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| Product NDC Code | 62332-104 | ||||
|---|---|---|---|---|---|
| Drug Name | Aripiprazole |
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| Type | Generic | ||||
| Pharm Class | Atypical Antipsychotic [EPC] | ||||
| Active Ingredients |
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| Route | ORAL | ||||
| Dosage Form | TABLET, ORALLY DISINTEGRATING | ||||
| RxCUI drug identifier | 643019, 643022 |
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| Application Number | ANDA202102 | ||||
| Labeler Name | Alembic Pharmaceuticals Inc. | ||||
| Packages |
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Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance Aripiprazole is not a controlled substance.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 Dependence In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Aripiprazole is not a controlled substance. 9.2 Abuse Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). 9.3 Dependence In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.
Overdosage of Aripiprazole
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE MedDRA terminology has been used to classify the adverse reactions. 10.1 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 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 1260 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 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. 10.2 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 : In the event of an overdose of aripiprazole, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of aripiprazole, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis : Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS 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 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)] 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, another indication, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to Abilify injection. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure. Aripiprazole has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, autistic disorder, Tourette’s disorder, or other 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 1 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. Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were (6.1): •Adult patients with schizophrenia: akathisia •Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor • Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy • Pediatric patients (6 to 18 years) with Tourette’s disorder: sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, increased appetite To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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%). 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 another indication), 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 System Organ Class Preferred Term Percentage of Patients Reporting Reaction * Aripiprazole (n=1843) Placebo (n=1166) 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 * Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. 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 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 (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 Preferred Term Percentage of Patients Reporting Reaction 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 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 Preferred Term Percentage of Patients Reporting Reaction Aripiprazole (n=121) Placebo (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, Autistic Disorder, Tourette’s Disorder, or Other Indication 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 one indication, 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 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 * Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. 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, 12.6%). 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, 11.8%). 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%; 15 mg, 18.5%). 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, –0.05). 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, –0.29). 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. 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, -0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. 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. 6% for placebo. 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-week), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. Other Adverse Reactions Observed During the Premarketing 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 adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: Adults - Oral Administration Blood and Lymphatic System Disorders: rare - thrombocytopenia Cardiac Disorders: in frequent – bradycardia, palpitations, rare – atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure Eye Disorders: infrequent – photophobia; rare -diplopia Gastrointestinal Disorders: infrequent - gastroesophageal reflux disease General Disorders and Administration Site Conditions: frequent - asthenia; infrequent – peripheral edema, chest pain; rare – face edema Hepatobiliary Disorders: rare - hepatitis, jaundice Immune System Disorders: rare -hypersensitivity Injury, Poisoning, and Procedural Complications: infrequent – fall; rare – heat stroke Investigations: frequent - blood prolactin decreased, weight decreased, infrequent - hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare – blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: frequent – anorexia; rare -hypokalemia, hyponatremia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: infrequent - muscular weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased Nervous System Disorders: infrequent - parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare – akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; < 1/10,000 patients -choreoathetosis Psychiatric Disorders: infrequent – aggression, loss of libido, delirium; rare – libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking Renal and Urinary Disorders: rare - urinary retention, nocturia Reproductive System and Breast Disorders: infrequent - erectile dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism Respiratory, Thoracic, and Mediastinal Disorders: infrequent -nasal congestion, dyspnea Skin and Subcutaneous Tissue Disorders: infrequent - rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare - urticaria Vascular Disorders: infrequent – hypotension, hypertension 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 - oculogyric crisis Gastrointestinal Disorders: infrequent -tongue dry, tongue spasm Investigations: frequent - blood insulin increased Nervous System Disorders: infrequent - sleep talking Renal and Urinary Disorders: frequent – enuresis Skin and Subcutaneous Tissue Disorders: infrequent - hirsutism Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups, blood glucose fluctuation, oculogyric crisis, drug reaction with eosinophilia and systemic symptoms (DRESS) and fecal incontinence.
| Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole | ||
|---|---|---|
| System Organ Class Preferred Term | Percentage of Patients Reporting Reaction* | |
| Aripiprazole (n=1843) | Placebo (n=1166) | |
| Blurred Vision | 3 | 1 |
| 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 |
| Fatigue | 6 | 4 |
| Pain | 3 | 2 |
| Musculoskeletal Stiffness | 4 | 3 |
| Pain in Extremity | 4 | 2 |
| Myalgia | 2 | 1 |
| Muscle Spasms | 2 | 1 |
| Headache | 27 | 23 |
| Dizziness | 10 | 7 |
| Akathisia | 10 | 4 |
| Sedation | 7 | 4 |
| Extrapyramidal Disorder | 5 | 3 |
| Tremor | 5 | 3 |
| Somnolence | 5 | 3 |
| Agitation | 19 | 17 |
| Insomnia | 18 | 13 |
| Anxiety | 17 | 13 |
| Restlessness | 5 | 3 |
| Pharyngolaryngeal Pain | 3 | 2 |
| Cough | 3 | 2 |
| * Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. | ||
| | | |
| | | |
| 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 |
| | | |
| | | |
| Sedation | 13 | 6 |
| Somnolence | 13 | 1 |
| Nausea | 11 | 4 |
| Headache | 10 | 3 |
| Nasopharyngitis | 9 | 0 |
| Fatigue | 8 | 0 |
| Increased Appetite | 7 | 1 |
| Blurred Vision | 3 | 0 |
| 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 |
| Fatigue | 10 | 2 |
| Pyrexia | 4 | 1 |
| Irritability | 2 | 1 |
| Asthenia | 2 | 1 |
| Nasopharyngitis | 6 | 3 |
| Weight Increased | 3 | 1 |
| Increased Appetite | 7 | 3 |
| Decreased Appetite | 5 | 4 |
| Musculoskeletal Stiffness | 2 | 1 |
| Muscle Rigidity | 2 | 1 |
| 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 |
| Epistaxis | 2 | 1 |
| Rash | 2 | 1 |
| * Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. | ||
Aripiprazole Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 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 CYP3A4 inhibitors Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks 7.1 Drugs Having Clinically Important Interactions with Aripiprazole Table 25: Clinically Important Drug Interactions with Aripiprazole: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., 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.g., 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.g., 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. 7.2 Drugs Having No Clinically Important Interactions with Aripiprazole 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.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [see Clinical Pharmacology (12.3)] .
| | |
| 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 | Administer half of usual dose |
| Strong CYP2D6 | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
| | | |
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., 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 | With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone | With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| 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 |
| Benzodiazepines (e.g., 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 | Monitor sedation and blood pressure. Adjust dose accordingly. |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of aripiprazole in schizophrenia is unclear. However, the efficacy of aripiprazole in the listed indications could bemediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. 12.2 Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D 2 and D 3 , serotonin 5-HT 1A and 5-HT 2A receptors (K i values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4 , serotonin 5-HT 2C and 5-HT 7 , alpha 1 -adrenergic and histamine H 1 receptors (K i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i =98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). 12.3 Pharmacokinetics 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 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At steady-state, the pharmacokinetics of aripiprazole is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours. Pharmacokinetic studies showed that aripiprazole orally disintegrating tablets are bioequivalent to ABILIFY tablets. ORAL ADMINISTRATION Absorption Tablet: 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 or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. 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 receptor occupancy indicating brain penetration of aripiprazole in humans. Metabolism and Elimination Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. Drug Interaction Studies Effects 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 and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3-fold increase in mean C max and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. Figure 1: The effects of other drugs on aripiprazole pharmacokinetics Figure 2: The effects of other drugs on dehydro-aripiprazole pharmacokinetics The effects of aripiprazole on the exposures of other drugs are summarized in Figure 3. Figure 3: The effects of aripiprazole on pharmacokinetics of other drugs Effect of Aripiprazole on Other Drugs Studies in Specific Populations Exposures 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: Effects of intrinsic factors on aripiprazole pharmacokinetics Figure 5: Effects of intrinsic factors on dehydro-aripiprazole pharmacokinetics: Figure 1 Figure 2 Figure 3 Figure 4 Figure 5
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action The mechanism of action of aripiprazole in schizophrenia is unclear. However, the efficacy of aripiprazole in the listed indications could bemediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D 2 and D 3 , serotonin 5-HT 1A and 5-HT 2A receptors (K i values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4 , serotonin 5-HT 2C and 5-HT 7 , alpha 1 -adrenergic and histamine H 1 receptors (K i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i =98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM).
