PRELAPSE STUDY: 
NON-PIVOTAL INVESTIGATOR-INITIATED STUDY

The PRELAPSE study analyzed the time to first psychiatric hospitalization with ABILIFY MAINTENA vs clinician’s choice over 2 years
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PRELAPSE Safety
Study Design
Primary endpoint
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This study was an investigator-initiated project funded by Lundbeck and Otsuka America Pharmaceutical, Inc. The funders participated in the design of the study but had no influence on the conduct of the trial and were not involved in data collection or analysis, in the writing of the manuscript, or in the decision to submit it for publication.

The Prevention of Relapse in Schizophrenia (PRELAPSE) study was an investigator-initiated, multicenter, cluster-randomized clinical trial that randomized 41 sites in the US to receive either ABILIFY MAINTENA or clinician’s choice

Study site randomization

Study site randomization, Chart

*LAIs included ABILIFY MAINTENA (15.4%) or another LAI (15.4%) at time of consent.

†1 site was withdrawn from each arm due to 0 recruited patients for a total of 39 sites analyzed.

‡LAIs included ABILIFY MAINTENA (3.9%) and another LAI (23.5%) at the time of consent.

LAI=long-acting injectable.

Study design

Inclusion criteria
Schizophrenia diagnosis confirmed by the Structured Clinical Interview for DSM-5, Research Version (SCID-5)
<5 years of lifetime antipsychotic use
Age of 18 to 35 years
Ability to provide informed consent
Exclusion criteria
Primary DSM-5 diagnosis other than schizophrenia
Pregnant or lactating women
Unstable medical condition
Prior clozapine use
ABILIFY MAINTENA sites only: History of intolerance to aripiprazole

DSM-5=Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

Study limitations

  • Only 1 study medication (ABILIFY MAINTENA)
  • Clinicians at ABILIFY MAINTENA sites offered ABILIFY MAINTENA without charge to patients in addition to other available services
  • Clinician’s choice sites allowed the use of LAIs, and sites were required to have clinical support; therefore, clinician’s choice sites had higher use of LAIs at baseline and during the study than US statistics would suggest
  • 51% of patients (n=130) at clinician’s choice sites received an LAI at some point during the study

Primary endpoint: Time to first psychiatric hospitalization with ABILIFY MAINTENA vs clinician’s choice over 2 years

Risk of first hospitalization was significantly reduced for patients taking ABILIFY MAINTENA in a 2-year study of adults with early-phase schizophrenia

Number of patients at riskSurvival probabilityABILIFY MAINTENA (n=234)Clinician’s choice (n=255)00.20.40.61.00.8Days from randomizationREDUCED RISK OF HOSPITALIZATION(HR=0.56 [95% CI, 0.34-0.92])§44%234183157147127255186148116930180360540720
0180360540Survival probability ABILIFY MAINTENA (n=234) Clinician’s choice (n=255)Days from randomization44%REDUCED RISK OF FIRST HOSPITALIZATION(HR=0.56 [95% CI, 0.34-0.92])§23418315714725518614811672012793Number of patients at risk00.20.40.61.00.8

Adapted from Kane JM, et al. JAMA Psychiatry. 2020;77(12):1217-1224.

§22.2% of ABILIFY MAINTENA patients met criteria for first hospitalization vs 36.0% of clinician’s choice patients.
CI=confidence interval; HR=hazard ratio.

The hazard ratio was used to calculate the reduction in risk of first psychiatric hospitalization for patients on ABILIFY MAINTENA vs clinician’s choice.

Clinician’s choice

  • Clinician’s choice was defined as treatment as usual, such as medication, including possible oral or LAI antipsychotics, and other available services

Important Warning and Precaution Regarding 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.

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Important Warning and Precaution Regarding 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.

Safety information from the PRELAPSE Study

PRELAPSE Study: Adverse events reported after baseline assessment in ≥5% of patients

Percentages of patients reporting reaction
Adverse eventABILIFY MAINTENA
(n=222)		Clinician’s choiceII
(n=241)
Worsening of psychotic symptoms23.040.2
Weight gain14.419.5
Suicidal ideation without suicide attempt8.69.5
Depression10.48.3
Anxiety12.26.2
Hyperprolactinemia4.112.9
Elevated cholesterol levels6.810.0
Hepatic enzyme abnormalities6.89.1
Insomnia8.67.1
Hypertension5.47.5
Somnolence7.24.6
Hostility/aggression7.22.9
Tachycardia3.25.0
Restlessness6.30.8
0.86.37.54.62.95.05.47.27.23.27.18.69.16.810.06.812.94.16.212.28.310.49.58.619.514.440.223.0Percentages of patients reporting reactionABILIFY MAINTENA (n=222)Clinician’s choiceII(n=241)Adverse eventWorsening of psychotic symptomsWeight gainSuicidal ideation without suicide attemptHepatic enzyme abnormalitiesDepressionInsomniaAnxietyHypertensionHyperprolac-tinemiaSomnolenceTachycardiaElevated cholesterol levelsHostility/aggressionRestlessness

Clinician’s choice was defined as treatment as usual, such as medication, including possible oral or LAI antipsychotics, and other available services.

Does not include the 1 patient in the clinician’s choice group who died by suicide. Patients who made suicide attempts concurrent with recorded suicidal ideation are not included; patients who made suicide attempts but also had suicidal ideation not concurrent with an attempt are included.

PRELAPSE=Prevention of Relapse in Schizophrenia.

Important Warning and Precaution Regarding 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.

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ABILIFY MAINTENA has been evaluated for safety in 2128 adult patients with schizophrenia and 804 adult patients with bipolar I disorder.

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Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

Reference: 1. Kane JM, Schooler NR, Marcy P, et al. Effect of long-acting injectable antipsychotics vs usual care on time to first hospitalization in early-phase schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2020;77(12):1217-1224.

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.