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FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS (5.1)].
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of adjunctive ABILIFY or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ABILIFY is not approved for use in pediatric patients with depression [see WARNINGS AND PRECAUTIONS (5.2)].
1 INDICATIONS AND USAGE
1.1 Schizophrenia
Adults
ABILIFY is indicated for acute and maintenance treatment of Schizophrenia [see CLINICAL STUDIES (14.1)].
Adolescents
ABILIFY is indicated for the treatment of Schizophrenia in adolescents 13 to 17 years of age [see CLINICAL STUDIES (14.1)].1.2 Bipolar Disorder
Adults
ABILIFY is indicated for acute and maintenance treatment of manic and mixed episodes associated with Bipolar I Disorder with or without psychotic features [see CLINICAL STUDIES (14.2)].
1.3 Adjunctive Treatment of Major Depressive Disorder
Adults
ABILIFY is indicated for use as an adjunctive treatment to antidepressants for Major Depressive Disorder [see CLINICAL STUDIES (14.3)].
1.4 Agitation Associated with Schizophrenia or Bipolar Mania
Adults
ABILIFY Injection is indicated for the treatment of agitation associated with Schizophrenia or Bipolar Disorder, manic or mixed. "Psychomotor agitation" is defined in DSM-IV as "excessive motor activity associated with a feeling of inner tension." Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care (eg, threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior), leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation [see CLINICAL STUDIES (14.4)].
2 DOSAGE AND ADMINISTRATION
2.1 Schizophrenia
Usual Dose
Adults
The recommended starting and target dose for ABILIFY is 10 mg/day or 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY has been systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day. Dosage increases should not be made before 2 weeks, the time needed to achieve steady-state [see CLINICAL STUDIES (14.1)].
Adolescents
The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole was studied in pediatric 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. ABILIFY can be administered without regard to meals [see CLINICAL STUDIES (14.1)].Maintenance Therapy
Adults
While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, systematic evaluation of patients with Schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer, were discontinued from those medications, and were then administered ABILIFY 15 mg/day and observed for relapse during a period of up to 26 weeks, has demonstrated a benefit of such maintenance treatment [see CLINICAL STUDIES (14.1)]. Patients should be periodically reassessed to determine the need for maintenance treatment.
Pediatric Patients
The efficacy of ABILIFY for the maintenance treatment of Schizophrenia in the pediatric population has not been evaluated.
Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients with Schizophrenia from other antipsychotics to ABILIFY 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.
2.2 Bipolar Disorder
Usual Dose
Adults
In clinical trials, the starting dose was 30 mg given once a day, without regard to meals. A dose of 30 mg/day was found to be effective when administered as the tablet formulation. Approximately 15% of patients had their dose decreased to 15 mg based on assessment of tolerability. The safety of doses above 30 mg/day has not been evaluated in clinical trials [see CLINICAL STUDIES (14.2)].
Pediatric Patients
ABILIFY has not been evaluated in pediatric patients with Bipolar Disorder.
Maintenance Therapy
While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, adult patients with Bipolar I Disorder who had been symptomatically stable on ABILIFY Tablets (15 mg/day or 30 mg/day with a starting dose of 30 mg/day) for at least 6 consecutive weeks and then randomized to ABILIFY Tablets (15 mg/day or 30 mg/day) or placebo and monitored for relapse, demonstrated a benefit of such maintenance treatment [see CLINICAL STUDIES (14.2)]. While it is generally agreed that pharmacological treatment beyond an acute response in Mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of aripiprazole in such longer-term treatment (beyond 6 weeks). Physicians who elect to use ABILIFY for extended periods, that is, longer than 6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the individual.
2.3 Adjunctive Treatment of Major Depressive Disorder
Usual Dose
Adults
The recommended starting dose for ABILIFY as adjunctive treatment for patients already taking an antidepressant is 2 mg/day to 5 mg/day. The efficacy of ABILIFY as an adjunctive therapy for Major Depressive Disorder was established within a dose range of 2 mg/day to 15 mg/day. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week. The long-term efficacy of ABILIFY for the adjunctive treatment of Major Depressive Disorder has not been established [see CLINICAL STUDIES (14.3)].
