ARIPIPRAZOLE_- aripiprazole_tablet

The mechanism of action of aripiprazole in schizophrenia is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D 2 1A 2A Aripiprazole exhibits high affinity for dopamine D 2 3 1A 2A i 4 2C 7 1 1 i i 50 Aripiprazole activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D 2 Absorption Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. Aripiprazole can be administered with or without food. Administration of a 15 mg aripiprazole tablet with a standard high-fat meal did not significantly affect the C max max Distribution The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4. 9 L/kg), indicating extensive extravascular distribution. 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 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D 2 Metabolism and Elimination Metabolism Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro Excretion Following a single oral dose of [ 14 Drug Interaction Studies Effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4. 5-fold increase in mean C max max Figure 1: The Effect of Other Drugs on Aripiprazole Pharmacokinetics Figure 2: The Effect of Other Drugs on Dehydro-Aripiprazole Pharmacokinetics Figure 3: The Effect of Aripiprazole on Pharmacokinetics of Other Drugs Effect of Aripiprazole on Other Drugs Specific Populations Figure 4: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics aripiprazole-figure1. jpg Figure 2 Figure 3 Figure 4 Figure 5.

Aripiprazole tablets are indicated for the treatment of: Schizophrenia Aripiprazole is an atypical antipsychotic. The oral formulations are indicated for:.

Initial Dose Recommended Dose Maximum Dose Schizophrenia en dash adults (2. 1) 10 to 15 mg/day 10 to 15 mg/day 30 mg/day Schizophrenia en dash adolescents (2. 1) 2 mg/day 10 mg/day 30 mg/day Irritability associated with autistic disorder en dash pediatric patients (2. 4) 2 mg/day 5 to 10 mg/day 15 mg/day Tourette’s disorder en dash (2. 5) Patients <50 kg 2 mg/day 5 mg/day 10 mg/day Patients >=50 kg 2 mg/day 10 mg/day 20 mg/day Known CYP2D6 poor metabolizers: Half of the usual dose (2. 6) Adults [see Clinical Studies [see Clinical Studies Adolescents [see Clinical Studies Switching from Other Antipsychotics Pediatric Patients (6 to 17 years) [see Clinical Studies (14. 4)] Pediatric Patients (6 to 18 years) [see Clinical Studies (14. 5)] Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e. , a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response. Table 1: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, CYP3A4 Inhibitors, and/or CYP3A4 Inducers Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e. , itraconazole, clarithromycin) Administer a quarter of usual dose Strong CYP2D6 (e. , quinidine, fluoxetine, paroxetine) or Administer half of usual dose Strong CYP2D6 and Administer a quarter of usual dose Strong CYP3A4 inducers (e. , carbamazepine, rifampin) Double usual dose over 1 to 2 weeks.

