ARIPIPRAZOLE- aripiprazole_tablet

The mechanism of action of aripiprazole in schizophrenia or bipolar mania, 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 For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours. Oral administration Absorption Tablet: max max Distribution 2 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 max max Figure 1: The Effect of Other Drugs on Aripiprazole Pharmacokinetics Effect of Other Drugs on Aripiprazole Figure 2: The Effect of Other Drugs on Dehydro-Aripiprazole Pharmacokinetics Effect of Other Drugs on Aripiprazole The effect of aripiprazole on the exposures of other drugs are summarized in Figure 3. Figure 3: The Effect of Aripiprazole on Pharmacokinetics of Other Drugs Effect of Aripiprazole Specific Populations Exposure of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults. Figure 4: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics Special Populations Figure 5: Effect of Intrinsic Factors on Dehydro-Aripiprazole Pharmacokinetics Effects of other drugs on aripiprazole Effects of other drugs on dehydro-aripiprazole Effects of aripiprazole on pharmacokinetics of other drugs Effects of intrinsic factors on aripiprazole Effects of intrinsic factors on dehydro-aripiprazole.

Aripiprazole Oral Tablets, are indicated for the treatment of: Schizophrenia Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder Adjunctive Treatment of Major Depressive Disorder Irritability Associated with Autistic Disorder Treatment of Tourette’s Disorder Aripiprazole tablets are an atypical antipsychotic. Schizophrenia ( 14. 1 Acute Treatment of Manic and Mixed Episodes associated with Bipolar I ( 14. 2 Adjunctive Treatment of Major Depressive Disorder ( 14. 3 Irritability Associated with Autistic Disorder ( 14. 4 Treatment of Tourette’s disorder ( 14.

Initial Recommended Maximum Schizophrenia en dash adults ( 2. 1 10 to 15 10 to 15 mg/day 30 Schizophrenia en dash adolescents 2. 1 2 mg/day 10 mg/day 30 Bipolar mania en dash adults: monotherapy 2. 2 15 mg/day 15 mg/day 30 Bipolar mania en dash adults: adjunct to 2. 2 10 to 15 15 mg/day 30 Bipolar mania en dash pediatric patients: 2. 2 2 mg/day 10 mg/day 30 Major Depressive Disorder en dash adults: 2. 3 2 to 5 mg/day 5 to 10 mg/day 15 Irritability associated with autistic 2. 4 2 mg/day 5 to 10 mg/day 15 Tourette’s 2. 5 Patients < 50 kg 2 mg/day 5 mg/day 10 Patients >= 50 kg 2 mg/day 10 mg/day 20 Oral formulations: Administer once daily without regard to meals ( 2 2. 7 Adults see Clinical Studies ( 14. 1 see Clinical Studies 14. 1 Adolescents [see Clinical Studies 14. 1 Switching from Other Antipsychotics Acute Treatment of Manic and Mixed Episodes [see Clinical Studies ( 14. 2 Adults The recommended starting dose for aripiprazole as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week [see Clinical Studies ( 14. 3 Pediatric Patients (6 to 17 years) The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day. Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week [see Clinical Studies ( 14. 4 Pediatric Patients (6 to 18 years) The recommended dosage range for Tourette’s Disorder is 5 to 20 mg/day. For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than one week. For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on Day 8. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than one week [see Clinical Studies ( 14. 5 Patients should be periodically reassessed to determine the continued need for maintenance treatment. 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 2). 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 2: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 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 Double usual dose over 1 to 2 weeks When adjunctive aripiprazole is administered to patients with major depressive disorder, aripiprazole should be administered without dosage adjustment as specified in Dosage and Administration ( 2.