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics 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 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At steady-state, the pharmacokinetics of aripiprazole is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours. Pharmacokinetic studies showed that aripiprazole orally disintegrating tablets are bioequivalent to ABILIFY tablets. ORAL ADMINISTRATION Absorption Tablet: 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 or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. 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 receptor occupancy indicating brain penetration of aripiprazole in humans. Metabolism and Elimination Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. Drug Interaction Studies Effects 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 and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3-fold increase in mean C max and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. Figure 1: The effects of other drugs on aripiprazole pharmacokinetics Figure 2: The effects of other drugs on dehydro-aripiprazole pharmacokinetics The effects of aripiprazole on the exposures of other drugs are summarized in Figure 3. Figure 3: The effects of aripiprazole on pharmacokinetics of other drugs Effect of Aripiprazole on Other Drugs Studies in Specific Populations Exposures 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: Effects of intrinsic factors on aripiprazole pharmacokinetics Figure 5: Effects of intrinsic factors on dehydro-aripiprazole pharmacokinetics: Figure 1 Figure 2 Figure 3 Figure 4 Figure 5
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Aripiprazole orally disintegrating tablets are 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)
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Aripiprazole is an atypical antipsychotic drug that is available as Aripiprazole Orally Disintegrating Tablets. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C 23 H 27 Cl 2 N 3 O 2 and its molecular weight is 448.39. The chemical structure is: Aripiprazole Orally Disintegrating Tablets, USP are available in 10 mg and 15 mg strengths. Inactive ingredients include mannitol, aspartame, calcium stearate, crospovidone, vanilla, silicified microcrystalline cellulose, and lactose monohydrate. Colorants include iron oxide red. Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Initial Dose Recommended Dose Maximum Dose Schizophrenia – adults (2.1) 10 to 15 mg /day 10 to 15 mg /day 30 mg /day Schizophrenia – adolescents (2.1) 2 mg /day 10 mg /day 30 mg /day Irritability associated with autistic disorder – pediatric patients (2.4) 2 mg/day 5 to 10 mg/day 15 mg/day Tourette’s disorder – (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 •Oral formulations: Administer once daily without regard to meals (2) •Known CYP2D6 poor metabolizers: Half of the usual dose (2.7) 2.1 Schizophrenia Adults The recommended starting and target dose for aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.1)] . Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either aripiprazole orally disintegrating tablets 15 mg/day or placebo, and observed for relapse [see Clinical Studies (14.1)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment. Adolescents The recommended target dose of aripiprazole orally disintegrating tablets is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Aripiprazole orally disintegrating tablets can be administered without regard to meals [see Clinical Studies (14.1)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment. Switching from Other Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to aripiprazole or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Irritability Associated with Autistic Disorder 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 1 week [see Clinical Studies (14.4)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment. 2.5 Tourette’s Disorder 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 1 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 1 week. [See Clinical Studies (14.5)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment. 2.7 Dosage Adjustments for Cytochrome P450 Considerations 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 orally disintegrating tablets dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole orally disintegrating tablets 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.g., 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 Orally Disintegrating Tablets in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers Factors Dosage Adjustments for A ripiprazole Orally Disintegrating Tablets Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer a quarter of usual dose Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over 1 to 2 weeks 2.8 Dosing of Oral Solution The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see Clinical Pharmacology (12.3)]. 2.9 Dosing of Orally Disintegrating Tablets The dosing for aripiprazole orally disintegrating tablets is the same as for the oral tablets [see Dosage and Administration (2.1 and 2.4)].