Pediatric Patients
The efficacy of ABILIFY for the adjunctive treatment of Major Depressive Disorder in the pediatric population has not been evaluated.
2.4 Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)
Usual Dose
Adults
The recommended dose in these patients is 9.75 mg. The effectiveness of aripiprazole injection in controlling agitation in Schizophrenia and Bipolar Mania was demonstrated over a dose range of 5.25 mg to 15 mg. No additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical factors warrant. If agitation warranting a second dose persists following the initial dose, cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of repeated doses of aripiprazole injection in agitated patients has not been systematically evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg or injections given more frequently than every 2 hours have not been adequately evaluated in clinical trials [see CLINICAL STUDIES (14.4)].
If ongoing aripiprazole therapy is clinically indicated, oral aripiprazole in a range of 10 mg/day to 30 mg/day should replace aripiprazole injection as soon as possible [see DOSAGE AND ADMINISTRATION (2.1 and 2.2)].
Administration of ABILIFY Injection
To administer ABILIFY Injection, draw up the required volume of solution into the syringe as shown in Table 1. Discard any unused portion.
| Single-Dose | Required Volume of Solution |
|---|---|
| 5.25 mg | 0.7 mL |
| 9.75 mg | 1.3 mL |
| 15 mg | 2 mL |
ABILIFY Injection is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Pediatric Patients
ABILIFY Intramuscular Injection has not been evaluated in pediatric patients.
2.5 Dosage Adjustment
Dosage adjustments are not routinely indicated on the basis of age, gender, race, or renal or hepatic impairment status [see USE IN SPECIFIC POPULATIONS (8.4- 8.10)].
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Dosage adjustment for patients taking aripiprazole concomitantly with strong CYP3A4 inhibitors: When concomitant administration of aripiprazole with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated, the aripiprazole dose should be reduced to one-half the usual dose. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased [see DRUG INTERACTIONS (7.1)].
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Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP2D6 inhibitors: When concomitant administration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs, aripiprazole dose should be reduced at least to one-half of its normal dose. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased [see DRUG INTERACTIONS (7.1)]. When adjunctive ABILIFY is administered to patients with Major Depressive Disorder, ABILIFY should be administered without dosage adjustment as specified in DOSAGE AND ADMINISTRATION (2.3).
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Dosage adjustment for patients taking potential CYP3A4 inducers: When a potential CYP3A4 inducer such as carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should be reduced to 10 mg to 15 mg [see DRUG INTERACTIONS (7.1)].
2.6 Dosing of Oral Solution
The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see CLINICAL PHARMACOLOGY (12.3)].
2.7 Dosing of Orally Disintegrating Tablets
The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets [see DOSAGE AND ADMINISTRATION (2.1, 2.2, and 2.3)].
3 DOSAGE FORMS AND STRENGTHS
ABILIFY® (aripiprazole) Tablets are available as described in Table 2.
| Tablet Strength | Tablet Color/Shape | Tablet Markings |
| 2 mg | green modified rectangle | "A-006" and "2" |
| 5 mg | blue modified rectangle | "A-007" and "5" |
| 10 mg | pink modified rectangle | "A-008" and "10" |
| 15 mg | yellow round | "A-009" and "15" |
| 20 mg | white round | "A-010" and "20" |
| 30 mg | pink round | "A-011" and "30" |
ABILIFY® DISCMELT™ (aripiprazole) Orally Disintegrating Tablets are available as described in Table 3.
| Tablet Strength | Tablet Color/Shape | Tablet Markings |
| 10 mg | pink (with scattered specks) round | "A" and "640" "10" |
| 15 mg | yellow (with scattered specks) round | "A" and "641" "15" |
ABILIFY® (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light yellow solution, supplied in child-resistant bottles along with a calibrated oral dosing cup.
ABILIFY® (aripiprazole) Injection for Intramuscular Use is a clear, colorless solution available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials.
4 CONTRAINDICATIONS
Known hypersensitivity reaction to ABILIFY. Reactions have ranged from pruritus/urticaria to anaphylaxis [see ADVERSE REACTIONS (6.3)].
5 WARNINGS AND PRECAUTIONS
5.1 Use in Elderly Patients with Dementia-Related Psychosis
Increased Mortality
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].