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 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 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 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, bipolar disorder, major depressive disorder, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7,619 Aripiprazole has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette’s disorder 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 (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) 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. Commonly observed adverse reactions (incidence >=5% and at least twice that for placebo) were ( 6. 1 Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Adult Patients with Schizophrenia The following findings are based on a pool of five placebo-controlled trials (four 4 week and one 6 week) in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Commonly Observed Adverse Reactions The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%). Adult Patients with Bipolar Mania Monotherapy Commonly Observed Adverse Reactions Table 16: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with Oral Aripiprazole Monotherapy Preferred Term Percentage of Patients Reporting Reaction Aripiprazole (n=917) Placebo (n=753) Akathisia 13 4 Sedation 8 3 Restlessness 6 3 Tremor 6 3 Extrapyramidal Disorder 5 2 Less Common Adverse Reactions in Adults Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses >=2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset. Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction * System Organ Class Aripiprazole Placebo Preferred Term (n=1,843) (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. Adult Patients with Adjunctive Therapy with Bipolar Mania The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which aripiprazole was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate. Adverse Reactions Associated with Discontinuation of Treatment In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive aripiprazole compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively). Commonly Observed Adverse Reactions The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder. Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania Table 18 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate. Table 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder Percentage of Patients Reporting Reaction * Aripiprazole + Placebo + System Organ Class Preferred Term Li or Val dagger Li or Val dagger (n=253) (n=130) Gastrointestinal Disorders Nausea 8 5 Vomiting 4 0 Salivary Hypersecretion 4 2 Dry Mouth 2 1 Infections and Infestations Nasopharyngitis 3 2 Investigations Weight Increased 2 1 Nervous System Disorders Akathisia 19 5 Tremor 9 6 Extrapyramidal Disorder 5 1 Dizziness 4 1 Sedation 4 2 Psychiatric Disorders Insomnia 8 4 Anxiety 4 1 Restlessness 2 1 * dagger Pediatric Patients (13 to 17 years) with Schizophrenia The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor. Pediatric Patients (10 to 17 years) with Bipolar Mania The following findings are based on one 4-week, placebo-controlled trial in which oral aripiprazole was administered in doses of 10 or 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 19. Table 19: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction Preferred Term Aripiprazole (n=197) Placebo (n=97) Somnolence 23 3 Extrapyramidal Disorder 20 3 Fatigue 11 4 Nausea 11 4 Akathisia 10 2 Blurred Vision 8 0 Salivary Hypersecretion 6 0 Dizziness 5 1 Pediatric Patients (6 to 17 years) with Autistic Disorder The following findings are based on two 8 week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 to 15 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 20. Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction Aripiprazole Placebo Preferred Term (n=212) (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 The following findings are based on one 8 week and one 10 week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 to 20 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with Tourette's disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 21. Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral 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, Bipolar Mania, Autistic Disorder, or Tourette’s Disorder Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette’s disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with aripiprazole (doses >=2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo. Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction* System Organ Class Aripiprazole Placebo Preferred Term (n=732) (n=370) Eye Disorders Blurred Vision Gastrointestinal Disorders Abdominal Discomfort Vomiting Nausea Diarrhea Salivary Hypersecretion Abdominal Pain Upper Constipation 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 Tissue Disorders Rash 2 1 * Adult Patients Receiving Aripiprazole as Adjunctive Treatment of Major Depressive Disorder The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which aripiprazole was administered at doses of 2 to 20 mg as adjunctive treatment to continued antidepressant therapy. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions was 6% for adjunctive aripiprazole-treated patients and 2% for adjunctive placebo-treated patients. Commonly Observed Adverse Reactions The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with major depressive disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision. Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder Table 23 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses >=2 mg/day) and for which the incidence in patients treated with adjunctive aripiprazole was greater than the incidence in patients treated with adjunctive placebo in the combined dataset. Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder Percentage of Patients Reporting Reaction * System Organ Class Preferred Term Aripiprazole + ADT dagger (n=371) Placebo + ADT dagger (n=366) Eye Disorders 6 1 Blurred Vision Gastrointestinal Disorders Constipation 5 2 General Disorders and Administration Site Conditions Fatigue 8 4 Feeling Jittery 3 1 Infections and Infestations Upper Respiratory Tract Infection 6 4 Investigations Weight Increased 3 2 Metabolism and Nutrition Disorders Increased Appetite 3 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 3 Myalgia 3 1 Nervous System Disorders Akathisia 25 4 Somnolence 6 4 Tremor 5 4 Sedation 4 2 Dizziness 4 2 Disturbance in Attention 3 1 Extrapyramidal Disorder 2 0 Psychiatric Disorders Restlessness 12 2 Insomnia 8 2 * dagger Dose-Related Adverse Reactions Schizophrenia Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7. 1%; 10 mg, 8. 5%; 15 mg, 8. 7%; 20 mg, 7. 5%; 30 mg, 12. 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. 0%; 10 mg, 13. 0%; 30 mg, 21. 6%); somnolence (incidences were placebo, 6. 0%; 10 mg, 11. 6%); and tremor (incidences were placebo, 2. 0%; 10 mg, 2. 0%; 30 mg, 11. Bipolar Mania In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3. 1%; 10 mg, 12. 2%; 30 mg, 27. 3%); somnolence (incidences were placebo, 3. 1%; 10 mg, 19. 4%; 30 mg, 26. 3%); akathisia (incidences were placebo, 2. 2%; 30 mg, 11. 1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3. 1%; 30 mg, 8. Autistic Disorder In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3. 8%; 10 mg, 22. 0%; 15 mg, 18. Tourette’s Disorder In a study of pediatric patients (7 to 17 years of age) with Tourette’s disorder, no common adverse reaction(s) had a dose response relationship. Extrapyramidal Symptoms Schizophrenia In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (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 Simpson Angus Rating Scale (aripiprazole, 0. 24; placebo, en dash0. Similarly, in a long-term (26 week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo. Bipolar Mania In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy aripiprazole-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy aripiprazole-treated patients was 13% vs. In the 6 week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive aripiprazole-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 10% vs. 2% for placebo. In the adult bipolar mania trials with monotherapy aripiprazole, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0. 50; placebo, en dash0. 01 and aripiprazole, 0. 21; placebo, en dash0. Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the bipolar mania trials with aripiprazole as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0. 73; placebo, 0. 07 and aripiprazole, 0. 30; placebo, 0. Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive aripiprazole and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0. 90; placebo, −0. Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. Major Depressive Disorder In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% vs. 4% for adjunctive placebo-treated patients. In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0. 31; placebo, 0. 03 and aripiprazole, 0. 22; placebo, 0. Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups. Autistic Disorder In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9% for placebo. In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0. 1; placebo, en dash0. Tourette’s Disorder In the short-term, placebo-controlled trials in Tourette’s disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 4% vs. In the pediatric (6 to 18 years) short-term Tourette’s disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for aripiprazole and placebo. Dystonia Symptoms 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. Additional Findings Observed in Clinical Trials Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials The adverse reactions reported in a 26 week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 <=49 days), and were of limited duration (7/12 <=10 days). Tremor infrequently led to discontinuation (<1%) of aripiprazole. In addition, in a long-term (52 weeks), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder. Other Adverse Reactions Observed During Clinical Trial Evaluation of Aripiprazole The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a 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 a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent infrequent rare Adults - Oral Administration 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 rare 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 - Oral Administration Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below. Eye Disorders: infrequent Gastrointestinal Disorders: infrequent Investigations: frequent Nervous System Disorders: infrequent Renal and Urinary Disorders frequent Skin and Subcutaneous Tissue Disorders: infrequent en dash hirsutism The following adverse reactions have been identified during post-approval use of aripiprazole tablets. 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.

Aripiprazole Tablets 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. 2 Known hypersensitivity to aripiprazole ( 4.