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5. 1)] Cerebrovascular Adverse Events, Including Stroke [see Warnings and Precautions (5. 2)] Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5. 3)] Neuroleptic Malignant Syndrome (NMS) [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/Convulsions [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)] Suicide [see Warnings and Precautions (5. 14)] Dysphagia [see Warnings and Precautions (5. 15)] Commonly observed adverse reactions (incidence >=5% and at least twice that for placebo) were (6. 1): To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions in adult patients in clinical trials (>=10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. The most common adverse reactions in the pediatric clinical trials (>=10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased. Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, other indications, dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7,619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3,390 patients were treated with oral aripiprazole for at least 180 days and 1,933 patients treated with oral aripiprazole had at least one year of exposure. Aripiprazole has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, autistic disorder, or Tourette’s Disorder or another indication and who had approximately 1,342 patient-years of exposure to oral aripiprazole. A total of 959 pediatric patients were treated with oral aripiprazole for at least 180 days and 556 pediatric patients treated with oral aripiprazole had at least one year of exposure. The conditions and duration of treatment with aripiprazole tablets included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure. Adult Patients with Schizophrenia Commonly Observed Adverse Reactions Less Common Adverse Reactions in Adults Table 15: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Aripiprazole System Organ Class Preferred Term Percentage of Patients Reporting Reaction * Aripiprazole (n=1,843) Placebo (n=1,166) Eye Disorders Blurred Vision 3 1 Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 * An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Pediatric Patients (13 to 17 years) with Schizophrenia Adverse Reactions Associated with Discontinuation of Treatment Commonly Observed Adverse Reactions Pediatric Patients (6 to 17 years) with Autistic Disorder Adverse Reactions Associated with Discontinuation of Treatment Commonly Observed Adverse Reactions Table 18: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Aripiprazole Percentage of Patients Reporting Reaction Preferred Term Aripiprazole (n=212) Placebo (n=101) Sedation 21 4 Fatigue 17 2 Vomiting 14 7 Somnolence 10 4 Tremor 10 0 Pyrexia 9 1 Drooling 9 0 Decreased Appetite 7 2 Salivary Hypersecretion 6 1 Extrapyramidal Disorder 6 0 Lethargy 5 0 Pediatric Patients (6 to 18 years) with Tourette’s Disorder Adverse Reactions Associated with Discontinuation of Treatment Commonly Observed Adverse Reactions Table 19: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette’s Disorder Treated with Aripiprazole Percentage of Patients Reporting Reaction Aripiprazole Placebo Preferred Term (n=121) (n=72) Sedation 13 6 Somnolence 13 1 Nausea 11 4 Headache 10 3 Nasopharyngitis 9 0 Fatigue 8 0 Increased Appetite 7 1 Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Another Indication, Autistic Disorder, or Tourette’s Disorder Table 20: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Aripiprazole Percentage of Patients Reporting Reaction * System Organ Class Preferred Term Aripiprazole (n=732) Placebo (n=370) Eye Disorders Blurred Vision 3 0 Gastrointestinal Disorders Abdominal Discomfort 2 1 Vomiting 8 7 Nausea 8 4 Diarrhea 4 3 Salivary Hypersecretion 4 1 Abdominal Pain Upper 3 2 Constipation 2 2 General Disorders and Administration Site Conditions Fatigue 10 2 Pyrexia 4 1 Irritability 2 1 Asthenia 2 1 Infections and Infestations Nasopharyngitis 6 3 Investigations Weight Increased 3 1 Metabolism and Nutrition Disorders Increased Appetite 7 3 Decreased Appetite 5 4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 2 1 Muscle Rigidity 2 1 Nervous System Disorders Somnolence 16 4 Headache 12 10 Sedation 9 2 Tremor 9 1 Extrapyramidal Disorder 6 1 Akathisia 6 4 Drooling 3 0 Lethargy 3 0 Dizziness 3 2 Dystonia 2 1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 2 1 Skin and Subcutaneous Disorders Rash 2 1 * Dose-Related Adverse Reactions Schizophrenia In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5%; 10 mg, 13%; 30 mg, 21. 6%); somnolence (incidences were placebo, 6%; 10 mg, 11%; 30 mg, 21. 6%); and tremor (incidences were placebo, 2%; 10 mg, 2%; 30 mg, 11. Autistic Disorder Tourette’s Disorder Extrapyramidal Symptoms Schizophrenia Objectively collected data from those trials was collected for EPS using the Simpson Angus Scale (SAS), for akathisia using the Barnes Akathisia Rating Scale (BARS), and for dyskinesias using the Assessments of Involuntary Movement Scales (AIMS). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the BARS (aripiprazole, 0. 08; placebo, en dash0. In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the SAS (aripiprazole, 0. 24; placebo, en dash0. Autistic Disorder In the pediatric (6 to 17 years) short-term autistic disorder trials, the SAS showed a significant difference between aripiprazole and placebo (Aripiprazole, 0. 1; placebo, en dash 0. Changes in the BARS and the AIMS were similar for the aripiprazole and placebo groups. Tourette’s Disorder In the pediatric (6 to 18 years) short-term Tourette’s Disorder trials, changes in the SAS, BARS and AIMS were not clinically meaningfully different for aripiprazole and placebo. Dystonia Additional Findings Observed in Clinical Trials Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole Reactions are categorized by body system according to the following definitions: frequent infrequent Adults Blood and Lymphatic System Disorders: rare Cardiac Disorders: infrequent rare Eye Disorders: infrequent rare Gastrointestinal Disorders: infrequent General Disorders and Administration Site Conditions: frequent infrequent rare Hepatobiliary Disorders: rare Immune System Disorders: rare Injury, Poisoning, and Procedural Complications: infrequent rare Investigations: frequent infrequent Metabolism and Nutrition Disorders: frequent rare Musculoskeletal and Connective Tissue Disorders: infrequent rare Nervous System Disorders: infrequent rare <1/10,000 patients Psychiatric Disorders: infrequent rare Renal and Urinary Disorders: rare Reproductive System and Breast Disorders: infrequent rare Respiratory, Thoracic, and Mediastinal Disorders: infrequent Skin and Subcutaneous Tissue Disorders: infrequent rare Vascular Disorders: infrequent Pediatric Patients Eye Disorders: infrequent Gastrointestinal Disorders: infrequent Investigations: frequent Nervous System Disorders: infrequent Renal and Urinary Disorders: frequent Skin and Subcutaneous Tissue Disorders: infrequent The following adverse reactions have been identified during postapproval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), hiccups, oculogyric crisis, and pathological gambling, and fecal incontinence.

Aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6. Known hypersensitivity to aripiprazole (4).

Pregnancy Lactation: Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth. org/clinical-and-research-programs/pregnancyregistry/ Risk Summary Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) (see Data) (see Clinical Considerations). [see Use in Specific Populations (8. In animal reproduction studies, aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m 2 2 (see Data) The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal Adverse Reactions Extrapyramidal 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 (including aripiprazole) 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 recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. In pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the MRHD of 30 mg/day based on mg/m 2 In pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the MRHD of 30 mg/day based on mg/m 2 In pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the MRHD of 30 mg/day based on mg/m 2 In pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the MRHD of 30 mg/day based on mg/m 2 In rats treated orally with aripiprazole peri- and postnatally from gestation Day 17 through postpartum Day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the MRHD of 30 mg/day based on mg/m 2 In rats injected intravenously with aripiprazole from gestation Day 6 through lactation Day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the MRHD of 30 mg/day based on mg/m 2 Risk Summary Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period can lead to variable effects on milk supply in the post-partum period, including clinically relevant decreases in milk supply which may be reversible with discontinuation of the drug. There are also reports of aripiprazole exposure during pregnancy and no maternal milk supply in the post-partum period. Effects on milk supply are likely mediated through decreases in prolactin levels, which have been observed [see Adverse Reactions (6. 1)] The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12. 3)] Schizophrenia Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see Dosage and Administration (2. 1), Adverse Reactions (6. 1), and Clinical Studies (14. Bipolar I Disorder Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Irritability Associated with Autistic Disorder [see Indications and Usage (1), Dosage and Administration (2. 4), Adverse Reactions (6. 4)] Tourette’s Disorder [see Dosage and Administration (2. 5), Adverse Reactions (6. 5)] Juvenile Animal Studies Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 No dosage adjustment is recommended for elderly patients [see Boxed Warning, Warnings and Precautions (5. 1), and Clinical Pharmacology (12. 3)] Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were >=65 years old and 799 (6%) were >=75 years old. Placebo-controlled studies of aripiprazole in schizophrenia or other indications did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Aripiprazole is not approved for the treatment of patients with psychosis associated with Alzheimer’s disease [see Boxed Warning and Warnings and Precautions (5. Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2. 6) and Clinical Pharmacology (12. No dosage adjustment for aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12. No dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.

Dosage adjustment due to drug interactions (7. 1): Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP2D6 or Administer half of usual dose Strong CYP2D6 and Administer a quarter of usual dose Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks Table 22: Clinically Important Drug Interactions with Aripiprazole: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e. , itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e. , quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12. Reduce the aripiprazole dosage when administered concomitantly with a strong CYP3A4 inhibitor or a strong CYP2D6 inhibitor [see Dosage and Administration (2. Strong CYP3A4 Inducers (e. , carbamazepine, rifampin) Concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12. Increase the aripiprazole dosage when administered concomitantly with a strong CYP3A4 inducer [see Dosage and Administration (2. Antihypertensive Drugs Due to its alpha 1 Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5. Benzodiazepines (e. , lorazepam) 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)] Monitor sedation and blood pressure. Adjust dose accordingly. Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, and lorazepam. In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e. , dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e. , warfarin), CYP2C19 (e. , omeprazole, warfarin, escitalopram), or CYP3A4 (e. , dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with aripiprazole [see Clinical Pharmacology (12.

