ABILIFY (ARIPIPRAZOLE) tablet
Otsuka America Pharmaceutical, Inc.

Otsuka America Pharmaceutical, Inc.
ABILIFY
ARIPIPRAZOLE
STARCH, CORN
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
FERRIC OXIDE YELLOW
FD&C BLUE NO. 2--ALUMINUM LAKE
ARIPIPRAZOLE
ARIPIPRAZOLE
modified rectangle
A;006;2
ABILIFY
ARIPIPRAZOLE
STARCH, CORN
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
FD&C BLUE NO. 2--ALUMINUM LAKE
ARIPIPRAZOLE
ARIPIPRAZOLE
modified rectangle
A;007;5
ABILIFY
ARIPIPRAZOLE
STARCH, CORN
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
FERRIC OXIDE RED
ARIPIPRAZOLE
ARIPIPRAZOLE
modified rectangle
A;008;10
ABILIFY
ARIPIPRAZOLE
STARCH, CORN
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
FERRIC OXIDE YELLOW
ARIPIPRAZOLE
ARIPIPRAZOLE
A;009;15
ABILIFY
ARIPIPRAZOLE
STARCH, CORN
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
ARIPIPRAZOLE
ARIPIPRAZOLE
A;010;20
ABILIFY
ARIPIPRAZOLE
STARCH, CORN
HYDROXYPROPYL CELLULOSE (1600000 WAMW)
LACTOSE MONOHYDRATE
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
FERRIC OXIDE RED
ARIPIPRAZOLE
ARIPIPRAZOLE
A;011;30
ABILIFY
ARIPIPRAZOLE
FRUCTOSE
GLYCERIN
LACTIC ACID, DL-
METHYLPARABEN
PROPYLENE GLYCOL
PROPYLPARABEN
SODIUM HYDROXIDE
SUCROSE
WATER
ARIPIPRAZOLE
ARIPIPRAZOLE
natural orange cream and other natural flavors
ABILIFY
ARIPIPRAZOLE
ACESULFAME POTASSIUM
ASPARTAME
CALCIUM SILICATE
CROSCARMELLOSE SODIUM
CROSPOVIDONE (120 .MU.M)
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
TARTARIC ACID
XYLITOL
FD&C BLUE NO. 2
ALUMINUM OXIDE
PHENYLALANINE
ARIPIPRAZOLE
ARIPIPRAZOLE
pink with scattered specks
A;640;10
crème de vanilla (natural and artificial flavors)
ABILIFY
ARIPIPRAZOLE
ACESULFAME POTASSIUM
ASPARTAME
CALCIUM SILICATE
CROSCARMELLOSE SODIUM
CROSPOVIDONE (120 .MU.M)
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
TARTARIC ACID
XYLITOL
FD&C BLUE NO. 2
ALUMINUM OXIDE
PHENYLALANINE
ARIPIPRAZOLE
ARIPIPRAZOLE
yellow with scattered specks
A;641;15
crème de vanilla (natural and artificial flavors)
ABILIFY
ARIPIPRAZOLE
BETADEX SULFOBUTYL ETHER SODIUM
TARTARIC ACID
SODIUM HYDROXIDE
ARIPIPRAZOLE
ARIPIPRAZOLE

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24 years; there was a reduction in risk with antidepressant use in patients aged 65 years and older [see Warnings and Precautions (5.3)].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.3)].

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS

See full prescribing information for complete boxed warning.

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY is not approved for the treatment of patients with dementia-related psychosis. (5.1)
  • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Monitor for worsening and emergence of suicidal thoughts and behaviors. (5.3)

1 INDICATIONS AND USAGE

ABILIFY (aripiprazole) Oral Tablets, Orally-Disintegrating Tablets, and Oral Solution are indicated for the treatment of:

  • Schizophrenia
  • Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder
  • Adjunctive Treatment of Major Depressive Disorder
  • Irritability Associated with Autistic Disorder
  • Treatment of Tourette's Disorder

ABILIFY Injection is indicated for the treatment of:

  • Agitation associated with schizophrenia or bipolar mania

ABILIFY is an atypical antipsychotic. The oral formulations are indicated for:

  • Schizophrenia (14.1)
  • Acute Treatment of Manic and Mixed Episodes associated with Bipolar I (14.2)
  • Adjunctive Treatment of Major Depressive Disorder (14.3)
  • Irritability Associated with Autistic Disorder (14.4)
  • Treatment of Tourette's disorder (14.5)

The injection is indicated for:

  • Agitation associated with schizophrenia or bipolar mania (14.6)

