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SCHIZOPHRENIA CLINICAL DATA

ABILIFY MAINTENA® (aripiprazole): proven efficacy and demonstrated safety for adult patients living with schizophrenia
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12-week short-term study
52-week maintenance study

12-WEEK SHORT-TERM STUDY

Study design

12-week, randomized, double-blind, placebo-controlled study evaluated acutely relapsed* adult patients with schizophrenia were randomized to either ABILIFY MAINTENA (n=168) or intramuscular placebo (n=172). After initial injection, patients received 14 days of oral aripiprazole or oral placebo based on treatment arm. Safety was assessed throughout the duration of the study.1

*Baseline characteristics: PANSS Total Score ≥80 and a PANSS score >4 on each of 4 specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, and unusual thought content). Patients were required to remain as inpatients for at least the first 2 weeks of treatment, after which hospitalization status was determined on the basis of the investigator’s judgment of the patient’s clinical status. Those discharged were followed with clinic visits and phone calls.1

PANSS=Positive and Negative Syndrome Scale.

Study design

A 12-week, randomized, double-blind, placebo-controlled study in which acutely relapsed adult patients with schizophrenia were randomized to either ABILIFY MAINTENA (n=168) or intramuscular placebo (n=172). After initial injection, patients received 14 days of oral aripiprazole or oral placebo based on treatment arm.1

  • Primary endpoint was mean change in PANSS Total Score from baseline to Week 101
  • Safety was assessed throughout the duration of the study1

12-week study evaluated mean change in PANSS Total Score in acutely relapsed adult patients with schizophrenia1†

†Baseline characteristics: PANSS Total Score >80 and PANSS score >4 on each of 4 specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, and unusual thought content). Patients were required to remain as inpatients for at least the first 2 weeks of treatment, after which hospitalization status was determined on the basis of the investigator’s judgment of the patient’s clinical status. Those discharged were followed with clinic visits and phone calls.1

Screening phase

Patients without prior exposure received oral aripiprazole to establish tolerability1

  • Patients had a mean PANSS Total Score of 103 (range 82 to 144) and a CGI-S score of 5.2 (markedly ill) at baseline

93.5% of patients were treated with an antipsychotic other than aripiprazole or no antipsychotic prior to study entry.2

Patients were receiving a range of medications prior to study enrollment2‡
Risperidone 21.5%
Quetiapine 15.3%
Olanzapine  8.2%
Aripiprazole  6.5%
Another antipsychotic   22%
No antipsychotic26.5%

‡Percentages provided were patient-reported estimations. All patients underwent a 7-day washout period at trial entry.
CGI-S=Clinical Global Impression-Severity.

Statistically significant improvement in PANSS Total Score vs placebo as early as Week 1 and through Week 121

Primary endpoint: Mean change in PANSS Total Score from baseline to Week 101

Weeks from randomization -35 -30 -25 -5 -20 0 -10 -15 Least squares mean reduction from baseline in PANSS Total Score ABILIFY MAINTENA Placebo -11.7 -12.6 -5.0 -8.9 -26.8 Week 10 (P <0.0001) Week 1 (P <0.001) EARLY AND CONTINUED SYMPTOM REDUCTION FROM WEEK 1 TO WEEK 123 Concomitant treatment with oral aripiprazole or placebo for 14 days after first injection4 0 2 1 12 10 4 6 8 -27.2 Week 12 (P <0.0001) 162 162 144 99 99 134 126 108 167 167 157 81 68 140 117 96 Number of patients
Number of patients 0 2 1 -35 -30 -25 -5 -20 0 -10 -15 4 6 8 162 162 144 134 126 108 167 167 157 140 117 96 Least squares mean reduction from baseline in PANSS Total Score ABILIFY MAINTENA Placebo -11.7 -5.0 -8.9 Week 1 (P <0.001) EARLY AND CONTINUED SYMPTOM REDUCTION FROM WEEK 1 TO WEEK 123 Concomitant treatment with oral aripiprazole or placebo for 14 days after first injection4 Weeks from randomization 12 10 99 99 81 68 -12.6 -26.8 Week 10 (P <0.0001) -27.2 Week 12 (P <0.0001)
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Important Warning and Precaution Regarding 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.