Pregnancy: 8. 1 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). In animal reproduction studies, oral and intravenous 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 estimated 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 9258 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 Limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0. 3% of the maternal weight-adjusted dosage. There are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established. 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. Bipolar I Disorder Safety and effectiveness in pediatric patients with bipolar mania were established in a 4 week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see Dosage and Administration ( 2. 2 Adverse Reactions ( 6. 1 and Clinical Studies ( 14. 2 The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. However, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Irritability Associated with Autistic Disorder Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see Indications and Usage ( 1 Dosage and Administration 2. 4 Adverse Reactions ( 6. 1 Clinical Studies ( 14. 4 Tourette’s Disorder Safety and effectiveness of aripiprazole in pediatric patients with Tourette’s Disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [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. 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 oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were >=65 years old and 78 (10%) were >=75 years old. Placebo-controlled studies of aripiprazole injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of patients aged 65 years 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. 1 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. 3 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. 3 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 25: 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 CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [ see Clinical Pharmacology ( 12. 3 ] With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see Dosage and Administration ( 2. 7 Strong CYP3A4 Inducers (e. , carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [ see Clinical Pharmacology 12. 3 With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see Dosage and Administration 2. 7 Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions 5. 8 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, 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 co-administered with aripiprazole. [see Clinical Pharmacology ( 12.

OVERDOSAGE
MedDRA terminology has been used to classify the adverse reactions. 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 oral 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 oral 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 oral 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. 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 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 the oral formulations 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. 1 Four short-term monotherapy trials and one 6 week adjunctive trial in adult patients and one short-term monotherapy trial in pediatric patients (ages 10 to 17 years) with manic or mixed episodes [see Clinical Studies (1 4. 2 One maintenance monotherapy trial and one maintenance adjunctive trial in adult patients with bipolar I disorder [see Clinical Studies ( 14. 2 Two short-term trials in adult patients with MDD who had an inadequate response to antidepressant therapy during the current episode [see Clinical Studies ( 14. 3 Two short-term trials in pediatric patients (ages 6 to 17 years) for the treatment of irritability associated with autistic disorder [see Clinical Studies ( 14. 4 Two short-term trials in pediatric patients (ages 6 to 18 years) with Tourette’s disorder [see Clinical Studies ( 14. 5 Adults Pediatric Patients Table 26: Schizophrenia Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference* (95% CI) Study 1 Aripiprazole (15 mg/day) dagger 98. 2) Aripiprazole (30 mg/day) dagger 99. 1) Placebo 100. 36) -- Study 2 Aripiprazole (20 mg/day) dagger 92. 8) Aripiprazole (30 mg/day) dagger 94. 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) Study 4 Aripiprazole (2 mg/day) 90. 47) Aripiprazole (5 mg/day) 92. 19) Aripiprazole (10 mg/day) dagger 90. 58) Placebo 90. 97) -- Study 6 Aripiprazole (10 mg/day) dagger 93. 21) Aripiprazole (30 mg/day) dagger 94. 13) Placebo 94. 93) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. dagger Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5) aripiprazole-graph Acute Treatment of Manic and Mixed Episodes Adults Monotherapy The efficacy of aripiprazole as monotherapy in the acute treatment of manic episodes was established in four 3 week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and two of the studies also included patients with or without a rapid-cycling course. The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11 item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) Scale. In the four positive, 3 week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated aripiprazole in a range of 15 mg to 30 mg, once daily (with a starting dose of 30 mg/day in two studies and 15 mg/day in two studies), aripiprazole was superior to placebo in the reduction of Y-MRS total score (Studies 1 to 4 in Table 27) and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint. Adjunctive Therapy The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6 week, placebo-controlled study (n=384) with a 2 week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features. Patients were initiated on open-label lithium (0. 