2 DOSAGE AND ADMINISTRATION

Initial Dose Recommended Dose Maximum Dose
Schizophrenia – adults (2.1) 10 to 15 mg/day 10 to 15 mg/day 30 mg/day
Schizophrenia – adolescents (2.1) 2 mg/day 10 mg/day 30 mg/day
Bipolar mania – adults: monotherapy (2.2) 15 mg/day 15 mg/day 30 mg/day
Bipolar mania – adults: adjunct to lithium or valproate (2.2) 10 to 15 mg/day 15 mg/day 30 mg/day
Bipolar mania – pediatric patients: monotherapy or as an adjunct to lithium or valproate (2.2) 2 mg/day 10 mg/day 30 mg/day
Major Depressive Disorder – adults: adjunct to antidepressants (2.3) 2 to 5 mg/day 5 to 10 mg/day 15 mg/day
Irritability associated with autistic disorder – pediatric patients (2.4) 2 mg/day 5 to 10 mg/day 15 mg/day
Tourette's disorder – (2.5) Patients <50 kg 2 mg/day 5 mg/day 10 mg/day
Patients ≥50 kg 2 mg/day 10 mg/day 20 mg/day
Agitation associated with schizophrenia or bipolar mania – adults (2.6) 9.75 mg /1.3 mL injected IM 30 mg/day injected IM
  • Oral formulations: Administer once daily without regard to meals (2)
  • IM injection: Wait at least 2 hours between doses. Maximum daily dose 30 mg (2.6)
  • Known CYP2D6 poor metabolizers: Half of the usual dose (2.7)

2.1 Schizophrenia

Adults

The recommended starting and target dose for ABILIFY is 10 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 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.1)].

Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either ABILIFY 15 mg/day or placebo, and observed for relapse [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

Adolescents

The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 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)]. Patients should be periodically reassessed to determine the need for maintenance treatment.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to 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 I Disorder

Acute Treatment of Manic and Mixed Episodes

Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. ABILIFY can be given without regard to meals. The recommended target dose of ABILIFY is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials.

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. ABILIFY can be given without regard to meals [see Clinical Studies (14.2)].

2.3 Adjunctive Treatment of Major Depressive Disorder

Adults

The recommended starting dose for ABILIFY as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.3)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

2.4 Irritability Associated with Autistic Disorder

Pediatric Patients (6 to 17 years)

The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day.

Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.4)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

2.5 Tourette's Disorder

Pediatric Patients (6 to 18 years)

The recommended dosage range for Tourette's Disorder is 5 to 20 mg/day.

For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than one week.

For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on Day 8. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than one week [see Clinical Studies (14.5)].

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

2.6 Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)

Adults

The recommended dose in these patients is 9.75 mg. The recommended dosage range is 5.25 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 ABILIFY 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 (14.6)].

If ongoing ABILIFY therapy is clinically indicated, oral ABILIFY in a range of 10 to 30 mg/day should replace ABILIFY 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.

Table 1: ABILIFY Injection Dosing Recommendations
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.

2.7 Dosage Adjustments for Cytochrome P450 Considerations

Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 2). When the coadministered drug is withdrawn from the combination therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.

Table 2: Dose Adjustments for ABILIFY in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers
Factors Dosage Adjustments for ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors
(e.g., itraconazole, clarithromycin)
Administer a quarter of usual dose
Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors
(e.g., itraconazole, clarithromycin)
Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over 1 to 2 weeks

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).

2.8 Dosing of Oral Solution

The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see Clinical Pharmacology (12.3)].

2.9 Dosing of Orally Disintegrating Tablets

The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

3 DOSAGE FORMS AND STRENGTHS

ABILIFY® (aripiprazole) Tablets are available as described in 3.

Table 3: ABILIFY Tablet Presentations
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 4.

Table 4: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations
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.

  • Tablets: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg (3)
  • Orally Disintegrating Tablets: 10 mg and 15 mg (3)
  • Oral Solution: 1 mg/mL (3)
  • Injection: 9.75 mg/1.3 mL single-dose vial (3)

4 CONTRAINDICATIONS

ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6.2)].

  • Known hypersensitivity to ABILIFY (4)

5 WARNINGS AND PRECAUTIONS

  • Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.2)
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4)
  • Tardive Dyskinesia: Discontinue if clinically appropriate (5.5)
  • Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain (5.6)
    • Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes (5.6)
    • Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics (5.6)
    • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Monitor weight (5.6)
  • Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation (5.7)
  • Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8)
  • Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including ABILIFY. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.10)
  • Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.11)
  • Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.12)
  • Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients (5.14)

5.1 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. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease

In three, 10 week, placebo-controlled studies of ABILIFY in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56 to 99 years), the adverse reactions that were reported at an incidence of ≥3% and ABILIFY incidence at least twice that for placebo were lethargy [placebo 2%, ABILIFY 5%], somnolence (including sedation) [placebo 3%, ABILIFY 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, ABILIFY 5%], excessive salivation [placebo 0%, ABILIFY 4%], and lightheadedness [placebo 1%, ABILIFY 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, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see Boxed Warning].

5.2 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 (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-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 ABILIFY. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.3 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

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 to 24 years) 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 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years 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 1,000 patients treated) are provided in Table 5.