Cerebrovascular Adverse Events, Including Stroke
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 (eg, stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78-88 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 [see also BOXED WARNING].
Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease
In three 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation (placebo 0%, aripiprazole 4%), and lightheadedness (placebo 1%, aripiprazole 4%).
The safety and efficacy of ABILIFY in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with ABILIFY, vigilance should be exercised, particularly for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see also BOXED WARNING].
5.2 Clinical Worsening and Suicide Risk
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 18-24) with Major Depressive Disorder (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 4.
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
| Increases Compared to Placebo | |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25-64 | 1 fewer case |
| ≥65 | 6 fewer cases |
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 Major Depressive Disorder 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 patient's 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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ABILIFY 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 ABILIFY is not approved for use in treating depression in the pediatric population.
5.3 Neuroleptic Malignant Syndrome (NMS)
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 (eg, 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.
5.4 Tardive Dyskinesia
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, ABILIFY 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 ABILIFY, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus
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 few reports of hyperglycemia in patients treated with ABILIFY [see ADVERSE REACTIONS (6.2, 6.3)]. Although fewer patients have been treated with ABILIFY, it is not known if this more limited experience is the sole reason for the paucity of such reports. 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 which did not include ABILIFY suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because ABILIFY was not marketed at the time these studies were performed, it is not known if ABILIFY 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 (eg, 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.
5.6 Orthostatic Hypotension
Aripiprazole may cause orthostatic hypotension, perhaps due to its a1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=1894) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1.2%, 0.3%), postural dizziness (0.6%, 0.4%), and syncope (0.6%, 0.5%); of pediatric patients 13 to 17 years of age with Schizophrenia (n=202) on oral ABILIFY included orthostatic hypotension (1.5%, 0%), postural dizziness (1.0%, 0%), and syncope (0.5%, 0%); and of patients on ABILIFY Injection (n=501) included orthostatic hypotension (0.6%, 0%), postural dizziness (0.2%, 0.5%), and syncope (0.4%, 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 (5%, 3%), in pediatric patients with Schizophrenia (0%, 0%), or in aripiprazole injection-treated patients (3%, 2%).
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).
If parenteral benzodiazepine therapy is deemed necessary in addition to aripiprazole injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension [see DRUG INTERACTIONS (7.3)].
5.7 Seizures/Convulsions
In short-term placebo-controlled trials, seizures/convulsions occurred in 0.2% (3/1894) of adult patients treated with oral aripiprazole, in 0% (0/202) of pediatric patients (13 to 17 yrs) with Schizophrenia, and in 0.2% (1/501) of adult aripiprazole injection-treated patients.
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, eg, Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
5.8 Potential for Cognitive and Motor Impairment
ABILIFY, 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=1894) treated with oral ABILIFY (11%, 7%), in pediatric patients with Schizophrenia (17%, 6%), and in adult patients on ABILIFY Injection (9%, 6%). Somnolence (including sedation) led to discontinuation in 0.2% (4/1894) of adult patients and 0.5% (1/202) pediatric patients (13 to 17 yrs) with Schizophrenia on oral ABILIFY in short-term, placebo-controlled trials, but did not lead to discontinuation of any adult patients on ABILIFY Injection.
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 ABILIFY does not affect them adversely.
5.9 Body Temperature Regulation
Disruption of the body’s 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, (eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see ADVERSE REACTIONS (6.3)].
5.10 Suicide
The possibility of a suicide attempt is inherent in psychotic illnesses, Bipolar Disorder, and Major Depressive Disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ABILIFY should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see ADVERSE REACTIONS (6.2, 6.3)].
In two 6-week placebo-controlled studies of aripiprazole as adjunctive treatment of Major Depressive Disorder, the incidences of suicidal ideation and suicide attempts were 0% (0/371) for aripiprazole and 0.5% (2/366) for placebo.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see WARNINGS AND PRECAUTIONS (5.1) and ADVERSE REACTIONS (6.3)].
5.12 Use in Patients with Concomitant Illness
Clinical experience with ABILIFY in patients with certain concomitant systemic illnesses is limited [see USE IN SPECIFIC POPULATIONS (8.6, 8.7)].