| Initial Dose | Recommended Dose | Maximum Dose | ||
| Schizophrenia – adults (2.1) | 10 to 15 mg /day | 10 to 15 mg /day | 30 mg /day | |
| Schizophrenia – adolescents (2.1) | 2 mg /day | 10 mg /day | 30 mg /day | |
| Irritability associated with autistic disorder – pediatric patients (2.4) | 2 mg/day | 5 to 10 mg/day | 15 mg/day | |
| Tourette’s disorder – (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 | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) | Administer a quarter of usual dose |
| Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) | Administer half of usual dose |
| Strong CYP2D6 | Administer a quarter of usual dose |
| Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) | Double usual dose over 1 to 2 weeks |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Aripiprazole Orally Disintegrating Tablets are available as described in Table 4. Table 4: Aripiprazole Orally Disintegrating Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 10 mg light pink (mottled) round “256” 15 mg light pink (mottled) round “L257” Orally Disintegrating Tablets: 10 mg and 15 mg (3)
| | | |
| light pink (mottled) round | “256” | |
| light pink (mottled) round | “L257” |
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Aripiprazole Orally Disintegrating Tablets, USP are indicated for the treatment of: •Schizophrenia [see Clinical Studies (14.1)] • Irritability Associated with Autistic Disorder [see Clinical Studies (14.4)] • Treatment of Tourette’s Disorder [see Clinical Studies (14.5)] Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. Aripiprazole is an atypical antipsychotic. The oral formulations are indicated for: • Schizophrenia (14.1) • Irritability Associated with Autistic Disorder (14.4) • Treatment of Tourette’s disorder (14.5)
Spl product data elements
Usually a list of ingredients in a drug product.Aripiprazole Aripiprazole ARIPIPRAZOLE ARIPIPRAZOLE MANNITOL CROSPOVIDONE ASPARTAME LACTOSE MONOHYDRATE FERRIC OXIDE RED CALCIUM STEARATE SILICON DIOXIDE MICROCRYSTALLINE CELLULOSE light pink round, flat, beveled edge 256 Aripiprazole Aripiprazole ARIPIPRAZOLE ARIPIPRAZOLE MANNITOL CROSPOVIDONE ASPARTAME LACTOSE MONOHYDRATE FERRIC OXIDE RED CALCIUM STEARATE SILICON DIOXIDE MICROCRYSTALLINE CELLULOSE light pink round, flat, beveled edge L257
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and/or Pharmacology 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 body surface area. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m 2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m 2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). 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 -receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4-week and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. Mutagenesis The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. 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 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. 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 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m 2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m 2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). 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 -receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4-week and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. Mutagenesis The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. 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 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. 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 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. 13.2 Animal Toxicology and/or Pharmacology 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 body surface area. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PACKAGE LABEL.PRINCIPAL DISPLAY PANEL -10 mg NDC 62332-103-30 Aripiprazole Orally Disintegrating Tablets, USP 10 mg Rx only 30 Tablets (3 x 10 unit dose) PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE PROVIDED SEPARATELY. Alembic 30tablets
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL -15 mg NDC 62332-104-30 Aripiprazole Orally Disintegrating Tablets, USP 15 mg Rx only 30 Tablets (3 x 10 unit dose) PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE PROVIDED SEPARATELY. Alembic 30 tablets (3 x 10 unit dose)
Aripiprazole: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Discuss the following issues with patients prescribed Aripiprazole Orally Disintegrating Tablets: Clinical Worsening of Depression and Suicide Risk Patients, their families, and caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Warnings and Precautions (5.3)]. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with aripiprazole orally disintegrating tablets and should counsel them in its appropriate use. A patient Medication Guide including information about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for aripiprazole orally disintegrating tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. It should be noted that aripiprazole orally disintegrating tablets are not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder. Pathological Gambling and Other Compulsive Behaviors Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while take aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions, (5.7)] . Use of Orally Disintegrating Tablet Do not open the blister until ready to administer. For single tablet removal, open the package and peel back the foil on the blister to expose the tablet. Do not push the tablet through the foil because this could damage the tablet. Immediately upon opening the blister, using dry hands, remove the tablet and place the entire aripiprazole orally disintegrating tablet on the tongue. Tablet disintegration occurs rapidly in saliva. It is recommended that aripiprazole orally disintegrating tablets be taken without liquid. However, if needed, it can be taken with liquid. Do not attempt to split the tablet. Interference with Cognitive and Motor Performance Because aripiprazole orally disintegrating tablets may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that aripiprazole orally disintegrating tablets therapy does not affect them adversely [see Warnings and Precautions (5.12)] . Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)] . Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with aripiprazole orally disintegrating tablets. Advise patients that aripiprazole orally disintegrating tablets may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to aripiprazole orally disintegrating tablets during pregnancy [see Use in Specific Populations (8.1)]. Lactation Aripiprazole orally disintegrating tablets use during pregnancy may affect milk supply. Advise the lactating patient to discuss any plans for breastfeeding with their healthcare provider, and to monitor the breastfed infant for dehydration and lack of appropriate weight gain [see Use in Specific Populations (8.2)]. Phenylketonurics Phenylalanine is a component of aspartame. Each aripiprazole orally disintegrating tablet contains the following amounts: 10 mg - 1.12 mg phenylalanine and 15 mg - 1.68 mg phenylalanine. ABILIFY ® is a trademark of Otsuka Pharmaceutical Company. Medication Guide available at http://www.alembicusa.com/medicationguide. aspx or call 1-866-210-9797. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA Revised: 09/2024
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.MEDICATION GUIDE Aripiprazole (ar" i pip' ra zole ) Orally Disintegrating Tablets, USP What is the most important information I should know about aripiprazole orally disintegrating tablets? (For other side effects, also see “What are the possible side effects of aripiprazole orally disintegrating tablets ?”). Serious side effects may happen when you take aripiprazole orally disintegrating tablets , including: Increased risk of death in elderly patients with dementia-related psychosis: Medicines like aripiprazole orally disintegrating tablets can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). Aripiprazole orally disintegrating tablets is not approved for the treatment of patients with dementia-related psychosis. Risk of suicidal thoughts or actions: Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions: Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 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. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or 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. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. What are aripiprazole orally disintegrating tablets? Aripiprazole orally disintegrating tablets are a prescription medicine used to treat: Schizophrenia irritability associated with autistic disorder Tourette’s disorder It is not known if aripiprazole orally disintegrating tablets are 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 orally disintegrating tablets if you are allergic to aripiprazole or any of the ingredients in aripiprazole orally disintegrating tablets. See the end of this Medication Guide for a complete list of ingredients in aripiprazole orally disintegrating tablets. Before taking aripiprazole orally disintegrating 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 orally disintegrating 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 orally disintegrating tablets will harm your unborn baby. If you become pregnant while receiving aripiprazole orally disintegrating 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 orally disintegrating tablets. low white blood cell count. phenylketonuria. Aripiprazole orally disintegrating tablets containphenylalanine. Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Aripiprazole orally disintegrating tablets and other medicines may affect each other causing possible serious side effects. Aripiprazole orally disintegrating tablets may affect the way other medicines work, and other medicines may affect how aripiprazole orally disintegrating tablets works. Your healthcare provider can tell you if it is safe to take aripiprazole orally disintegrating tablets with your other medicines. Do not start or stop any medicines while taking aripiprazole orally disintegrating 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 orally disintegrating tablets? Take aripiprazole orally disintegrating tablets exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole orally disintegrating tablets yourself. Aripiprazole orally disintegrating tablets can be taken with or without food. Aripiprazole orally disintegrating tablets should be swallowed whole. If you miss a dose of aripiprazole orally disintegrating 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 orally disintegrating tablets at the same time. If you have been prescribed aripiprazole orally disintegrating tablets, take it as follows: Do not open the blister until ready to take the aripiprazole orally disintegrating tablets. To remove one aripiprazole orally disintegrating tablet, open