Table 5:
Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18 14 additional cases
18 to 24 5 additional cases
Decreases Compared to Placebo
25 to 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, i.e., 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 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 healthcare 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.

5.4 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 ABILIFY. Rare cases of NMS occurred during ABILIFY 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.

5.5 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.

Tardive dyskinesia 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.

5.6 Metabolic Changes

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/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 reports of hyperglycemia in patients treated with ABILIFY [see Adverse Reactions (6.1, 6.2)]. 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 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 reactions 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.

Adults

In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in ABILIFY-treated patients (+4.4 mg/dL; median exposure 25 days; N=1,057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 6 shows the proportion of ABILIFY-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).

Table 6: Changes in Fasting Glucose from Placebo-Controlled Monotherapy Trials in Adult Patients
  Category Change (at least once) from Baseline Treatment Arm n/N %
Fasting Glucose Normal to High
(<100 mg/dL to ≥126 mg/dL)
ABILIFY 31/822 3.8
Placebo 22/605 3.6
  Borderline to High
(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)
ABILIFY 31/176 17.6
Placebo 13/142 9.2

At 24 weeks, the mean change in fasting glucose in ABILIFY-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].

The mean change in fasting glucose in adjunctive ABILIFY-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 7 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder.

Table 7: Changes in Fasting Glucose from Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder
  Category Change (at least once) from Baseline Treatment Arm n/N %
Fasting Glucose Normal to High
(<100 mg/dL to ≥126 mg/dL)
ABILIFY 2/201 1.0
Placebo 2/204 1.0
  Borderline to High
(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)
ABILIFY 4/34 11.8
Placebo 3/37 8.1

Pediatric Patients and Adolescents

In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), the mean change in fasting glucose in ABILIFY-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).

In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in ABILIFY-treated patients (–0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (–0.6 mg/dL; N=33).

In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette's disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in ABILIFY-treated patients (0.79 mg/dL; N=90) was not significantly different than in placebo-treated patients (–1.66 mg/dL; N=58).

Table 8 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and pediatric bipolar patients (median exposure of 42 to 43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 year) with Tourette's Disorder (median exposure 57 days).

Table 8: Changes in Fasting Glucose from Placebo-Controlled Trials in Pediatric and Adolescent Patients
Category Change (at least once) from Baseline Indication Treatment Arm n/N %
Fasting Glucose
Normal to High
(<100 mg/dL to ≥126 mg/dL)
Pooled Schizophrenia and Bipolar Disorder ABILIFY 2/236 0.8
Placebo 2/110 1.8
Irritability Associated with Autistic Disorder ABILIFY 0/73 0
Placebo 0/32 0
Tourette's Disorder ABILIFY 3/88 3.4
Placebo 1/58 1.7
Fasting Glucose
Borderline to High
(≥100 mg/dL and <126mg/dL to ≥126 mg/dL)
Pooled Schizophrenia and Bipolar Disorder ABILIFY 1/22 4.5
Placebo 0/12 0
Irritability Associated with Autistic Disorder ABILIFY 0/9 0
Placebo 0/1 0
Tourette's Disorder ABILIFY 0/11 0
Placebo 0/4 0

At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in ABILIFY-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively].

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

There were no significant differences between ABILIFY- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.

Adults

Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days).

Table 9: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Adults
Treatment Arm n/N %
Total Cholesterol
Normal to High
(<200 mg/dL to ≥240 mg/dL)
ABILIFY 34/1,357 2.5
Placebo 27/973 2.8
Fasting Triglycerides
Normal to High
(<150 mg/dL to ≥200 mg/dL)
ABILIFY 40/539 7.4
Placebo 30/431 7.0
Fasting LDL Cholesterol
Normal to High
(<100 mg/dL to ≥160 mg/dL)
ABILIFY 2/332 0.6
Placebo 2/268 0.7
HDL Cholesterol
Normal to Low
(≥40 mg/dL to <40 mg/dL)
ABILIFY 121/1,066 11.4
Placebo 99/794 12.5

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between ABILIFY- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.

Table 10 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adult patients with major depressive disorder (median exposure 42 days).

Table 10: Changes in Blood Lipid Parameters from Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder
Treatment Arm n/N %
Total Cholesterol
Normal to High
(<200 mg/dL to ≥240 mg/dL)
ABILIFY 3/139 2.2
Placebo 7/135 5.2
Fasting Triglycerides
Normal to High
(<150 mg/dL to ≥200 mg/dL)
ABILIFY 14/145 9.7
Placebo 6/147 4.1
Fasting LDL Cholesterol
Normal to High
(<100 mg/dL to ≥160 mg/dL)
ABILIFY 0/54 0
Placebo 0/73 0
HDL Cholesterol
Normal to Low
(≥40 mg/dL to <40 mg/dL)
ABILIFY 17/318 5.3
Placebo 10/286 3.5

Pediatric Patients and Adolescents

Table 11 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days).