ABILIFY has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies [see WARNINGS AND PRECAUTIONS (5.1, 5.6)].
6 ADVERSE REACTIONS
6.1 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]
- Clinical Worsening and Suicide Risk [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.2)]
- Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS (5.3)]
- Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS (5.4)]
- Hyperglycemia and Diabetes Mellitus [see WARNINGS AND PRECAUTIONS (5.5)]
- Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS (5.6)]
- Seizures/Convulsions [see WARNINGS AND PRECAUTIONS (5.7)]
- Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS (5.8)]
- Body Temperature Regulation [see WARNINGS AND PRECAUTIONS (5.9)]
- Suicide [see WARNINGS AND PRECAUTIONS (5.10)]
- Dysphagia [see WARNINGS AND PRECAUTIONS (5.11)]
- Use in Patients with Concomitant Illness [see WARNINGS AND PRECAUTIONS (5.12)]
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 trial (≥10%) were extrapyramidal disorder, headache, and somnolence.
Aripiprazole has been evaluated for safety in 12,925 patients who participated in multiple-dose, clinical trials in Schizophrenia, Bipolar Disorder, Major Depressive Disorder, and Dementia of the Alzheimer's type, and who had approximately 7482 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3338 patients were treated with oral aripiprazole for at least 180 days and 1898 patients treated with oral aripiprazole had at least 1 year of exposure.
Aripiprazole has been evaluated for safety in 281 pediatric patients (13 to 17 yrs) who participated in multiple-dose, clinical trials in Schizophrenia and who had approximately 119 patient-years of exposure to oral aripiprazole. A total of 147 pediatric patients were treated with oral aripiprazole for at least 180 days.
The conditions and duration of treatment with aripiprazole 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.
6.2 Clinical Studies Experience
Adult Patients with Schizophrenia
The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
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- and placebo-treated patients.
Commonly Observed Adverse Reactions
The only commonly observed adverse reaction associated with the use of aripiprazole in patients with Schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).
Adult Patients with Bipolar Mania
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.
Adverse Reactions Associated with Discontinuation of Treatment
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 (9%) patients. The types of adverse reactions that led to discontinuation were similar between the aripiprazole- and placebo-treated patients.
Commonly Observed Adverse Reactions
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 5.
| Percentage of Patients Reporting Reaction | ||
|---|---|---|
|
Preferred Term | Aripiprazole (n=597) | Placebo (n=436) |
| Constipation | 13 | 6 |
| Akathisia | 15 | 3 |
| Sedation | 8 | 3 |
| Tremor | 7 | 3 |
| Restlessness | 6 | 3 |
| Extrapyramidal Disorder | 5 | 2 |
Less Common Adverse Reactions in Adults
Table 6 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.
| Percentage of Patients Reporting Reactiona | ||
|---|---|---|
| System Organ Class Preferred Term | Aripiprazole (n=1523) | Placebo (n=849) |
| a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. | ||
| b Including blood pressure increased. | ||
| Eye Disorders | ||
| Blurred Vision | 3 | 1 |
| Gastrointestinal Disorders | ||
| Nausea | 16 | 12 |
| Vomiting | 12 | 6 |
| Constipation | 11 | 7 |
| Dyspepsia | 10 | 8 |
| Dry Mouth | 5 | 4 |
| Abdominal Discomfort | 3 | 2 |
| Stomach Discomfort | 3 | 2 |
| Salivary Hypersecretion | 2 | 1 |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 6 | 5 |
| Pain | 3 | 2 |
| Peripheral Edema | 2 | 1 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia | 5 | 4 |
| Pain in Extremity | 4 | 2 |
| Nervous System Disorders | ||
| Headache | 30 | 25 |
| Dizziness | 11 | 8 |
| Akathisia | 10 | 4 |
| Sedation | 7 | 4 |
| Extrapyramidal Disorder | 6 | 4 |
| Tremor | 5 | 3 |
| Somnolence | 5 | 4 |
| Psychiatric Disorders | ||
| Anxiety | 20 | 17 |
| Insomnia | 19 | 14 |
| Restlessness | 5 | 3 |
| Respiratory, Thoracic, and Mediastinal Disorders | ||
| Pharyngolaryngeal Pain | 4 | 3 |
| Cough | 3 | 2 |
| Nasal Congestion | 3 | 2 |
| Vascular Disorders | ||
| Hypertensionb | 2 | 1 |
An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.