the package and peel back the foil on the blister to expose the tablet. Do not push the tablet through the foil because this could damage the tablet. Immediately upon opening the blister, using dry hands, remove the tablet and place the entire aripiprazole orally disintegrating tablet on the tongue. Tablet disintegration occurs rapidly in saliva. It is recommended that aripiprazole orally disintegrating tablets be taken without liquid. However, if needed, it can be taken with liquid. Do not attempt to split the aripiprazole orally disintegrating tablet. If you take too much aripiprazole orally disintegrating 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 orally disintegrating tablets? Do not drive, operate heavy machinery, or do other dangerous activities until you know how aripiprazole orally disintegrating tablets affects you. Aripiprazole orally disintegrating 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 orally disintegrating tablets? Aripiprazole orally disintegrating tablets may cause serious side effects, including: See “What is the most important information I should know about aripiprazole orally disintegrating tablets?” Stroke in elderly people (cerebrovascular problems) that can lead to death Neuroleptic malignant syndrome (NMS). Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms. Uncontrolled body movements (tardive dyskinesia). Aripiprazole orally disintegrating tablets may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving aripiprazole orally disintegrating tablets. Tardive dyskinesia may also start after you stop receiving aripiprazole orally disintegrating tablets. Problems with your metabolism such as: High blood sugar (hyperglycemia) and diabetes . Increases in blood sugar can happen in some people who take aripiprazole orally disintegrating tablets. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes), your healthcare provider should check your blood sugar before you start aripiprazole orally disintegrating tablets and during your treatment. Call your healthcare provider if you have any of these symptoms of high blood sugar while taking aripiprazole orally disintegrating tablets: feel very thirsty need to urinate more than usual feel very hungry feel weak or tired feel sick to your stomach feel confused, or your breath smells fruity Increased fat levels (cholesterol and triglycerides) in your blood. Weight gain. You and your healthcare provider should check your weight regularly. Unusual urges. Some people taking aripiprazole orally disintegrating tablets have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider. Orthostatic hypotension (decreased blood pressure). Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position. Falls. Aripiprazole orally disintegrating tablets may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. Low white blood cell count Seizures (convulsions) Problems 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 “What should I avoid while receiving aripiprazole orally disintegrating tablets?” Difficulty swallowing that can cause food or liquid to get into your lungs. The most common side effects of aripiprazole orally disintegrating 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 orally disintegrating 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 orally disintegrating 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 orally disintegrating tablets? Store aripiprazole orally disintegrating tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Keep aripiprazole orally disintegrating tablets and all medicines out of the reach of children. General information about the safe and effective use of aripiprazole orally disintegrating tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use aripiprazole orally disintegrating tablets for a condition for which it was not prescribed. Do not give aripiprazole orally disintegrating 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 orally disintegrating tablets that was written for healthcare professionals. What are the ingredients in aripiprazole orally disintegrating tablets ? Active ingredient: aripiprazole Inactive ingredients: Aripiprazole Orally Disintegrating Tablets : mannitol, aspartame, calcium stearate, crospovidone, vanilla, silicified microcrystalline cellulose, and lactose monohydrate. Colorants include iron oxide red. Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. ABILIFY® is a trademark of Otsuka Pharmaceutical Company. For more information about aripiprazole orally disintegrating tablets call 1-866-210-9797. Medication Guide available at http://www.alembicusa.com/medicationguide. aspx or call 1-866-210-9797. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 09/2024
