Aripiprazole (tablet)

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# Black Box Warning

# Overview
Aripiprazole (tablet) is an atypical antipsychotic that is FDA approved for the treatment of schizophrenia, manic and mixed episodes associated with bipolar I disorder. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Aripiprazole Orally Disintegrating Tablets are indicated for the treatment of:
- 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.

### Dosage
- 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.
- 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 15 mg/day or placebo, and observed for relapse.
- Patients should be periodically reassessed to determine the continued need for maintenance treatment.
- The recommended target dose of aripiprazole 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 can be administered without regard to meals. Patients should be periodically reassessed to determine the continued need for maintenance treatment.
- 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.
- 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. Aripiprazole can be given without regard to meals. The recommended target dose of aripiprazole 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.
- Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years) as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target dose of 10 mg/day after 2 additional days. 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. Aripiprazole can be given without regard to meals.
- 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.
- 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. When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level. - When the coadministered CYP3A4 inducer is withdrawn, aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.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.
- 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.
- The dosing for Aripiprazole Orally Disintegrating Tablets is the same as for the oral tablets.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aripiprazole (tablet) in adult patients.

### NonGuideline-Supported Use
- Aripiprazole 10-15 mg/day added to sertraline 100-200 mg/day

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Aripiprazole (tablet) in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aripiprazole (tablet) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Aripiprazole (tablet) in pediatric patients.

# Contraindications
- Aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole.
- Reactions have ranged from pruritus/urticaria to anaphylaxis.

# Warnings
- Increased mortality in elderly patients with dementia-related psychosis
increased mortality.
- 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.
- Safety Experience in Elderly Patients with Psychosis Associated with Alzheimers Disease
- In three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimers disease (n=938; mean age: 82.4 years; range: 56 to 99 years), the adverse events that were reported at an incidence of 3% and aripiprazole incidence at least twice that for placebo were lethargy , somnolence (including sedation) , and incontinence (primarily, urinary incontinence) , excessive salivation , and lightheadedness .
- The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with aripiprazole, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration.
- In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 3.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric.
- Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for aripiprazole should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
- It should be noted that aripiprazole is not approved for use in treating depression in the pediatric population.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
- The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, aripiprazole should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, drug discontinuation should be considered. However, some patients may require treatment with aripiprazole despite the presence of the syndrome.
- Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of  hyperglycemia-related adverse reactions  in patients treated with the atypical antipsychotics. Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
- In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 3 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).
- In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with aripiprazole. After 26 weeks, 32.8% of patients gained 7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations ), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD.
- When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.
- 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 may cause orthostatic hypotension, perhaps due to its 1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%, ); of pediatric patients 6 to 18 years of age (n=732) on oral aripiprazole included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%).
- The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure 20 mmHg accompanied by an increase in heart rate 25 when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%), in pediatric oral aripiprazole-treated patients aged 6 to 18 years (0.4%, 1%).
- Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).
- In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) monitored frequently during the first few months of therapy.In such patients, consider discontinuation of aripiprazole at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
- Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue aripiprazole in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC counts until recovery.
- In short-term, placebo-controlled trials, patients with a history of seizures excludedseizures/convulsions occurred in 0.1% (3/2467) of undiagnosedadult patients treated with oral aripiprazole, in 0.1% (1/732) of pediatric patients (6 to 18 years).
- As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
- Aripiprazole, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2467) treated with oral aripiprazole (11%, 6%), in pediatric patients ages 6 to 17 (n=611) (24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% ((20/732) of pediatric patients (6 to 18 years) on oral aripiprazole in short-term, placebo-controlled trials.
- Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with aripiprazole does not affect them adversely.
- Disruption of the bodys ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).
- The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for aripiprazole should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimers dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