Pediatric Patients (13 to 17 years) with Schizophrenia
The following findings are based on one 6-week placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 yrs) was 5% and 2%, respectively.
Commonly Observed Adverse Reactions
Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with Schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.
Less Common Adverse Reactions in Pediatric Patients (13 to 17 years) with Schizophrenia
Table 7 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in Schizophrenia) including only those reactions that occurred in 2% or more of adolescent 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.
| Percentage of Patients Reporting Reactiona | ||
|---|---|---|
| System Organ Class | Aripiprazole | Placebo |
| Preferred Term | (n=202) | (n=100) |
| a Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. | ||
| Gastrointestinal Disorders | ||
| Nausea | 9 | 6 |
| Constipation | 2 | 1 |
| Diarrhea | 2 | 0 |
| Dry Mouth | 2 | 1 |
| Salivary Hypersecretion | 2 | 1 |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 3 | 1 |
| Infections and Infestations | ||
| Nasopharyngitis | 5 | 4 |
| Metabolism and Nutrition Disorders | ||
| Increased Appetite | 3 | 0 |
| Nervous System Disorders | ||
| Extrapyramidal Disorder | 17 | 5 |
| Somnolence | 16 | 6 |
| Headache | 13 | 10 |
| Akathisia | 8 | 5 |
| Tremor | 7 | 2 |
| Dizziness | 5 | 3 |
| Dystonia | 2 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 2 | 0 |
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 aripiprazole was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions was 6% for adjunctive aripiprazole-treated patients and 2% for adjunctive placebo-treated patients.
Commonly Observed Adverse Reactions
The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with Major Depressive Disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.
Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder
Table 8 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.
| Percentage of Patients Reporting Reactiona | ||
|---|---|---|
| System Organ Class Preferred Term | Aripiprazole+ADT* (n=371) | Placebo+ADT* (n=366) |
| a Adverse reactions reported by at least 2% of patients treated with adjunctive aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. * Antidepressant Therapy |
||
| Eye Disorders | ||
| Blurred Vision | 6 | 1 |
| Gastrointestinal Disorders | ||
| Constipation | 5 | 2 |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 8 | 4 |
| Feeling Jittery | 3 | 1 |
| Infections and Infestations | ||
| Upper Respiratory Tract Infection | 6 | 4 |
| Investigations | ||
| Weight Increased | 3 | 2 |
| Metabolism and Nutrition Disorders | ||
| Increased Appetite | 3 | 2 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Arthralgia | 4 | 3 |
| Myalgia | 3 | 1 |
| Nervous System Disorders | ||
| Akathisia | 25 | 4 |
| Somnolence | 6 | 4 |
| Tremor | 5 | 4 |
| Sedation | 4 | 2 |
| Dizziness | 4 | 2 |
| Disturbance in Attention | 3 | 1 |
| Extrapyramidal Disorder | 2 | 0 |
| Psychiatric Disorders | ||
| Restlessness | 12 | 2 |
| Insomnia | 8 | 2 |
Patients with Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)
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.
Adverse Reactions Associated with Discontinuation of Treatment
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.
Commonly Observed Adverse Reactions
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).
Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania
Table 9 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.
| Percentage of Patients Reporting Reactiona | ||
|---|---|---|
| System Organ Class Preferred Term | Aripiprazole (n=501) | Placebo (n=220) |
| a Adverse reactions reported by at least 2% of patients treated with aripiprazole injection, except adverse reactions which had an incidence equal to or less than placebo. | ||
| Cardiac Disorders | ||
| Tachycardia | 2 | <1 |
| Gastrointestinal Disorders | ||
| Nausea | 9 | 3 |
| Vomiting | 3 | 1 |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 2 | 1 |
| Nervous System Disorders | ||
| Headache | 12 | 7 |
| Dizziness | 8 | 5 |
| Somnolence | 7 | 4 |
| Sedation | 3 | 2 |
| Akathisia | 2 | 0 |
Dose-Related Adverse Reactions
Schizophrenia
Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with Schizophrenia comparing various fixed doses (2 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 [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).