Table 11: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients in Schizophrenia and Bipolar Disorder
Treatment Arm n/N %
Total Cholesterol
Normal to High
(<170 mg/dL to ≥200 mg/dL)
ABILIFY 3/220 1.4
Placebo 0/116 0
Fasting Triglycerides
Normal to High
(<150 mg/dL to ≥200 mg/dL)
ABILIFY 7/187 3.7
Placebo 4/85 4.7
HDL Cholesterol
Normal to Low
(≥40 mg/dL to <40 mg/dL)
ABILIFY 27/236 11.4
Placebo 22/109 20.2

In monotherapy trials of adolescents with schizophrenia and pediatric patients with bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between ABILIFY- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.

Table 12 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder.

Table 12: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients with Autistic Disorder
Treatment Arm n/N %
Total Cholesterol
Normal to High
(<170 mg/dL to ≥200 mg/dL)
ABILIFY 1/95 1.1
Placebo 0/34 0
Fasting Triglycerides
Normal to High
(<150 mg/dL to ≥200 mg/dL)
ABILIFY 0/75 0
Placebo 0/30 0
HDL Cholesterol
Normal to Low
(≥40 mg/dL to <40 mg/dL)
ABILIFY 9/107 8.4
Placebo 5/49 10.2

Table 13 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette's Disorder.

Table 13: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients with Tourette's Disorder
Treatment Arm n/N %
Total Cholesterol
Normal to High
(<170 mg/dL to ≥200 mg/dL)
ABILIFY 1/85 1.2
Placebo 0/46 0
Fasting Triglycerides
Normal to High
(<150 mg/dL to ≥200 mg/dL)
ABILIFY 5/94 5.3
Placebo 2/55 3.6
HDL Cholesterol
Normal to Low
(≥40 mg/dL to <40 mg/dL)
ABILIFY 4/108 3.7
Placebo 2/67 3.0

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Adults

In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in ABILIFY-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in ABILIFY-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.

In the trials adding ABILIFY to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive ABILIFY or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive ABILIFY was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo.

Table 14 shows the percentage of adult patients with weight gain ≥7% of body weight by indication.

Table 14: Percentage of Patients from Placebo-Controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight
Indication Treatment Arm N Patients
n (%)
Weight gain ≥7% of body weight Schizophrenia4 to 6 weeks duration ABILIFY 852 69 (8.1)
Placebo 379 12 (3.2)
Bipolar Mania3 weeks duration. ABILIFY 719 16 (2.2)
Placebo 598 16 (2.7)
Major Depressive Disorder
(Adjunctive Therapy)6 weeks duration.
ABILIFY 347 18 (5.2)
Placebo 330 2 (0.6)

Pediatric Patients and Adolescents

In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in ABILIFY-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in ABILIFY-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients.

In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in ABILIFY-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients.

In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette's Disorder with median exposure of 57 days, the mean change in body weight in ABILIFY-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients.

Table 15 shows the percentage of pediatric and adolescent patients with weight gain ≥7% of body weight by indication.

Table 15: Percentage of Patients from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain ≥7% of Body Weight
Indication Treatment Arm N Patients n (%)
Weight gain ≥7% of body weight Pooled Schizophrenia and Bipolar Mania4 to 6 weeks duration ABILIFY 381 20 (5.2)
Placebo 187 3 (1.6)
Irritability Associated with Autistic Disorder8 weeks duration. ABILIFY 209 55 (26.3)
Placebo 98 7 (7.1)
Tourette's Disorder8 to 10 weeks duration. ABILIFY 105 21 (20.0)
Placebo 66 5 (7.6)

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 ABILIFY. 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 [SD]), 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.

In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with ABILIFY. The mean change in weight z-score was 0.26 SDs for patients receiving >9 months of treatment.

When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.

5.7 Pathological Gambling and Other Compulsive Behaviors

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

5.8 Orthostatic Hypotension

ABILIFY may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=2,467) included (ABILIFY 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 ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 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%) [see Adverse Reactions (6.1)].

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 bpm when comparing standing to supine values) for ABILIFY was not meaningfully different from placebo (ABILIFY incidence, placebo incidence): in adult oral ABILIFY-treated patients (4%, 2%), in pediatric oral ABILIFY-treated patients aged 6 to 18 years (0.4%, 1%), or in ABILIFY injection-treated patients (3%, 2%).

ABILIFY 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) [see Drug Interactions (7.1)].

If parenteral benzodiazepine therapy is deemed necessary in addition to ABILIFY injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension [see Drug Interactions (7.1)].

5.9 Falls

Antipsychotics, including ABILIFY, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.10 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY. 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. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY 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 ABILIFY in patients with severe neutropenia (absolute neutrophil count <1,000/mm3) and follow their WBC counts until recovery.

5.11 Seizures/Convulsions

In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2,467) of undiagnosed adult patients treated with oral ABILIFY, in 0.1% (1/732) of pediatric patients (6 to 18 years), and in 0.2% (1/501) of adult ABILIFY injection-treated patients.