0 mEq/L) or valproate (50 to 125 mcg/mL) at therapeutic serum levels and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score >=16 and <=25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either aripiprazole (15 mg/day or an increase to 30 mg/day as early as Day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6 week, placebo-controlled phase, adjunctive aripiprazole starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0. 0 mEq/L or 50 to 125 mcg/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y-MRS total score (Study 5 in Table 27) and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6 week endpoint. Pediatric Patients The efficacy of aripiprazole in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4 week, placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score >=20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of aripiprazole (10 or 30 mg/day) to placebo. The aripiprazole dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in change from baseline to Week 4 on the Y-MRS total score (Study 6 in Table 27). Table 27: Bipolar Studies Study Number Treatment Group Primary Efficacy Measure: Y-MRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * Study 1 Aripiprazole (30 / 15 mg/day) dagger 29. 76) Study 2 Aripiprazole (30 / 15 mg/day) dagger 27. 80) Study 3 Aripiprazole (15 to 30 mg/day) dagger 28. 51) Study 4 Aripiprazole (15 to 30 mg/day) dagger 28. 11) Study 5 Aripiprazole (15 or 30 mg/day)dagger 23. 95) Study 6 (Pediatric,10 to 17 years) Aripiprazole (10 mg/day) dagger dagger 29. 50) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * dagger Doses statistically significantly superior to placebo. Maintenance Treatment of Bipolar I Disorder Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7) Adjunctive Maintenance Therapy 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 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8) Aripiprazole-fig-16. jpg Aripiprazole-fig-17 Adults The efficacy of aripiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6 week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17 item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose. The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10 item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3 item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme). In the two trials (n=381, n=362), aripiprazole was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, aripiprazole was also superior to placebo in reducing the mean SDS score. In both trials, patients received aripiprazole adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10. An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females. Table 28: Adjunctive Treatment of Major Depressive Disorder Studies Study Number Treatment Group Primary Efficacy Measure : MADRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * (95% CI) Study 1 Aripiprazole (5 to 20 dagger +Antidepressant 25. 15) Placebo +Antidepressant 27. 64) -- Study 2 Aripiprazole (5 to 20 dagger +Antidepressant 26. 37) Placebo +Antidepressant 26. 67) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * dagger Pediatric Patients The efficacy of aripiprazole (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 29). 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 29). All three doses of aripiprazole significantly improved scores on the ABC-I subscale compared with placebo. Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric) Study Number Treatment Group Primary Efficacy Measure: ABC-I Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference * (95% CI) Study 1 Aripiprazole (2 to 15 mg/day) dagger 29. 1) Placebo 30. 43) -- Study 2 Aripiprazole (5 mg/day) dagger 28. 4) Aripiprazole (10 mg/day) dagger 28. 3) Aripiprazole (15 mg/day) 28. 3) Placebo 28. 39) -- 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 less than 50 kg in the low dose aripiprazole group started at 2 mg per day with a target dose of 5mg per day after 2 days. Patients >= 50 kg in the low dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at Day 7. Patients <50 kg in the high dose aripiprazole group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at Day 7. Patients >= 50 kg in the high dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at Day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. aripiprazole (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) 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) In the 10 week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette’s disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or aripiprazole, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. aripiprazole demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of aripiprazole at the end of 10 week treatment was 6. Table 30: Tourette’s Disorder Studies (Pediatric) Study Number Treatment Group Primary Efficacy Measure: YGTSS TTS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differenc e* (95% CI) Study 1 Aripiprazole (low dose) dagger 29. 3) Aripiprazole (high dose) dagger 31. 9) Placebo 30. 55) -- Study 2 Aripiprazole (2 to 20 mg/day) dagger 28. 9) Placebo 29. 64) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * dagger aripiprazole-fig-18.