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 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) with schizophrenia [see Clinical Studies (14.1)] • One maintenance monotherapy trial in adult patients with bipolar I disorder [see Clinical Studies (14.2)] • 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)] Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 14.1 Schizophrenia 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 26), 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 26), 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 26), 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 26), the primary outcome measure of the study. The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure. Thus, the efficacy of 10, 15, 20, 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 26), 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 26: Schizophrenia Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Study 1 Aripiprazole (15 mg/day) † 98.5 (17.2) -15.5 (2.4) -12.6 (-18.9, -6.2) Aripiprazole (30 mg/day) † 99 (19.2) -11.4 (2.39) -8.5 (-14.8, -2.1) Placebo 100.2 (16.5) -2.9 (2.36) --- Study 2 Aripiprazole (20 mg/day) † 92.6 (19.5) -14.5 (2.23) -9.6 (-15.4, -3.8) Aripiprazole (30 mg/day) † 94.2 (18.5) -13.9 (2.24) -9 (-14.8, -3.1) Placebo 94.3 (18.5) -5 (2.17) --- Study 3 Aripiprazole (10 mg/day) † 92.7 (19.5) -15 (2.38) -12.7 (-19, -6.41) Aripiprazole (15 mg/day) † 93.2 (21.6) -11.7 (2.38) -9.4 (-15.71, -3.08) Aripiprazole (20 mg/day) † 92.5 (20.9) -14.4 (2.45) -12.1 (-18.53, -5.68) Placebo 92.3 (21.8) -2.3 (2.35) --- Study 4 Aripiprazole (2 mg/day) 90.7 (14.5) -8.2 (1.9) -2.9 (-8.29, 2.47) Aripiprazole (5 mg/day) 92 (12.6) -10.6 (1.93) -5.2 (-10.7, 0.19) Aripiprazole (10 mg/day) † 90 (11.9) -11.3 (1.88) -5.9 (-11.3, -0.58) Placebo 90.8 (13.3) -5.3 (1.97) --- Study 6 (Pediatric, 13 to 17 years) Aripiprazole (10 mg/day) † 93.6 (15.7) -26.7 (1.91) -5.5 (-10.7, -0.21) Aripiprazole (30 mg/day) † 94 (16.1) -28.6 (1.92) -7.4 (-12.7, -2.13) Placebo 94.6 (15.6) -21.2 (1.93) --- * Difference (drug minus placebo) in least-squares mean change from baseline. † Doses statistically significantly superior to placebo. Figure 6 : Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5) figure 6 14.2 Maintenance Treatment of Bipolar I Disorder 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) Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. figure 7 14.4 Irritability Associated with Autistic Disorder 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 subjects 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) † 29.6 (6.37) -12.9 (1.44) -7.9 (-11.7, -4.1) Placebo 30.2 (6.52) -5 (1.43) -- Study 2 Aripiprazole (5 mg/day) † 28.6 (7.56) -12.4 (1.36) -4 (-7.7, -0.4) Aripiprazole (10 mg/day) † 28.2 (7.36) -13.2 (1.25) -4.8 (-8.4, -1.3) Aripiprazole (15 mg/day) † 28.9 (6.41) -14.4 (1.31) -6 (-9.6, -2.3) Placebo 28 (6.89) -8.4 (1.39) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * Difference (drug minus placebo) in least-squares mean change from baseline. † Doses statistically significantly superior to placebo. 14.5 Tourette’s Disorder 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.e., 0 to 50). 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 per day with a target dose of 5 mg 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 6.54 mg/day. 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 Difference * (95% CI) Study 1 Aripiprazole (low dose) † 29.2 (5.63) -13.4 (1.59) -6.3 (-10.2, -2.3) Aripiprazole (high dose) † 31.2 (6.4) -16.9 (1.61) -9.9 (-13.8, -5.9) Placebo 30.7 (5.95) -7.1 (1.55) -- Study 2 Aripiprazole (2 to 20 mg/day) † 28.3 (5.51) -15 (1.51) -5.3 (-9.8, -0.9) Placebo 29.5 (5.6) -9.6 (1.64) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. * Difference (drug minus placebo) in least-squares mean change from baseline. † Doses statistically significantly superior to placebo. figure 9
| Study 1 | Aripiprazole (15 mg/day)† | 98.5 (17.2) | -15.5 (2.4) | -12.6 (-18.9, -6.2) |
| Aripiprazole (30 mg/day)† | 99 (19.2) | -11.4 (2.39) | -8.5 (-14.8, -2.1) | |
| Placebo | 100.2 (16.5) | -2.9 (2.36) | --- | |
| Aripiprazole (20 mg/day)† | 92.6 (19.5) | -14.5 (2.23) | -9.6 (-15.4, -3.8) | |
| Aripiprazole (30 mg/day)† | 94.2 (18.5) | -13.9 (2.24) | -9 (-14.8, -3.1) | |
| Placebo | 94.3 (18.5) | -5 (2.17) | --- | |
| Study 3 | Aripiprazole (10 mg/day)† | 92.7 (19.5) | -15 (2.38) | -12.7 (-19, -6.41) |
| Aripiprazole (15 mg/day)† | 93.2 (21.6) | -11.7 (2.38) | -9.4 (-15.71, -3.08) | |
| Aripiprazole (20 mg/day)† | 92.5 (20.9) | -14.4 (2.45) | -12.1 (-18.53, -5.68) | |
| Placebo | 92.3 (21.8) | -2.3 (2.35) | --- | |
| Study 4 | Aripiprazole (2 mg/day) | 90.7 (14.5) | -8.2 (1.9) | -2.9 (-8.29, 2.47) |
| Aripiprazole (5 mg/day) | 92 (12.6) | -10.6 (1.93) | -5.2 (-10.7, 0.19) | |
| Aripiprazole (10 mg/day)† | 90 (11.9) | -11.3 (1.88) | -5.9 (-11.3, -0.58) | |
| Placebo | 90.8 (13.3) | -5.3 (1.97) | --- | |
| Study 6 (Pediatric, 13 to 17 years) | Aripiprazole (10 mg/day)† | 93.6 (15.7) | -26.7 (1.91) | -5.5 (-10.7, -0.21) |
| Aripiprazole (30 mg/day)† | 94 (16.1) | -28.6 (1.92) | -7.4 (-12.7, -2.13) | |
| Placebo | 94.6 (15.6) | -21.2 (1.93) | --- | |
| | | | ||
| | | | ||
| Study 1 | Aripiprazole (2 to 15 mg/day)† | 29.6 (6.37) | -12.9 (1.44) | -7.9 (-11.7, -4.1) |
| Placebo | 30.2 (6.52) | -5 (1.43) | -- | |
| Study 2 | Aripiprazole (5 mg/day)† | 28.6 (7.56) | -12.4 (1.36) | -4 (-7.7, -0.4) |
| Aripiprazole (10 mg/day)† | 28.2 (7.36) | -13.2 (1.25) | -4.8 (-8.4, -1.3) | |
| Aripiprazole (15 mg/day)† | 28.9 (6.41) | -14.4 (1.31) | -6 (-9.6, -2.3) | |
| Placebo | 28 (6.89) | -8.4 (1.39) | -- | |
| | | | ||
| | | | ||
| Study 1 | Aripiprazole (low dose)† | 29.2 (5.63) | -13.4 (1.59) | -6.3 (-10.2, -2.3) |
| Aripiprazole (high dose)† | 31.2 (6.4) | -16.9 (1.61) | -9.9 (-13.8, -5.9) | |
| Placebo | 30.7 (5.95) | -7.1 (1.55) | -- | |
| Study 2 | Aripiprazole (2 to 20 mg/day)† | 28.3 (5.51) | -15 (1.51) | -5.3 (-9.8, -0.9) |
| Placebo | 29.5 (5.6) | -9.6 (1.64) | -- | |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use 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, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia or other indications did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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)].