As with other antipsychotic drugs, ABILIFY 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.

5.12 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 (ABILIFY incidence, placebo incidence): in adult patients (n=2,467) treated with oral ABILIFY (11%, 6%), in pediatric patients ages 6 to 17 years (n=611; 24%, 6%), and in adult patients (n=501) on ABILIFY Injection (9%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) 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.

5.13 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 ABILIFY 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) [see Adverse Reactions (6.2)].

5.14 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 (6.1, 6.2)].

5.15 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. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions are discussed in more detail in other sections of the labeling:

The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

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

ABILIFY has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's disorder and who had approximately 1,342 patient-years of exposure to oral ABILIFY. A total of 959 pediatric patients were treated with oral ABILIFY for at least 180 days and 556 pediatric patients treated with oral ABILIFY had at least one year of exposure.

The conditions and duration of treatment with ABILIFY (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure.

Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were (6.1):

  • Adult patients with schizophrenia: akathisia
  • Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor
  • Adult patients (monotherapy) with bipolar mania: akathisia, sedation, restlessness, tremor, and extrapyramidal disorder
  • Adult patients (adjunctive therapy with lithium or valproate) with bipolar mania: akathisia, insomnia, and extrapyramidal disorder
  • Pediatric patients (10 to 17 years) with bipolar mania: somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness
  • Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision
  • Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy
  • Pediatric patients (6 to 18 years) with Tourette's disorder: sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, increased appetite
  • Adult patients with agitation associated with schizophrenia or bipolar mania: nausea

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Adult Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4 week and one 6 week) in which oral ABILIFY was administered in doses ranging from 2 to 30 mg/day.

Commonly Observed Adverse Reactions

The only commonly observed adverse reaction associated with the use of ABILIFY in patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) was akathisia (ABILIFY 8%; placebo 4%).

Adult Patients with Bipolar Mania

Monotherapy

The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral ABILIFY was administered at doses of 15 or 30 mg/day.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of ABILIFY in patients with bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 16.

Table 16: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with Oral ABILIFY Monotherapy
Preferred Term Percentage of Patients Reporting Reaction
ABILIFY
(n=917)
Placebo
(n=753)
Akathisia 13 4
Sedation 8 3
Restlessness 6 3
Tremor 6 3
Extrapyramidal Disorder 5 2

Less Common Adverse Reactions in Adults

Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with ABILIFY (doses ≥2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo in the combined dataset.

Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral ABILIFY
Percentage of Patients Reporting ReactionAdverse reactions reported by at least 2% of patients treated with oral ABILIFY, except adverse reactions which had an incidence equal to or less than placebo.
System Organ Class
Preferred Term
ABILIFY
(n=1,843)
Placebo
(n=1,166)
Eye Disorders
  Blurred Vision 3 1
Gastrointestinal Disorders
  Nausea 15 11
  Constipation 11 7
  Vomiting 11 6
  Dyspepsia 9 7
  Dry Mouth 5 4
  Toothache 4 3
  Abdominal Discomfort 3 2
  Stomach Discomfort 3 2
General Disorders and Administration Site Conditions
  Fatigue 6 4
  Pain 3 2
Musculoskeletal and Connective Tissue Disorders
  Musculoskeletal Stiffness 4 3
  Pain in Extremity 4 2
  Myalgia 2 1
  Muscle Spasms 2 1
Nervous System Disorders
  Headache 27 23
  Dizziness 10 7
  Akathisia 10 4
  Sedation 7 4
  Extrapyramidal Disorder 5 3
  Tremor 5 3
  Somnolence 5 3
Psychiatric Disorders
  Agitation 19 17
  Insomnia 18 13
  Anxiety 17 13
  Restlessness 5 3
Respiratory, Thoracic, and Mediastinal Disorders
  Pharyngolaryngeal Pain 3 2
  Cough 3 2

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adult Patients with Adjunctive Therapy with Bipolar Mania

The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which ABILIFY was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive ABILIFY compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive ABILIFY-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with adjunctive ABILIFY and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.

Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania

Table 18 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive ABILIFY (doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder
Percentage of Patients Reporting ReactionAdverse reactions reported by at least 2% of patients treated with oral ABILIFY, except adverse reactions which had an incidence equal to or less than placebo.
System Organ Class
Preferred Term
ABILIFY +
Li or ValLithium or Valproate
(n=253)
Placebo +
Li or Val

(n=130)
Gastrointestinal Disorders
  Nausea 8 5
  Vomiting 4 0
  Salivary Hypersecretion 4 2
  Dry Mouth 2 1
Infections and Infestations
  Nasopharyngitis 3 2
Investigations
  Weight Increased 2 1
Nervous System Disorders
  Akathisia 19 5
  Tremor 9 6
  Extrapyramidal Disorder 5 1
  Dizziness 4 1
  Sedation 4 2
Psychiatric Disorders
  Insomnia 8 4
  Anxiety 4 1
  Restlessness 2 1

Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral ABILIFY was administered in doses ranging from 2 to 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of ABILIFY in adolescent patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Pediatric Patients (10 to 17 years) with Bipolar Mania

The following findings are based on one 4-week, placebo-controlled trial in which oral ABILIFY was administered in doses of 10 or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 19.