In the study of pediatric patients (13 to 17 years of age) with Schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 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%).
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 (13-17 years) patients, 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. 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 aripiprazole-treated patients was 15% vs. 8% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 15% vs. 4% for placebo. 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.
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). In the Bipolar Mania trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.61; placebo, 0.03 and aripiprazole, 0.25; placebo, -0.06). Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. 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.
Similarly, in a long-term (26-week), placebo-controlled trial of Schizophrenia, 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 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.
Dystonia
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.
Laboratory Test Abnormalities
A between group comparison for 3-week to 6-week, placebo-controlled trials 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 the 6-week trials of aripiprazole as adjunctive therapy for Major Depressive Disorder, there were no clinically important differences between the adjunctive aripiprazole-treated and adjunctive placebo-treated patients in the median change from baseline in prolactin, fasting glucose, HDL, LDL, or total cholesterol measurements. The median % change from baseline in triglycerides was 5% for adjunctive aripiprazole-treated patients vs. 0% for adjunctive placebo-treated patients.
In a long-term (26-week), placebo-controlled trial there were no medically important differences between the aripiprazole and placebo patients in the mean change from baseline in prolactin, fasting glucose, triglyceride, HDL, LDL, and total cholesterol measurements.
Weight Gain
In 4-week to 6- week trials in adults with Schizophrenia, there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.7 kg vs. -0.05 kg, respectively) and also a difference in the proportion of patients meeting a weight gain criterion of ≥7% of body weight [aripiprazole (8%) compared to placebo (3%)]. In a 6-week trial in pediatric patients (13 to 17 yrs) with Schizophrenia, there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.13 kg vs. -0.83 kg, respectively) and also a difference in the proportion of patients meeting a weight gain criterion of ≥7% of body weight [aripiprazole (5%) compared to placebo (1%)]. In 3-week trials in adults with Mania, the mean weight gain for aripiprazole and placebo patients was 0.0 kg vs. -0.2 kg, respectively. The proportion of patients meeting a weight gain criterion of ≥7% of body weight was aripiprazole (3%) compared to placebo (2%).
In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing antidepressant treatment. The mean weight gain with adjunctive aripiprazole was 1.7 kg vs. 0.4 kg with adjunctive placebo. The proportion of patients meeting a weight gain criterion of ≥7% of body weight was 5% with adjunctive aripiprazole compared to 1% with adjunctive placebo.
Table 10 provides the weight change results from a long-term (26-week), placebo-controlled study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ≥7% of body weight relative to baseline, categorized by BMI at baseline. Although there was no mean weight increase, the aripiprazole group tended to show more patients with a ≥7% weight gain.
| BMI <23 | BMI 23-27 | BMI >27 | ||||
| Placebo (n=54) | Aripiprazole (n=59) | Placebo (n=48) | Aripiprazole (n=39) | Placebo (n=49) | Aripiprazole (n=53) |
|
| Mean change from baseline (kg) | -0.5 | -0.5 | -0.6 | -1.3 | -1.5 | -2.1 |
| % with ≥7% increase BW | 3.7% | 6.8% | 4.2% | 5.1% | 4.1% | 5.7% |
Table 11 provides the weight change results from a long-term (52-week) study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ≥7% of body weight relative to baseline, categorized by BMI at baseline:
| BMI <23 (n=314) | BMI 23-27 (n=265) | BMI >27 (n=260) |
|
| Mean change from baseline (kg) | 2.6 | 1.4 | -1.2 |
| % with ≥7% increase BW | 30% | 19% | 8% |
ECG Changes
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 3 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
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 [8% (12/153) for ABILIFY vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of ABILIFY. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor for ABILIFY was 5% (40/859). A similar profile was observed in a long-term study in Bipolar Disorder.
Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole
Following is a list of MedDRA terms that reflect adverse reactions as defined in ADVERSE REACTIONS (6.1) reported by patients treated with oral aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of 12,925 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. Events already listed in other parts of ADVERSE REACTIONS (6), or those considered in WARNINGS AND PRECAUTIONS (5) or OVERDOSAGE (10) have been excluded. 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.