OVERDOSAGE
MedDRA terminology has been used to classify the adverse reactions. Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving aripiprazole ingestions up to 195 mg with no fatalities. 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. Management of Overdosage No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal max Hemodialysis
NONCLINICAL TOXICOLOGY
Carcinogenesis Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 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. 5, 2 and 5 times and 0. 3, 1 and 3 times the MRHD of 30 mg/day based on mg/m 2 2 An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D 2 Mutagenesis The mutagenic potential of aripiprazole was tested in the in vitro in vitro in vitro in vitro in vivo in vitro in vitro in vivo Impairment of Fertility Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0. 6, 2, and 6 times the MRHD of 30 mg/day based on mg/m 2 Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m 2 Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg/day and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg/day which are 13 and 19 times the MRHD of 30 mg/day based on mg/m 2.
CLINICAL STUDIES
Efficacy of aripiprazole was established in the following adequate and well-controlled trials: Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13 to 17 years) with schizophrenia [see Clinical Studies (14. see Clinical Studies (14. [see Clinical Studies (14. 4)] [see Clinical Studies (14. 5)] Adults The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and the active comparators. In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 1 in Table 23), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale. In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 2 in Table 23), PANSS positive subscale, PANSS negative subscale, and CGI-severity score. In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the PANSS total score (Study 3 in Table 23), PANSS positive subscale, and the PANSS negative subscale. In a 6 week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score(Study 4 in Table 23), the primary outcome measure of the study. The 2 mg and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure. Thus, the efficacy of 10 mg, 15 mg, 20 mg, and 30 mg daily doses was established in two studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies. An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race. A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from their antipsychotic medications and randomized to aripiprazole 15 mg/day or placebo for up to 26 weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement score of >=5 (minimally worse), scores >=5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or >=20% increase in the PANSS total score. Patients receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6). Pediatric Patients The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score >=70 at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 23), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Table 23: Schizophrenia Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * Study 1 Aripiprazole (15 mg/day) dagger 98. 2) Aripiprazole (30 mg/day) dagger 99 (19. 1) Placebo 100. 36) --- Study 2 Aripiprazole (20 mg/day) dagger 92. 8) Aripiprazole (30 mg/day) dagger 94. 24) -9 (-14. 1) Placebo 94. 17) --- Study 3 Aripiprazole (10 mg/day) dagger 92. 41) Aripiprazole (15 mg/day) dagger 93. 08) Aripiprazole (20 mg/day) dagger 92. 68) Placebo 92. 35) --- Study 4 Aripiprazole (2 mg/day) 90. 47) Aripiprazole (5 mg/day) 92 (12. 19) Aripiprazole (10 mg/day) dagger 90 (11. 58) Placebo 90. 97) --- Study 6 (Pediatric, 13 to 17 years) Aripiprazole (10 mg/day) dagger 93. 21) Aripiprazole (30 mg/day) dagger 94 (16. 13) Placebo 94. 93) --- Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5) aripiprazole-fig-6. jpg Monotherapy Maintenance Therapy A maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label aripiprazole and who had maintained a clinical response for at least 6 weeks. The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label aripiprazole (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind fashion, to either the same dose of aripiprazole they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, aripiprazole was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study (Study 7 in Figure 7). A total of 55 mood events were observed during the double-blind treatment phase. Nineteen were from the aripiprazole group and 36 were from the placebo group. The number of observed manic episodes in the aripiprazole group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the aripiprazole group (9) was similar to that in the placebo group (11). An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences. Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7) figure 7 Pediatric Patients The efficacy of aripiprazole in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these patients were under 13 years of age. Efficacy was evaluated using two assessment scales: The Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC- I). The ABC-I subscale measured symptoms of irritability in autistic disorder. The results of these trials are as follows: In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or aripiprazole 2 to 15 mg/day. Aripiprazole, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of aripiprazole at the end of 8-week treatment was 8. 6 mg/day (Study 1 in Table 26). In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of aripiprazole (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. Aripiprazole dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 26). All three doses of aripiprazole significantly improved scores on the ABC-I subscale compared with placebo. Table 26: Irritability Associated with Autistic Disorder Studies (Pediatric) Primary Efficacy Measure: ABC-I Study Number Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo- subtracted Difference * Study 1 Aripiprazole (2 to15 mg/day) dagger 29. 1) Placebo 30. 43) -- Study 2 Aripiprazole (5 mg/day) dagger dagger 28. 4) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * dagger Pediatric Patients The efficacy of aripiprazole in the treatment of Tourette’s Disorder was established in one 8-week (7 to 17 years of age) and one 10-week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette’s Disorder and had a Total Tic score (TTS) >=20 to 22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age. The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i. The results of these trials are as follows: In the 8-week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette’s Disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose aripiprazole, high dose aripiprazole, or placebo. The target doses for the low and high dose aripiprazole groups were based on weight. Patients <50 kg in the low dose aripiprazole group started at 2 mg/day with a target dose of 5 mg/day after 2 days. Patients >=50 kg in the low dose aripiprazole group, started at 2 mg/day increased to 5 mg/day after 2 days, with a subsequent increase to a target dose of 10 mg/day at Day 7. Patients <50 kg in the high dose aripiprazole group started at 2 mg/day increased to 5 mg/day after 2 days, with a subsequent increase to a target dose of 10 mg/day at Day 7. Patients >=50 kg in the high dose aripiprazole group, started at 2 mg/day increased to 5 mg/day after 2 days, with a subsequent increase to a dose of 10 mg/day at Day 7 and were allowed weekly increases of 5 mg/day up to a target dose 20 mg/day at Day 21. Aripiprazole (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 27) and on the CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9. Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette’s Disorder Study 1) Table 27: Tourette’s Disorder Studies (Pediatric) Primary Efficacy Measure: YGTSS TTS Study Number Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * Aripiprazole (low dose) dagger dagger 29. 3) Study 1 Study 2 Aripiprazole (2 to 20 mg/day) dagger 28. 9) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * dagger aripiprazole-fig-9.

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