# Adverse Reactions

## Clinical Trials Experience

## Overall Adverse Reactions Profile
- The following are discussed in more detail in other sections of the labeling:
- Use in Elderly Patients with Dementia-Related Psychosis
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults
- Neuroleptic Malignant Syndrome (NMS)
- Tardive Dyskinesia
- Metabolic Changes
- Orthostatic Hypotension
- Leukopenia, Neutropenia, and Agranulocytosis
- Seizures/Convulsions
- Potential for Cognitive and Motor Impairment
- Body Temperature Regulation
- Suicide
- Dysphagia
- Use in Patients with Concomitant Illness
- The most common adverse reactions in adult patients in clinical trials (10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.
- The most common adverse reactions in the pediatric clinical trials (10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.
- Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, Dementia of the Alzheimers type, Parkinsons disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole 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 920 patients (6 to 17 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, or autistic disorder and who had approximately 517 patient-years of exposure to oral aripiprazole. A total of 465 pediatric patients were treated with oral aripiprazole for at least 180 days and 117 pediatric patients treated with oral aripiprazole had at least 1 year of exposure.
- The conditions and duration of treatment with aripiprazole (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure.
- Adverse events during exposure were obtained by collecting volunteered adverse events, as well as results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been used to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals experiencing adverse events.
- The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. - An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. There was no attempt to use investigator causality assessments; ie, all events meeting the defined criteria, regardless of investigator causality, are included.
- Throughout this section, adverse reactions are reported. These are adverse events that were considered to be reasonably associated with the use of ABILIFY (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for ABILIFY often cannot be reliably established in individual cases.
- The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses, and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

### Clinical Studies Experience
- 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 mg/day to 30 mg/day.
- Overall, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients.
- 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%).
- Monotherapy
- The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral aripiprazole was administered at doses of 15 mg/day or 30 mg/day.
- Overall, in patients with bipolar mania, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (11%) and placebo-treated (10%) patients. The types of adverse reactions that led to discontinuation were similar between the aripiprazole-treated and placebo-treated patients.
- Commonly observed adverse reactions associated with the use of aripiprazole in patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 14.
- 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 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.
- An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.
- The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which aripiprazole was administered at doses of 15 mg/day or 30 mg/day as adjunctive therapy with lithium or valproate.
- In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive aripiprazole compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).
- The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.
- 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 aripiprazole (doses of 15 mg/day 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.
- The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.
- 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 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.
- The following findings are based on one 4-week, placebo-controlled trial in which oral aripiprazole was administered in doses of 10 mg/day or 30 mg/day.
- The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.
- Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 17.
- The following findings are based on two 8-week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 mg/day to 15 mg/day.
- 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 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 18.
- Table 19 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, and up to 8 weeks in autistic disorder), including only those reactions that occurred in 1% 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.
- The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which aripiprazole was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.
- The incidence of discontinuation due to adverse reactions was 6% for adjunctive aripiprazole-treated patients and 2% for adjunctive placebo-treated patients.
- The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with major depressive disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.
- Table 20 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses 2 mg/day) and for which the incidence in patients treated with adjunctive aripiprazole was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.
- The following findings are based on a pool of three placebo-controlled trials of patients with agitation associated with schizophrenia or bipolar mania in which aripiprazole injection was administered at doses of 5.25 mg to 15 mg.
- Overall, in patients with agitation associated with schizophrenia or bipolar mania, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (0.8%) and placebo-treated (0.5%) patients.
- There was one commonly observed adverse reaction (nausea) associated with the use of aripiprazole injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo).
- Table 21 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (24-hour), including only those adverse reactions that occurred in 2% or more of patients treated with aripiprazole injection (doses 5.25 mg/day) and for which the incidence in patients treated with aripiprazole injection was greater than the incidence in patients treated with placebo in the combined dataset.

### Dose-Related Adverse Reactions
- 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 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 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 ; (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, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).
- In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).
- In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

### Extrapyramidal Symptoms
- 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.
- In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy aripiprazole-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy aripiprazole-treated patients was 13% vs. 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 aripiprazole-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 10% vs. 2% for placebo.
- In the adult bipolar mania trials with monotherapy aripiprazole, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.50; placebo, 0.01 and aripiprazole, 0.21; placebo, 0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the bipolar mania trials with aripiprazole as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.73; placebo, 0.07 and aripiprazole, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive aripiprazole and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.90; placebo, 0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.
- In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.
- In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups.
- 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.
- In the placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, the incidence of reported EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 2% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 2% vs. 0% for placebo. Objectively collected data on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment groups did not show a difference between aripiprazole and placebo.
- Class Effect: 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.
- A between group comparison for 3-week to 6-week, placebo-controlled trials in adults or 4-week to 8-week, placebo-controlled trials in pediatric patients (6 to 17 years) revealed no medically important differences between the aripiprazole and placebo groups in the proportions of patients experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no aripiprazole/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis in adult or pediatric patients.
- Between group comparisons for a pooled analysis of placebo-controlled trials in patients with schizophrenia, bipolar mania, or major depressive disorder revealed no significant differences between oral aripiprazole and placebo in the proportion of patients experiencing potentially important changes in ECG parameters. - Aripiprazole was associated with a median increase in heart rate of 2 beats per minute compared to no increase among placebo patients.
- In the pooled, placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, there were no significant differences between aripiprazole injection and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, as measured by standard 12-lead ECGs.

