CLINICAL SAFETY PROFILE

ABILIFY MAINTENA® (aripiprazole) has been evaluated for safety in more than 2000 adult patients living with schizophrenia

Adverse reactions in ≥2% of patients in a 12-week, double-blind, placebo-controlled study

Percentage of patients reporting reaction*
System Organ ClassPreferred TermAbilify Maintena (n=167)Placebo (n=172)
Gastrointestinal DisordersConstipation107
Dry mouth42
Diarrhea32
Vomiting31
Abdominal discomfort21
General disorders and administration site conditionsInjection site pain51
Infections and infestationsUpper respiratory tract infection42
InvestigationsIncreased weight177
Decreased weight42
Musculoskeletal and connective tissue disordersArthralgia41
Back pain42
Myalgia42
Musculoskeletal pain31
Nervous system disordersAkathisia114
Sedation51
Dizziness42
Tremor31
Respiratory, thoracic, and mediastinalNasal congestion21

1Nasal congestion24121AkathisiaSedationDizzinessTremor115431221ArthralgiaBack painMyalgiaMusculoskeletal pain44432Decreased weight47Increased weight172Upper respiratory tract infection41Injection site pain51Abdominal discomfort21Vomiting32Diarrhea32Dry mouth47Constipation10PREFERRED TERMABILIFY MAINTENA (n=167)PERCENTAGE OF PATIENTS REPORTING REACTION*GASTROINTESTINAL DISORDERSPLACEBO (n=172)GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONSINFECTIONS AND INFESTATIONSINVESTIGATIONSMUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERSRESPIRATORY, THORACIC, AND MEDIASTINALNERVOUS SYSTEM DISORDERS

*Table excludes adverse reactions that had an incidence ≤ placebo.

Adverse reactions with an incidence ≥5% of patients and at least twice that for placebo

7.0%16.8%INCREASED WEIGHT3.5%11.4%AKATHISIA0.6%5.4%INJECTION SITE PAIN1.2%5.4%SEDATIONABILIFY MAINTENAPlacebo
7.0%16.8%INCREASED WEIGHT3.5%11.4%AKATHISIA0.6%5.4%INJECTION SITE PAIN1.2%5.4%SEDATIONABILIFY MAINTENA (n=167) Placebo (n=172)

on ABILIFY MAINTENA or placebo discontinued due to these 4 adverse reactions1

0

patients

In a 12-week study, 4.2% of patients on ABILIFY MAINTENA discontinued due to all adverse reactions vs 7.6% with placebo2

The following safety information is derived from a 12-week, double-blind study in patients with schizophrenia.1

Prolactin and extrapyramidal symptoms (EPS) in schizophrenia1

 ABILIFY MAINTENA 400 mgPlacebo
PROLACTIN1,2Mean change from baseline to Week 12, ng/mL (SD) (P=0.0176)†-6.4 (13.5)-1.1 (14.5)
Potentially clinically revelant prolactin levels (>1x upper limit of normal)—any post-baseline visit, % (n/N)‡2.8% (4/142)11.4% (16/140)
ADVERSE REACTION1,2Incidence of EPS-related events, excluding akathisia, % (n/N)9.6% (16/167)5.2% (9/172)

-1.1 (14.5)Mean change from baseline to Week 12, ng/mL (SD) (P=0.0176)†-6.4(13.5)11.4% (16/140)Potentially clinically revelant prolactin levels (>1x upper limit of normal)—any post-baseline visit, % (n/N)‡2.8% (4/142)5.2% (9/172)Incidence of EPS-related events, excluding akathisia, % (n/N) 9.6% (16/167)PROLACTIN1,2ADVERSE REACTION1,2ABILIFY MAINTENA 400 mgPLACEBO

†ABILIFY MAINTENA, N=99; placebo, N=66.

‡Incidence for ABILIFY MAINTENA vs placebo in female subjects (6.3% vs 13.8%) and male subjects (1.8% vs 10.8%).1

n=number of patients with event; N=number of patients treated; SD=standard deviation.

Metabolic safety profile in schizophrenia

METABOLIC MEASURE1ABILIFY MAINTENA 400 mgPlacebo
Glucose% (n/N) of patients who shifted from normal to high (<100 mg/dL to ≥126 mg/dL)8.0% (7/88)0.0% (0/75)
TOTAL CHOLESTEROL% (n/N) of patients who shifted from normal to high (<200 mg/dL to ≥240 mg/dL)3.6% (3/83)2.7% (2/73)
LDL CHOLESTEROL% (n/N) of patients who shifted from normal to high (<200 mg/dL to ≥240 mg/dL)1.7% (1/59)2.0% (1/51)
HDL CHOLESTEROL% (n/N) of patients who shifted from normal to low (≥40 mg/dL to <40 mg/dL)13.5% (14/104)12.6% (11/87)
TRIGLYCERIDES% (n/N) of patients who shifted from normal to low (≥40 mg/dL to <40 mg/dL)7.1% (7/98)5.1% (4/78)
WEIGHT GAINMean change from baseline to Week 12, kg+3.5+0.8
Weight gain ≥7% of body weight, % (n/N)21.5% (31/144)8.5% (12/141)

0.0% (0/75)2.7% (2/73)2.0% (1/51)% (n/N) of patients who shifted from normal to high (<100 mg/dL to ≥126 mg/dL)% (n/N) of patients who shifted from normal to high (<200 mg/dL to ≥240 mg/dL) % (n/N) of patients who shifted from normal to high (<200 mg/dL to ≥240 mg/dL) % (n/N) of patients who shifted from normal to high (<200 mg/dL to ≥240 mg/dL) 8.0% (7/88)3.6% (3/83)1.7% (1/59)5.1% (4/78)5.1% (4/78)+0.88.5% (12/141)% (n/N) of patients who shifted from normal to low (≥40 mg/dL to <40 mg/dL)% (n/N) of patients who shifted from normal to low (≥40 mg/dL to <40 mg/dL)Mean change from baseline to Week 12, kgWeight gain ≥7% of body weight, % (n/N)7.1% (7/98)7.1% (7/98)+3.521.5% (31/144)ABILIFY MAINTENA400 mg METABOLIC MEASURE1PLACEBO GLUCOSETOTAL CHOLESTEROLLDL CHOLESTEROLHDL CHOLESTEROLTRIGLYCERIDESWEIGHT GAIN

HDL=high-density lipoprotein; LDL=low-density lipoprotein.

