Abilify Drug Information

ABILIFY (aripiprazole) Tablets are indicated for the treatment of: Schizophrenia Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder Adjunctive Treatment of Major Depressive Disorder Irritability Associated with Autistic Disorder Treatment of Tourette's Disorder ABILIFY is an atypical antipsychotic.

Bipolar I Disorder Acute Treatment of Manic and Mixed Episodes Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. ABILIFY can be given without regard to meals. The recommended target dose of ABILIFY is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate.

The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials. Recommended dosing as adjunctive therapy to lithium or valproate is the same.

Subsequent dose increases, if needed, should be administered in 5 mg/day increments.

Adjunctive Treatment of Major Depressive Disorder Adults

The recommended starting dose for ABILIFY as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week.

Patients should be periodically reassessed to determine the continued need for maintenance treatment.

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 should occur gradually, at intervals of no less than one week. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics.

Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than one week.

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 1 ). When the coadministered drug is withdrawn from the combination therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY 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 1: Dose Adjustments for ABILIFY in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, CYP3A4 Inhibitors, and/or CYP3A4 Inducers When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment as specified in Dosage and Administration.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

ABILIFY has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7,619 patient-years of exposure to oral ABILIFY and 749 patients with exposure to aripiprazole injection. A total of 3,390 patients were treated with oral ABILIFY for at least 180 days and 1,933 patients treated with oral ABILIFY had at least one year of exposure. ABILIFY has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's Disorder and who had approximately 1,342 patient-years of exposure to oral ABILIFY.

A total of 959 pediatric patients were treated with oral ABILIFY for at least 180 days and 556 pediatric patients treated with oral ABILIFY had at least one year of exposure. The conditions and duration of treatment with ABILIFY (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure. 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 ABILIFY 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 ABILIFY in patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) was akathisia (ABILIFY 8%; placebo 4%). Adult Patients with Bipolar Mania Monotherapy The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral ABILIFY was administered at doses of 15 or 30 mg/day. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in patients with bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 14.

Table 14: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with ABILIFY Monotherapy 5 2 Less Common Adverse Reactions in Adults Table 15 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with ABILIFY (doses ≥2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo in the combined dataset. Table 15: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with ABILIFY 3 2 An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Adult Patients with Adjunctive Therapy with Bipolar Mania The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which ABILIFY was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive ABILIFY compared to 6% for patients treated with adjunctive placebo. Commonly Observed Adverse Reactions The commonly observed adverse reactions associated with adjunctive ABILIFY and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder. Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania Table 16 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive ABILIFY (doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 16: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder years with Schizophrenia The following findings are based on one 6-week, placebo-controlled trial in which oral ABILIFY 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 pediatric patients (13 to 17 years) treated with ABILIFY and treated with placebo was 5% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in adolescent patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Table 17: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with ABILIFY years with Autistic Disorder The following findings are based on two 8-week, placebo-controlled trials in which oral ABILIFY 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 pediatric patients (6 to 17 years) treated with ABILIFY and treated with placebo was 10% and 8%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with autistic disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 18.

Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between pediatric patients (6 to 18 years) treated with ABILIFY and treated with placebo was 7% and 1%, respectively. Table 19: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with ABILIFY 7 1 Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Bipolar Mania, Autistic Disorder, or Tourette's Disorder Table 20 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette's Disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with ABILIFY (doses ≥2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo. Table 20: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients 6 to 2 1 Adult Patients Receiving ABILIFY as Adjunctive Treatment of Major Depressive Disorder The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which ABILIFY was administered at doses of 2 to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions was 6% for patients treated with adjunctive ABILIFY and 2% for patients treated with adjunctive placebo. Commonly Observed Adverse Reactions The commonly observed adverse reactions associated with the use of adjunctive ABILIFY in patients with major depressive disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision. Table 21: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder 8 2 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 mg/day of oral ABILIFY 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; incidences were placebo, 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, somnolence incidences were placebo, and tremor incidences were placebo, Bipolar Mania In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder incidences were placebo, somnolence incidences were placebo, akathisia incidences were placebo, and salivary hypersecretion incidences were placebo, 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, 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 ABILIFY-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for ABILIFY-treated patients was 8% vs. 4% for placebo. Objectively collected data from those trials was collected for EPS using the Simpson Angus Scale (SAS), for akathisia using the Barnes Akathisia Rating Scale (BARS), and for dyskinesias using the Assessments of Involuntary Movement Scales (AIMS).