MEDICATION GUIDE
Aripiprazole Tablets, USP (AR i PIP ra zole) What is the most important information I should know about Aripiprazole Tablets? (For other side effects, also see “ Serious side effects may happen when you take aripiprazole tablets, including: Increased risk of death in elderly patients with dementia-related psychosis: Risk of suicidal thoughts or actions Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling very agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Antidepressants are medicines used to treat depression and other illnesses. Antidepressant medicines have other side effects. Antidepressant medicines can interact with other medicines. Not all antidepressant medicines prescribed for children are FDA approved for use in children. What is Aripiprazole Tablets? Aripiprazole Tablets is a prescription medicine used to treat: schizophrenia manic or mixed episodes that happen with bipolar I disorder major depressive disorder (MDD) when aripiprazole is used with antidepressant medicines irritability associated with autistic disorder Tourette’s disorder It is not known if Aripiprazole is safe or effective in children: under 13 years of age with schizophrenia under 10 years of age with bipolar I disorder under 6 years of age with irritability associated with autistic disorder under 6 years of age with Tourette’s disorder Do not take aripiprazole if you Before taking aripiprazole tablets, tell your healthcare provider about all your medical conditions, including if you have or had: diabetes or high blood sugar in you or your family; your healthcare provider should check your blood sugar before you start aripiprazole tablets and also during therapy. seizures (convulsions). low or high blood pressure. heart problems or stroke. pregnancy or plans to become pregnant. It is not known if aripiprazole tablets will harm your unborn baby. If you become pregnant while receiving aripiprazole tablets, 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 go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ breast-feeding or plans to breast-feed. Aripiprazole passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive aripiprazole tablets. low white blood cell count. Tell your healthcare provider about all the medicines that you take, Aripiprazole Tablets and other medicines may affect each other causing possible serious side effects. Aripiprazole Tablets may affect the way other medicines work, and other medicines may affect how aripiprazole tablets works. Your healthcare provider can tell you if it is safe to take aripiprazole tablets with your other medicines. Do not start or stop any medicines while taking aripiprazole tablets without talking to your healthcare provider first. Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. How should I take Aripiprazole Tablets? Take aripiprazole tablets exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole tablets yourself. Aripiprazole Tablets can be taken with or without food. Aripiprazole tablets should be swallowed whole. If you miss a dose of aripiprazole tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of aripiprazole tablets at the same time. If you take too much aripiprazole tablets, call your healthcare provider or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room. What should I avoid while taking Aripiprazole Tablets? Do not drive, operate heavy machinery, or do other dangerous activities until you know how aripiprazole tablets affects you. Aripiprazole tablets may make you drowsy. Avoid getting over-heated or dehydrated. Do not over-exercise. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much or heavy clothing. Drink plenty of water. What are the possible side effects of Aripiprazole Tablets? Aripiprazole Tablets may cause serious side effects, including: See “What is the most important information I should know about Aripiprazole Tablets ?” Stroke in elderly people (cerebrovascular problems) that can lead to death Neuroleptic malignant syndrome (NMS). Uncontrolled body movements (tardive dyskinesia). Problems with your metabolism such as: High blood sugar (hyperglycemia) and diabetes. Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving aripiprazole tablets: Increased fat levels (cholesterol and triglycerides) in your blood. Weight gain. Unusual urges. Orthostatic hypotension (decreased blood pressure). Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position. Falls. Low white blood cell count Seizures (convulsions) Problems with control of your body temperature especially when you exercise a lot or are in an area that is very hot. It is important for you to drink water to avoid dehydration. See D ifficulty swallowing that can cause food or liquid to get into your lungs. The most common side effects of aripiprazole tablets in adults include: nausea dizziness vomiting anxiety constipation insomnia headache restlessness blurred vision inner sense of restlessness/need to move (akathisia) upper respiratory illness The most common side effects of aripiprazole tablets in children include: feeling sleepy insomnia headache nausea vomiting stuffy nose fatigue weight gain increased or decreased appetite uncontrolled movement such as restlessness, tremor increased saliva or drooling muscle stiffness These are not all the possible side effects of aripiprazole tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Aripiprazole Tablets, USP? Keep aripiprazole tablets and all medicines out of the reach of children. General information about the safe and effective use of Aripiprazole Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use aripiprazole tablets for a condition for which it was not prescribed. Do not give aripiprazole tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about aripiprazole tablets that was written for healthcare professionals. What are the ingredients in Aripiprazole Tablets, USP? Active ingredient Inactive ingredients Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

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