ABILIFY MAINTENA has been evaluated for safety in multiple studies in more than 800 adult patients living with bipolar I disorder

The following safety information was derived from a 52-week, open-label study in patients with bipolar I disorder initiated on ABILIFY MAINTENA.

Metabolic safety profile in bipolar I disorder

metabolic measure
GLUCOSE% of patients who experienced a shift from normal to high fasting glucose1.1%
% of patients who experienced a shift from borderline to high fasting glucose9.8%
% of patients who experienced shifts from normal to borderline to high fasting glucose2.9%
TOTAL CHOLESTEROL% of patients who experienced a shift from normal to high fasting cholesterol2.1%
LDL CHOLESTEROL% of patients who experienced a shift from normal to high fasting cholesterol2.2%
HDL CHOLESTEROL% of patients who experienced a shift from normal to low fasting cholesterol8.5%
TRIGLYCERIDES% of patients who experienced a shift from normal to high fasting triglycerides3.6%
% of patients who experienced a shift from normal to very high fasting triglycerides0.0%
% of patients who experienced a shift from normal or borderline to very high fasting triglycerides1.0%

% of patients who experienced a shift from normal to low fasting cholesterol% of patients who experienced a shift from normal to high fasting triglycerides% of patients who experienced a shift from normal to high fasting cholesterol% of patients who experienced a shift from normal to very high fasting triglycerides% of patients who experienced a shift from normal to high fasting cholesterol% of patients who experienced a shift from normal or borderline to very high fasting triglyceridesGLUCOSETOTAL CHOLESTEROLLDL CHOLESTEROLHDL CHOLESTEROLTRIGLYCERIDES1.1%9.8%8.5%2.9%3.6%2.1%0.0%2.2%1.0%METABOLIC MEASURE% of patients who experienced a shift from normal to high fasting glucose% of patients who experienced a shift from borderline to high fasting glucose% of patients who experienced shifts from normal to borderline to high fasting glucose

These safety data are from those patients who were initiated on ABILIFY MAINTENA during a 52-week, open-label study but did not participate in the 52-week, double-blind study.

  • In those patients who initiated ABILIFY MAINTENA, 1.8% discontinued ABILIFY MAINTENA treatment due to weight increase
  • ABILIFY MAINTENA was associated with mean increase in weight from baseline of 1.0 kg at Week 52
  • 21.4% of these patients demonstrated a ≥7% increase in body weight and 15.4% demonstrated a ≥7% decrease in body weight

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Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

References:  1. Data on file. ABIMAI-124. 2. Kane JM, Peters-Strickland T, Baker RA, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2014;75(11):1254-1260.

INDICATIONS and IMPORTANT SAFETY INFORMATION for ABILIFY MAINTENA® (aripiprazole)

INDICATIONS and IMPORTANT SAFETY INFORMATION for ABILIFY MAINTENA® (aripiprazole)

INDICATIONS

ABILIFY MAINTENA® (aripiprazole) is an atypical antipsychotic indicated for:

  • Treatment of schizophrenia in adults
  • Maintenance monotherapy treatment of bipolar I disorder in adults

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death (1.6 to 1.7 times) compared to placebo-treated patients. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis.

Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including ABILIFY MAINTENA. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of ABILIFY MAINTENA, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. Prescribing should be consistent with the need to minimize TD. If antipsychotic treatment is withdrawn, TD may remit, partially or completely.

Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes mellitus should be regularly monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes), should undergo baseline and periodic fasting blood glucose testing. 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 should also 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.
  • Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
  • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking aripiprazole. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping aripiprazole if such urges develop.

Orthostatic Hypotension: ABILIFY MAINTENA may cause orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Seizures: ABILIFY MAINTENA should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: ABILIFY MAINTENA may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, until they are certain ABILIFY MAINTENA does not affect them adversely.

Body Temperature Regulation: Use ABILIFY MAINTENA with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with ABILIFY MAINTENA. Use caution in patients at risk for aspiration pneumonia.

Alcohol: Advise patients to avoid alcohol while taking ABILIFY MAINTENA.

Concomitant Medication: Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. Avoid concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

Most Commonly Observed Adverse Reactions: The most commonly observed adverse reactions with ABILIFY MAINTENA in patients with schizophrenia (incidence ≥5% and at least twice that for placebo) were increased weight, akathisia, injection site pain, and sedation.

Injection Site Reactions: In a short-term, clinical trial with ABILIFY MAINTENA in patients with schizophrenia treated with gluteal administered ABILIFY MAINTENA, the percent of patients reporting any injection site-related adverse reaction was 5.4%, and 0.6% for placebo. In an open label study of ABILIFY MAINTENA administered in the deltoid or gluteal muscle, injection site pain was observed at approximately equal rates.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Neonates exposed to antipsychotic drugs, including ABILIFY MAINTENA, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Consider the benefits and risks of ABILIFY MAINTENA and possible risks to the fetus when prescribing ABILIFY MAINTENA to a pregnant woman. Advise pregnant women of potential fetal risk.

Lactation: Aripiprazole is present in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and any potential risks to the infant.

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

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.