### Additional Findings Observed in Clinical 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 . 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 ABILIFY. In addition, in a long-term (52-week), 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.
- Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with oral aripiprazole at multiple doses 2 mg/day during any phase of a trial within the database of 13,543 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it.
- Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients.
- Blood and Lymphatic System Disorders:
- 1/1000 patients and <1/100 patients - leukopenia, neutropenia, thrombocytopenia
- Cardiac Disorders:
- 1/1000 patients and <1/100 patients - bradycardia, palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fibrillation, angina pectoris, myocardial ischemia; <1/1000 patients - atrial flutter, supraventricular tachycardia, ventricular tachycardia
- Eye Disorders:
- 1/1000 patients and <1/100 patients - photophobia, diplopia, eyelid edema, photopsia
- Gastrointestinal Disorders:
- 1/1000 patients and <1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis; <1/1000 patients - pancreatitis.
- General Disorders and Administration Site Conditions:
- 1/100 patients - asthenia, peripheral edema, chest pain; 1/1000 patients and <1/100 patients - face edema, angioedema; <1/1000 patients - hypothermia
- Hepatobiliary Disorders:
- <1/1000 patients - hepatitis, jaundice
- Immune System Disorders:
- 1/1000 patients and <1/100 patients - hypersensitivity
- Injury, Poisoning, and Procedural Complications:
- 1/100 patients - fall; 1/1000 patients and <1/100 patients - self mutilation; <1/1000 patients - heat stroke
- Investigations:
- 1/100 patients - weight decreased, creatine phosphokinase increased; 1/1000 patients and <1/100 patients - hepatic enzyme increased, blood glucose increased, blood prolactin increased, blood urea increased, electrocardiogram QT prolonged, blood creatinine increased, blood bilirubin increased; <1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased, gamma-glutamyl transferase increased
- Metabolism and Nutrition Disorders:
- 1/1000 patients and <1/100 patients - hyperlipidemia, anorexia, diabetes mellitus (including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired, glycosuria, hyperglycemia, hypokalemia, hyponatremia, hypoglycemia, polydipsia; <1/1000 patients - diabetic ketoacidosis
- Musculoskeletal and Connective Tissue Disorders:
- 1/1000 patients and <1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; <1/1000 patients - rhabdomyolysis
- Nervous System Disorders:
- 1/100 patients - coordination abnormal; 1/1000 patients and <1/100 patients - speech disorder, parkinsonism, memory impairment, cogwheel rigidity, cerebrovascular accident, hypokinesia, tardive dyskinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia; <1/1000 patients - Grand Mal convulsion, choreoathetosis
- Psychiatric Disorders:
- 1/100 patients - suicidal ideation; 1/1000 patients and <1/100 patients - aggression, loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; <1/1000 patients - catatonia, sleep walking
- Renal and Urinary Disorders:
- 1/1000 patients and <1/100 patients - urinary retention, polyuria, nocturia
- Reproductive System and Breast Disorders:
- 1/1000 patients and <1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; <1/1000 patients - gynaecomastia, priapism
- Respiratory, Thoracic, and Mediastinal Disorders:
- 1/100 patients - nasal congestion, dyspnea, pneumonia aspiration
- Skin and Subcutaneous Tissue Disorders:
- 1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; 1/1000 patients and <1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria
- Vascular Disorders:
- 1/100 patients - hypertension; 1/1000 patients and <1/100 patients - hypotension
- Most adverse events observed in the pooled database of 920 pediatric patients, aged 6 to 17 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.
- Gastrointestinal Disorders:
- 1/1000 patients and <1/100 patients - tongue dry, tongue spasm
- Investigations:
- 1/100 patients - blood insulin increased
- Nervous System Disorders:
- 1/1000 patients and <1/100 patients - sleep talking
- Skin and Subcutaneous Tissue Disorders:
- 1/1000 patients and <1/100 patients - hirsutism
- Most adverse reactions observed in the pooled database of 749 adult patients treated with aripiprazole injection, were also observed in the adult population treated with oral aripiprazole. Additional adverse reactions observed in the aripiprazole injection population are listed below.
- General Disorders and Administration Site Conditions:
- 1/100 patients - injection site reaction; 1/1000 patients and <1/100 patients - venipuncture site bruise.