Table 19: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with Oral ABILIFY
Percentage of Patients Reporting Reaction
Preferred Term ABILIFY
(n=197)
Placebo
(n=97)
Somnolence 23 3
Extrapyramidal Disorder 20 3
Fatigue 11 4
Nausea 11 4
Akathisia 10 2
Blurred Vision 8 0
Salivary Hypersecretion 6 0
Dizziness 5 1

Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8 week, placebo-controlled trials in which oral ABILIFY was administered in doses of 2 to 15 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with autistic disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 20.

Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral ABILIFY
Percentage of Patients Reporting Reaction
Preferred Term ABILIFY
(n=212)
Placebo
(n=101)
Sedation 21 4
Fatigue 17 2
Vomiting 14 7
Somnolence 10 4
Tremor 10 0
Pyrexia 9 1
Drooling 9 0
Decreased Appetite 7 2
Salivary Hypersecretion 6 1
Extrapyramidal Disorder 6 0
Lethargy 5 0

Pediatric Patients (6 to 18 years) with Tourette's Disorder

The following findings are based on one 8 week and one 10 week, placebo-controlled trials in which oral ABILIFY was administered in doses of 2 to 20 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with Tourette's disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 21.

Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral ABILIFY
Percentage of Patients Reporting Reaction
Preferred Term ABILIFY
(n=121)
Placebo
(n=72)
Sedation 13 6
Somnolence 13 1
Nausea 11 4
Headache 10 3
Nasopharyngitis 9 0
Fatigue 8 0
Increased Appetite 7 1

Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Bipolar Mania, Autistic Disorder, or Tourette's Disorder

Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette's disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with ABILIFY (doses ≥2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo.

Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral ABILIFY
Percentage of Patients Reporting ReactionAdverse reactions reported by at least 2% of pediatric patients treated with oral ABILIFY, except adverse reactions which had an incidence equal to or less than placebo.
System Organ Class
Preferred Term
ABILIFY
(n=732)
Placebo
(n=370)
Eye Disorders
  Blurred Vision 3 0
Gastrointestinal Disorders
  Abdominal Discomfort 2 1
  Vomiting 8 7
  Nausea 8 4
  Diarrhea 4 3
  Salivary Hypersecretion 4 1
  Abdominal Pain Upper 3 2
  Constipation 2 2
General Disorders and Administration Site Conditions
  Fatigue 10 2
  Pyrexia 4 1
  Irritability 2 1
  Asthenia 2 1
Infections and Infestations
  Nasopharyngitis 6 3
Investigations
  Weight Increased 3 1
Metabolism and Nutrition Disorders
  Increased Appetite 7 3
  Decreased Appetite 5 4
Musculoskeletal and Connective Tissue Disorders
  Musculoskeletal Stiffness 2 1
  Muscle Rigidity 2 1
Nervous System Disorders
  Somnolence 16 4
  Headache 12 10
  Sedation 9 2
  Tremor 9 1
  Extrapyramidal Disorder 6 1
  Akathisia 6 4
  Drooling 3 0
  Lethargy 3 0
  Dizziness 3 2
  Dystonia 2 1
Respiratory, Thoracic, and Mediastinal Disorders
  Epistaxis 2 1
Skin and Subcutaneous Tissue Disorders
  Rash 2 1

Adult Patients Receiving ABILIFY as Adjunctive Treatment of Major Depressive Disorder

The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which ABILIFY was administered at doses of 2 to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions was 6% for adjunctive ABILIFY-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive ABILIFY in patients with major depressive disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.

Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder

Table 23 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive ABILIFY (doses ≥2 mg/day) and for which the incidence in patients treated with adjunctive ABILIFY was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder
Percentage of Patients Reporting ReactionAdverse reactions reported by at least 2% of patients treated with adjunctive ABILIFY, except adverse reactions which had an incidence equal to or less than placebo.
System Organ Class
Preferred Term
ABILIFY + ADTAntidepressant Therapy
(n=371)
Placebo + ADT

(n=366)
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 ABILIFY injection was administered at doses of 5.25 to 15 mg.

Commonly Observed Adverse Reactions

There was one commonly observed adverse reaction (nausea) associated with the use of ABILIFY injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo).

Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania

Table 24 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 ABILIFY injection (doses ≥5.25 mg/day) and for which the incidence in patients treated with ABILIFY injection was greater than the incidence in patients treated with placebo in the combined dataset.