Adults - Oral Administration
Blood and Lymphatic System Disorders:
- ≥1/1000 patients and <1/100 patients - leukopenia, neutropenia; <1/1000 patients - thrombocytopenia, agranulocytosis, idiopathic thrombocytopenic purpura
Cardiac Disorders:
- ≥1/1000 patients and <1/100 patients - cardiopulmonary failure, bradycardia, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, bundle branch block; <1/1000 patients - atrial flutter, ventricular tachycardia, complete atrioventricular block, supraventricular tachycardia
Eye Disorders:
- ≥1/1000 patients and <1/100 patients - eyelid edema, photophobia, diplopia, photopsia; <1/1000 patients - excessive blinking
Gastrointestinal Disorders:
- ≥1/1000 patients and <1/100 patients - dysphagia, gastroesophageal reflux disease, gastrointestinal hemorrhage, swollen tongue, ulcer, esophagitis, angioedema; <1/1000 patients - pancreatitis
General Disorders and Administration Site Conditions:
- ≥1/100 patients - asthenia, pyrexia; ≥1/1000 patients and <1/100 patients - mobility decreased, face edema; <1/1000 patients - hypothermia
Hepatobiliary Disorders:
- ≥1/1000 patients and <1/100 patients - cholecystitis, cholelithiasis; <1/1000 patients - hepatitis, jaundice
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 - creatine phosphokinase increased; ≥1/1000 patients and <1/100 patients - hepatic enzyme increased, blood urea increased, blood bilirubin increased, blood creatinine increased, electrocardiogram QT corrected interval prolonged, blood prolactin increased; <1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased, GGT increased
Metabolism and Nutrition Disorders:
- ≥1/1000 patients and <1/100 patients - anorexia, hyperlipidemia
Musculoskeletal and Connective Tissue Disorders:
- ≥1/100 patients - muscle spasms; ≥1/1000 patients and <1/100 patients - muscle rigidity; <1/1000 patients - rhabdomyolysis
Nervous System Disorders:
- ≥1/100 patients - coordination abnormal; ≥1/1000 patients and <1/100 patients - speech disorder, dyskinesia, parkinsonism, dystonia, cogwheel rigidity, memory impairment, cerebrovascular accident, hypokinesia, tardive dyskinesia, hypotonia, hypertonia, akinesia, myoclonus, bradykinesia; <1/1000 patients - Grand Mal convulsion, choreoathetosis
Psychiatric Disorders:
- ≥1/100 patients - agitation, irritability, suicidal ideation; ≥1/1000 patients and <1/100 patients - aggression, loss of libido, libido decreased, hostility, suicide attempt, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; <1/1000 patients - psychomotor agitation, premature ejaculation, 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 - erectile dysfunction, amenorrhea, menstruation irregular, breast pain; <1/1000 patients - gynaecomastia, priapism, galactorrhea
Respiratory, Thoracic, and Mediastinal Disorders:
- ≥1/100 patients - dyspnea; ≥1/1000 patients and <1/100 patients - pneumonia aspiration, respiratory distress; <1/1000 patients - pulmonary embolism, asphyxia
Skin and Subcutaneous Tissue Disorders:
- ≥1/100 patients - hyperhydrosis; ≥1/1000 patients and <1/100 patients - erythema, pruritus, ecchymosis, face edema, photosensitivity reaction, alopecia, urticaria
Vascular Disorders:
- ≥1/1000 patients and <1/100 patients - hypotension, deep vein thrombosis, phlebitis; <1/1000 patients - shock, thrombophlebitis
Pediatric Patients - Oral Administration
All adverse reactions observed in the pooled database of 281 pediatric patients aged 13 to 17 years were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.
Investigations:
- ≥1/100 patients - blood insulin increased
Nervous System Disorders:
- ≥1/1000 patients and <1/100 patients - sleep talking, psychomotor skills impaired
Skin and Subcutaneous Tissue Disorders:
- ≥1/1000 patients and <1/100 patients - hirsutism
Adults - Intramuscular Injection
All 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
6.3 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.
7 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.
7.1 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 levels.
Ketoconazole and Other CYP3A4 Inhibitors
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 t