## 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 establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), and blood glucose fluctuation.

# Drug Interactions
- Given the primary CNS effects of aripiprazole, caution should be used when ABILIFY is taken in combination with other centrally-acting drugs or alcohol.
- Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

### Potential for Other Drugs to Affect ABILIFY
- Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.
- Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood level.
- Coadministration of ketoconazole (200 mg/day for 14 days) with a 15 mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied. When ketoconazole is given concomitantly with aripiprazole, the aripiprazole dose should be reduced to one-half of its normal dose.
- Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; moderate inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased.
- Coadministration of a 10 mg single dose of aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 35%. Aripiprazole dose should be reduced to one-half of its normal dose when quinidine is given concomitantly with aripiprazole.
- Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment.
- Coadministration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg/day) resulted in an approximate 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced

### Potential for ABILIFY to Affect Other Drugs
- Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro.
- No effect of aripiprazole was seen on the pharmacokinetics of lithium or valproate.

### Drugs Having No Clinically Important Interactions with ABILIFY
- Coadministration of aripiprazole (given in a single dose of 15 mg) with a 40 mg single dose of the H2 antagonist famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole and, hence, its rate of absorption, reducing by 37% and 21% the Cmax of aripiprazole and dehydro-aripiprazole, respectively, and by 13% and 15%, respectively, the extent of absorption (AUC). No dosage adjustment of aripiprazole is required when administered concomitantly with famotidine.
- When valproate (500 mg/day-1500 mg/day) and aripiprazole (30 mg/day) were coadministered, at steady-state the Cmax and AUC of aripiprazole were decreased by 25%. No dosage adjustment of aripiprazole is required when administered concomitantly with valproate.
- When aripiprazole (30 mg/day) and valproate (1000 mg/day) were coadministered, at steady-state there were no clinically significant changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with aripiprazole.
- A pharmacokinetic interaction of aripiprazole with lithium is unlikely because lithium is not bound to plasma proteins, is not metabolized, and is almost entirely excreted unchanged in urine. Coadministration of therapeutic doses of lithium (1200 mg/day-1800 mg/day) for 21 days with aripiprazole (30 mg/day) did not result in clinically significant changes in the pharmacokinetics of aripiprazole or its active metabolite, dehydro-aripiprazole (Cmax and AUC increased by less than 20%). No dosage adjustment of aripiprazole is required when administered concomitantly with lithium.
- Coadministration of aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in clinically significant changes in the pharmacokinetics of lithium. No dosage adjustment of lithium is required when administered concomitantly with aripiprazole.
- Coadministration of 10 mg/day to 30 mg/day oral doses of aripiprazole for 14 days to patients with bipolar I disorder had no effect on the steady-state pharmacokinetics of 100 mg/day to 400 mg/day lamotrigine, a UDP-glucuronosyltransferase 1A4 substrate. No dosage adjustment of lamotrigine is required when aripiprazole is added to lamotrigine.
- Aripiprazole at doses of 10 mg/day to 30 mg/day for 14 days had no effect on dextromethorphan's O-dealkylation to its major metabolite, dextrorphan, a pathway dependent on CYP2D6 activity. Aripiprazole also had no effect on dextromethorphan's N-demethylation to its metabolite 3-methoxymorphinan, a pathway dependent on CYP3A4 activity. No dosage adjustment of dextromethorphan is required when administered concomitantly with aripiprazole.
- Aripiprazole 10 mg/day for 14 days had no effect on the pharmacokinetics of R-warfarin and S-warfarin or on the pharmacodynamic end point of International Normalized Ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with aripiprazole.
- Aripiprazole 10 mg/day for 15 days had no effect on the pharmacokinetics of a single 20 mg dose of omeprazole, a CYP2C19 substrate, in healthy subjects. No dosage adjustment of omeprazole is required when administered concomitantly with aripiprazole.
- Coadministration of lorazepam injection (2 mg) and aripiprazole injection (15 mg) to healthy subjects (n=40: 35 males and 5 females; ages 19-45 years old) did not result in clinically important changes in the pharmacokinetics of either drug. No dosage adjustment of aripiprazole is required when administered concomitantly with lorazepam. However, the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone and the orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone.
- Coadministration of 10 mg/day oral doses of aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of 10 mg/day escitalopram, a substrate of CYP2C19 and CYP3A4. No dosage adjustment of escitalopram is required when aripiprazole is added to escitalopram.
- Coadministration of 10 mg/day to 20 mg/day oral doses of aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of venlafaxine and O-desmethylvenlafaxine following 75 mg/day venlafaxine XR, a CYP2D6 substrate. No dosage adjustment of venlafaxine is required when aripiprazole is added to venlafaxine.
- A population pharmacokinetic analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 mg/day or 40 mg/day), paroxetine CR (37.5 mg/day or 50 mg/day), or sertraline (100 mg/day or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole. Aripiprazole dosing was 2 mg/day to 15 mg/day (when given with fluoxetine or paroxetine) or 2 mg/day to 20 mg/day (when given with sertraline).