Table 24: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with ABILIFY Injection
Percentage of Patients Reporting ReactionAdverse reactions reported by at least 2% of patients treated with ABILIFY injection, except adverse reactions which had an incidence equal to or less than placebo.
System Organ Class
Preferred Term
ABILIFY
(n=501)
Placebo
(n=220)
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, 5, 10, 15, 20, and 30 mg/day) of oral ABILIFY to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [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%).

Bipolar Mania

In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).

Autistic Disorder

In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

Tourette's Disorder

In a study of pediatric patients (7 to 17 years of age) with Tourette's disorder, no common adverse reaction(s) had a dose response relationship.

Extrapyramidal Symptoms

Schizophrenia

In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for ABILIFY-treated patients was 8% vs. 4% for placebo. 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 ABILIFY-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for ABILIFY-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 ABILIFY and placebo, with the exception of the Barnes Akathisia Scale (ABILIFY, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between ABILIFY and placebo, with the exception of the Simpson Angus Rating Scale (ABILIFY, 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 ABILIFY and placebo.

Bipolar Mania

In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy ABILIFY-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy ABILIFY-treated patients was 13% vs. 4% for placebo. In the 6 week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive ABILIFY-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive ABILIFY-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 10% vs. 2% for placebo.

In the adult bipolar mania trials with monotherapy ABILIFY, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between ABILIFY and placebo (ABILIFY, 0.50; placebo, –0.01 and ABILIFY, 0.21; placebo, –0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the ABILIFY and placebo groups. In the bipolar mania trials with ABILIFY as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive ABILIFY and adjunctive placebo (ABILIFY, 0.73; placebo, 0.07 and ABILIFY, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive ABILIFY 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 ABILIFY and placebo (ABILIFY, 0.90; placebo, −0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the ABILIFY and placebo groups.

Major Depressive Disorder

In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive ABILIFY-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive ABILIFY-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.

In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive ABILIFY and adjunctive placebo (ABILIFY, 0.31; placebo, 0.03 and ABILIFY, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive ABILIFY and adjunctive placebo groups.

Autistic Disorder

In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 3% vs. 9% for placebo.

In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between ABILIFY and placebo (ABILIFY, 0.1; placebo, –0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the ABILIFY and placebo groups.

Tourette's Disorder

In the short-term, placebo-controlled trials in Tourette's disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 4% vs. 6% for placebo.

In the pediatric (6 to 18 years) short-term Tourette's disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for ABILIFY and placebo.

Agitation Associated with Schizophrenia or Bipolar Mania

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 ABILIFY-treated patients was 2% vs. 2% for placebo and the incidence of akathisia-related events for ABILIFY-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 ABILIFY and placebo.

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Additional Findings Observed in Clinical Trials

Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials

The adverse reactions reported in a 26 week, double-blind trial comparing oral ABILIFY and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [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 weeks), active-controlled study, the incidence of tremor was 5% (40/859) for ABILIFY. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder.

Other Adverse Reactions Observed During Clinical Trial Evaluation of ABILIFY

The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients:

Adults - Oral Administration

  • Blood and Lymphatic System Disorders: rare – thrombocytopenia
  • Cardiac Disorders: infrequent – bradycardia, palpitations, rare – atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure
  • Eye Disorders: infrequent – photophobia; rare – diplopia
  • Gastrointestinal Disorders: infrequent – gastroesophageal reflux disease
  • General Disorders and Administration Site Conditions: frequent – asthenia; infrequent – peripheral edema, chest pain; rare – face edema
  • Hepatobiliary Disorders: rare – hepatitis, jaundice
  • Immune System Disorders: rare – hypersensitivity
  • Injury, Poisoning, and Procedural Complications: infrequent – fall; rare – heat stroke
  • Investigations: frequent – blood prolactin decreased, weight decreased, infrequent – hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare –blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased
  • Metabolism and Nutrition Disorders: frequent – anorexia; rare – hypokalemia, hyponatremia, hypoglycemia
  • Musculoskeletal and Connective Tissue Disorders: infrequent – muscular weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased
  • Nervous System Disorders: infrequent – parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare – akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients – choreoathetosis
  • Psychiatric Disorders: infrequent – aggression, loss of libido, delirium; rare – libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking
  • Renal and Urinary Disorders: rare – urinary retention, nocturia
  • Reproductive System and Breast Disorders: infrequent – erectile dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism
  • Respiratory, Thoracic, and Mediastinal Disorders: infrequent – nasal congestion, dyspnea
  • Skin and Subcutaneous Tissue Disorders: infrequent – rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare – urticaria
  • Vascular Disorders: infrequent – hypotension, hypertension

Pediatric Patients - Oral Administration

Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.