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use 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 (14.1)]. 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. 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. 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. Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 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), and Clinical Studies (14.4)]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. In this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. 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) and one 10-week trial (aged 6 to 18) in 194 pediatric patients [see Dosage and Administration (2.5), Adverse Reactions (6.1), and Clinical Studies (14.5)]. Maintenance efficacy in pediatric patients has not been systematically evaluated. 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 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. 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 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy 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) .Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother associated with untreated schizophrenia, other indications, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see Clinical Considerations). Aripiprazole exposure during pregnancy can have variable effects on milk supply in the post-partum period [see Use in Specific Populations (8.2)]. 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 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (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. In the U.S. 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. 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 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. 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 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the MRHD; this dose also caused maternal toxicity. 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 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the MHRD. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD. 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 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the MRHD; this dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD. In rats treated orally with aripiprazole peri- and post-natally 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 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the MHRD. An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. 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 body surface area, increased stillbirths were observed at 3 and 6 times the MRHD; and decreases in early postnatal pup weight and survival were observed at 6 times the MRHD; these doses also caused some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1) Lactation: Monitor the breastfed infant for dehydration and lack of appropriate weight gain (8.2). Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.'s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy 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) .Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother associated with untreated schizophrenia, other indications, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see Clinical Considerations). Aripiprazole exposure during pregnancy can have variable effects on milk supply in the post-partum period [see Use in Specific Populations (8.2)]. 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 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (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. In the U.S. 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. 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 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. 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 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the MRHD; this dose also caused maternal toxicity. 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 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the MHRD. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD. 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 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the MRHD; this dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD. In rats treated orally with aripiprazole peri- and post-natally 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 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the MHRD. An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. 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 body surface area, increased stillbirths were observed at 3 and 6 times the MRHD; and decreases in early postnatal pup weight and survival were observed at 6 times the MRHD; these doses also caused some maternal toxicity. There were no effects on postnatal behavioral and reproductive development. 8.2 Lactation 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 (6.2)]. The developmental 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. Clinical Considerations Monitor infants exposed to aripiprazole through breastmilk for dehydration and lack of appropriate weight gain. 8.4 Pediatric Use 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 (14.1)]. 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. 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. 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. Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 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), and Clinical Studies (14.4)]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. In this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. 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) and one 10-week trial (aged 6 to 18) in 194 pediatric patients [see Dosage and Administration (2.5), Adverse Reactions (6.1), and Clinical Studies (14.5)]. Maintenance efficacy in pediatric patients has not been systematically evaluated. 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 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. 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 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period. 8.5 Geriatric Use 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, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia or other indications did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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)]. 8.6 CYP2D6 Poor Metabolizers Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)] . 8.7 Hepatic and Renal Impairment 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)] . 8.8 Other Specific Populations No dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Aripiprazole Orally Disintegrating Tablets, USP are round tablets with markings on one side and plain on other side. Aripiprazole Orally Disintegrating Tablet is available in the strengths and packages listed in Table 33. Table 33: Aripiprazole Orally Disintegrating Tablets, USP Presentations Tablet Strength Tablet Color Tablet Markings Pack Size NDC Code 10 mg light pink (mottled) “256” Cartons of 30 (3 x10) blisters 62332-103-30 15 mg light pink(mottled) “L257” Cartons of 30 (3 x10) blisters 62333-104-30 16.2 Storage Tablets Store at 20° to 25°C (68° to 77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature].
| | | | | |
| light pink (mottled) | “256” | Cartons of 30 (3 x10) blisters | 62332-103-30 | |
| light pink(mottled) | “L257” | Cartons of 30 (3 x10) blisters | 62333-104-30 |
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)]. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.3)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.3)]. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis. (5.1) • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Monitor for worsening and emergence of suicidal thoughts and behaviors. (5.3)
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API