and miscarriage for the1-866-274-7823 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.face edemaindicated population are unknown. In the U.S. general population, the estimatedPATIENT COUNSELING INFORMATIONGeneral disorders and administration site conditions Hepatobiliary Disorders: hepatitis, jaundicebackground risk of major birth defects and miscarriage in clinically recognizedPhysicians are advised to discuss the FDA-approved patient labeling (Medication Guide) Immune System Disorders: hypersensitivitypregnancies is 2%-4% and 15%-20%, respectively. Advise pregnant women of thewith patients for whom they prescribe ARISTADA. Injection site pain 2 3 4 Injury, Poisoning, and Procedural Complications: fall, heat stroke potential risk to a fetus. Investigations Investigations: weight decreased, hepatic enzyme increased, blood glucose increased,Clinical Considerations: Fetal/Neonatal Adverse Reactions: Extrapyramidal and/orThis Brief Summary is based on ARISTADA Full Prescribing Informationblood lactate dehydrogenase increased, gamma glutamyl transferase increased, bloodwithdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence,RevMarch 2021Increased weight 1 2 2 prolactin increased, blood urea increased, blood creatinine increased, blood bilirubinrespiratory distress, and feeding disorder have been reported in neonates who wereManufactured and marketed by Alkermes, Inc., Waltham, MA 02451-1420increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Increased blood creatine0 2 1 Metabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemiaexposed to antipsychotic drugs during the third trimester of pregnancy. These symptomsALKERMES is a registered trademark of Alkermes, Inc. ARISTADA and logo, and phosphokinase Musculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis,have varied in severity. Monitor neonates for extrapyramidal and/or withdrawalmobility decreasedsymptoms and manage symptoms appropriately. Some neonates recover within ARISTADA INITIO , are registered trademarks of Alkermes Pharma Ireland Limited, Nervous system disorders Nervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia,hours or days without specific treatment; others required prolonged hospitalization.used by Alkermes, Inc., under license. Akathisia 4 11 11 myoclonus, bradykinesia, akinesia, coordination abnormal, speech disorder,Data: Animal Data for Aripiprazole Lauroxil: Aripiprazole lauroxil did not cause adverseHeadache 3 3 5 choreoathetosisdevelopmental or maternal effects in rats or rabbits when administered intramuscularly2021 Alkermes, Inc.All rights reserved.ARI-004455- v2Psychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia,during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant tic, homicidal ideation, catatonia, sleep walkingrats which are approximately 0.6 to 5 times the maximum recommended human'