In the adult schizophrenia trials, the objectively collected data did not show a difference between ABILIFY and placebo, with the exception of the BARS (ABILIFY, 0.08; placebo, –0.05). Similarly, in a long-term (26 week), placebo-controlled trial of schizophrenia in adults, objectively collected data for EPS using the SAS, for akathisia using the BARS, and for dyskinesias using the AIMS did not show a difference between ABILIFY and placebo. Bipolar Mania In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy ABILIFY-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy ABILIFY-treated patients was 13% vs. 4% for placebo.

In the 6-week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive ABILIFY-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive ABILIFY-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients treated with was 26% vs. 5% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 10% vs. 2% for placebo. Changes in the AIMS were similar for the ABILIFY and placebo groups.

In the bipolar mania trials with ABILIFY as adjunctive therapy with either lithium or valproate, the SAS and the BARS showed a significant difference between adjunctive ABILIFY and adjunctive placebo (ABILIFY, 0.73; placebo, 0.07 and ABILIFY, 0.30; placebo, 0.11). Major Depressive Disorder In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive ABILIFY-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive ABILIFY-treated patients was 25% vs. 4% for adjunctive placebo-treated patients. 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 ABILIFY-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 3% vs. 9% for placebo.

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 ABILIFY-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 4% vs. 6% for placebo. In the pediatric (6 to 18 years) short-term Tourette's Disorder trials, changes in the SAS, BARS and AIMS were not clinically meaningfully different for ABILIFY 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 ABILIFY 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. Tremor infrequently led to discontinuation (<1%) of ABILIFY. In addition, in a long-term (52 weeks), active-controlled study, the incidence of tremor was 5% (40/859) for ABILIFY.

A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder. Other Adverse Reactions Observed During the Premarketing Evaluation of ABILIFY 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients: Adults Blood and Lymphatic System Disorders: rare – thrombocytopenia Cardiac Disorders: infrequent – 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, sleepwalking Renal and Urinary Disorders: rare – urinary retention, nocturia Reproductive System and Breast Disorders: infrequent – erectile dysfunction; rare – gynecomastia, 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 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

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ABILIFY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), hiccups, oculogyric crisis, pathological gambling, and fecal incontinence.

• Drugs Having Clinically Important Interactions with ABILIFY Table 22: Clinically Important Drug Interactions with ABILIFY: 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) Concomitant use of ABILIFY with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone. Reduce the ABILIFY dosage when administered concomitantly with a strong CYP3A4 inhibitor or a strong CYP2D6 inhibitor. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) Concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone. Increase the ABILIFY dosage when administered concomitantly with a strong CYP3A4 inducer. Antihypertensive Drugs Due to its alpha 1 -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.

Drugs Having No Clinically Important Interactions with ABILIFY Based on pharmacokinetic studies, no dosage adjustment of ABILIFY is required when administered concomitantly with famotidine, valproate, lithium, and 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 coadministered with ABILIFY. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ABILIFY, 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 ABILIFY, 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 outcomes (see Data ). There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy (see Clinical Considerations ). Aripiprazole exposure during pregnancy may decrease milk supply in the post-partum period.

In animal reproduction studies, aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. 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 respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy.

These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.

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. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD.

An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. There were no effects on postnatal behavioral and reproductive development.

Pediatric Use Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established. The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight. 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.

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 Safety and effectiveness in pediatric patients with bipolar mania were established in a 4-week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years. The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated.

However, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Irritability Associated with Autistic Disorder Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years. 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 ABILIFY 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 ABILIFY treatment or switch to placebo. In this trial, the efficacy of ABILIFY for the maintenance treatment of irritability associated with autistic disorder was not established.

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.

Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values.

ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis. Known hypersensitivity to ABILIFY

MedDRA terminology has been used to classify the adverse reactions. Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with ABILIFY alone and in combination with other substances.

No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving ABILIFY ingestions up to 195 mg with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY 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 ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Management of Overdosage No specific information is available on the treatment of overdose with ABILIFY.

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 ABILIFY, 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 dose of ABILIFY, 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 ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.