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- In general, no dosage adjustment for ABILIFY is required on the basis of a patients age, gender, race, smoking status, hepatic function, or renal function.
- Pregnancy Category C: In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.
- Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the maximum recommended human dose MRHD on a mg/m2 basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg), and delayed skeletal ossification (10 mg/kg and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 mg/kg and 30 mg/kg), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 mg/kg and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.
- In pregnant rats receiving aripiprazole injection intravenously (3 mg/kg/day, 9 mg/kg/day, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose, which also caused some maternal toxicity.
- Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day (2 times, 3 times, and 11 times human exposure at MRHD based on AUC and 6 times, 19 times, and 65 times the MRHD based on mg/m2) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 mg/kg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 mg/kg and 100 mg/kg), and minor skeletal variations (100 mg/kg).
- In pregnant rabbits receiving aripiprazole injection intravenously (3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5 times the human exposure at the MRHD based on AUC and is 6 times the MRHD based on mg/m2.
- In a study in which rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the MRHD on a mg/m2 basis) of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were seen at this dose.
- In rats receiving aripiprazole injection intravenously (3 mg/kg/day, 8 mg/kg/day, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 mg/kg and 20 mg/kg, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg. These doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.
- There are no adequate and well-controlled studies in pregnant women. It is not known whether aripiprazole can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aripiprazole (tablet) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Aripiprazole (tablet) during labor and delivery.

### Nursing Mothers
- Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.
- 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.
- 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 . 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 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.
- 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.
- 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.

### Geriatic Use
There is no FDA guidance on the use of Aripiprazole (tablet) in geriatric settings.

### Gender
There is no FDA guidance on the use of Aripiprazole (tablet) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Aripiprazole (tablet) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Aripiprazole (tablet) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Aripiprazole (tablet) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aripiprazole (tablet) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Aripiprazole (tablet) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
There is limited information regarding Aripiprazole (tablet) Administration in the drug label.

### Monitoring
There is limited information regarding Aripiprazole (tablet) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Aripiprazole (tablet) and IV administrations.

# Overdosage
There is limited information regarding Aripiprazole (tablet) overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
The mechanism of action of aripiprazole in schizophrenia or bipolar mania is unknown.However, the efficacy of aripiprazole could bemediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

## Structure
There is limited information regarding Aripiprazole (tablet) Structure in the drug label.

## Pharmacodynamics
There is limited information regarding Aripiprazole (tablet) Pharmacodynamics in the drug label.

## Pharmacokinetics
There is limited information regarding Aripiprazole (tablet) Pharmacokinetics in the drug label.

## Nonclinical Toxicology
There is limited information regarding Aripiprazole (tablet) Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Aripiprazole (tablet) Clinical Studies in the drug label.

# How Supplied
There is limited information regarding Aripiprazole (tablet) How Supplied in the drug label.

## Storage
There is limited information regarding Aripiprazole (tablet) Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Aripiprazole (tablet) Patient Counseling Information in the drug label.

# Precautions with Alcohol
Alcohol-Aripiprazole (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
There is limited information regarding Aripiprazole (tablet) Brand Names in the drug label.

# Look-Alike Drug Names
There is limited information regarding Aripiprazole (tablet) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price