  • Eye Disorders: infrequent – oculogyric crisis
  • Gastrointestinal Disorders: infrequent – tongue dry, tongue spasm
  • Investigations: frequent – blood insulin increased
  • Nervous System Disorders: infrequent – sleep talking
  • Renal and Urinary Disorders frequent – enuresis
  • Skin and Subcutaneous Tissue Disorders: infrequent – hirsutism

Adults - Intramuscular Injection

Most adverse reactions observed in the pooled database of 749 adult patients treated with ABILIFY injection, were also observed in the adult population treated with oral ABILIFY. Additional adverse reactions observed in the ABILIFY injection population are listed below.

General Disorders and Administration Site Conditions:

≥1/100 patients - injection site reaction; ≥1/1,000 patients and <1/100 patients - venipuncture site bruise

6.2 Postmarketing Experience

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

7 DRUG INTERACTIONS

Dosage adjustment due to drug interactions (7.1):

Factors Dosage Adjustments for ABILIFY
Known CYP2D6 Poor Metabolizers Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose
Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks

7.1 Drugs Having Clinically Important Interactions with ABILIFY

Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see Clinical Pharmacology (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see Dosage and Administration (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see Clinical Pharmacology (12.3)]. With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see Dosage and Administration (2.7)].
Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.8)].
Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions (5.8)]. Monitor sedation and blood pressure. Adjust dose accordingly.

7.2 Drugs Having No Clinically Important Interactions with ABILIFY

Based on pharmacokinetic studies, no dosage adjustment of ABILIFY is required when administered concomitantly with famotidine, valproate, lithium, lorazepam.

In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with ABILIFY. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with ABILIFY [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1)

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ABILIFY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy (see Clinical Considerations).

In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.

In pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the MRHD of 30 mg/day based on mg/m2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the MRHD of 30 mg/day based on mg/m2 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the MRHD; this dose also caused maternal toxicity.

In pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the MRHD of 30 mg/day based on mg/m2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the MRHD. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD.

In pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the MRHD; this dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD.

In rats treated orally with aripiprazole peri- and postnatally from gestation Day 17 through postpartum Day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the MRHD of 30 mg/day based on mg/m2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the MRHD. An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

In rats injected intravenously with aripiprazole from gestation Day 6 through lactation Day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area, increased stillbirths were observed at 3 and 6 times the MRHD; and decreases in early postnatal pup weight and survival were observed at 6 times the MRHD; these doses also caused some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

8.2 Lactation

Risk Summary

Limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage. There are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole.

The development and health benefits of breastfeeding should be considered along with the mother's clinical need for ABILIFY and any potential adverse effects on the breastfed infant from ABILIFY or from the underlying maternal condition.

8.4 Pediatric Use

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

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12.3)].

Schizophrenia

Safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see Dosage and Administration (2.1), Adverse Reactions (6.1) , and Clinical Studies (14.1)]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

Bipolar I Disorder

Safety and effectiveness in pediatric patients with bipolar mania were established in a 4 week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see Dosage and Administration (2.2), Adverse Reactions (6.1) , and Clinical Studies (14.2)]. 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.

Irritability Associated with Autistic Disorder

Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see Indications and Usage (1), Dosage and Administration (2.4), Adverse Reactions (6.1) , and Clinical Studies (14.4)]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as >25% improvement on the ABC-I subscale, and a CGI-I rating of "much improved" or "very much improved") on 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.

Tourette's Disorder

Safety and effectiveness of aripiprazole in pediatric patients with Tourette's Disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [see Dosage and Administration (2.5), Adverse Reactions (6.1), and Clinical Studies (14.5)]. Maintenance efficacy in pediatric patients has not been systematically evaluated.

Juvenile Animal Studies

Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.

Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2 month recovery period.

8.5 Geriatric Use

No dosage adjustment is recommended for elderly patients [see Boxed Warning, Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Of the 13,543 patients treated with oral ABILIFY in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral ABILIFY in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Of the 749 patients treated with ABILIFY injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. Placebo-controlled studies of ABILIFY injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

ABILIFY is not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see Boxed Warning and Warnings and Precautions (5.1)].

8.6 CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8.7 Hepatic and Renal Impairment

No dosage adjustment for ABILIFY is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

8.8 Other Specific Populations

No dosage adjustment for ABILIFY is required on the basis of a patient's sex, race, or smoking status [see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

ABILIFY is not a controlled substance.

9.2 Abuse

ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

9.3 Dependence

In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.

10 OVERDOSAGE

MedDRA terminology has been used to classify the adverse reactions.

10.1 Human Experience

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

10.2 Management of Overdosage

No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.

Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and Cmax of aripiprazole by 50%.

Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

11 DESCRIPTION

Aripiprazole is an atypical antipsychotic drug that is available as ABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets, ABILIFY® (aripiprazole) Oral Solution, and ABILIFY® (aripiprazole) Injection, a solution for intramuscular injection. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 and its molecular weight is 448.38. The chemical structure is:

Chemical Structure

ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

ABILIFY DISCMELT Orally Disintegrating Tablets are available in 10 mg and 15 mg strengths. Inactive ingredients include acesulfame potassium, aspartame, calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla (natural and artifici