52-WEEK MAINTENANCE STUDY

Study design

52-week, multiphase maintenance study evaluated the time to relapse for adult patients with schizophrenia diagnosed ≥3 years with a history of symptom exacerbation or relapse when not receiving antipsychotic treatment.§ Phases consisted of an open-label phase 1 (conversion to oral aripiprazole), an open-label phase 2 (stabilization on oral aripiprazole 10 mg to 30 mg once daily), a single-blind phase 3 (conversion and stabilization on ABILIFY MAINTENA 400 mg; patients continued on oral aripiprazole 10 mg to 20 mg for the first 14 days following the initial ABILIFY MAINTENA dose), and a double-blind, placebo-controlled, randomized phase 4 in which patients received either ABILIFY MAINTENA (n=269) or placebo IM depot (n=134).3

§DSM-IV-TR criteria.
DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; IM=intramuscular.

The placebo-controlled, 52-week maintenance study evaluated the time to relapse for adult patients with schizophrenia3

Study design

A multiphase study that included open-label stabilization on oral aripiprazole, single-blind stabilization on ABILIFY MAINTENA (along with oral aripiprazole for the first 14 days), and a 52-week, randomized, double-blind, placebo-controlled study in which adult patients with schizophrenia were randomized to either ABILIFY MAINTENA (n=269) or intramuscular placebo (n=134).3

  • The study enrolled patients with schizophrenia diagnosed ≥3 years and a history of symptom exacerbation or relapse when not receiving antipsychotic treatment3II
    • In the open-label phase 1 (4-6 weeks): Patients were converted to oral aripiprazole (n=633)
    • In the open-label phase 2 (4-12 weeks): Patients were stabilized on oral aripiprazole 10 mg to 30 mg once daily (n=710)
    • In the single-blind phase 3 (12-36 weeks): Patients continued on oral aripiprazole 10 mg to 20 mg for the first 14 days following the initial ABILIFY MAINTENA 400 mg dose (n=576)
    • In the double-blind, placebo-controlled, randomized phase 4 (up to 52 weeks): Patients were randomized at baseline to either ABILIFY MAINTENA (n=269) or placebo (n=134)

Primary endpoint: Time from randomization to relapse3

Relapse was defined as one or more of the following3:

  • Clinical worsening
    • CGI-Improvement score ≥5 and an increase on any of 4 specific PANSS items to a score ≥4: with an absolute increase of ≥2 on that specific item since randomization or with an absolute increase of ≥4 on the combined score of these items since randomization
  • Psychiatric hospitalization
    • Due to worsening of psychotic symptoms
  • Risk of suicide
    • CGI-SS score of 4 (severely suicidal) or 5 (attempted suicide) on part 1 or CGI-SS score of 6 (much worse) or 7 (very much worse) on part 2
  • Violent behavior
    • Clinically significant self-injury, injury to another person, or property damage

IIDSM-IV-TR criteria.

PANSS items were conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content.3

CGI=Clinical Global Impression; CGI-SS=Clinical Global Impression of Severity of Suicidality.

ABILIFY MAINTENA significantly delayed time to relapse# vs placebo (HR=0.199 [95% CI, 0.1-0.3], P<0.0001)3,4**

Primary endpoint: Time from randomization to relapse3

Weeks from randomization0.00.20.40.60.8ABILIFY MAINTENA (n=269)Placebo (n=134)084524844403624283212162026913424411820185762763225414441236930523318668153531304510437Proportion of patients with relapse80%REDUCED RISKOF RELAPSEvs placeboNumber of patients at risk
0.00481216202428323640444852269244201186153130104766354443630231341188568534537272214129530.40.20.60.8Proportion of patients with relapseWeeks from randomizationNumber of patients at riskABILIFY MAINTENA (n=269)Placebo (n=134)80%REDUCED RISK OF RELAPSE vs placebo

#Relapse was defined as one or more of the following: clinical worsening, psychiatric hospitalization, risk of suicide, or violent behavior.3

**This figure is based on a total of 80 relapse events.3

CI=confidence interval; HR=hazard ratio.

The hazard ratio was used to calculate the reduction in risk of relapse for patients on ABILIFY MAINTENA vs placebo.

Key secondary endpoint:
Percent of patients meeting relapse criteria3††

The percent of patients who relapsed was 4x higher on placebo than ABILIFY MAINTENA (HR=5.03 [95% CI, 3.15-8.02]).

RELAPSED WITHABILIFY MAINTENARELAPSED WITHPLACEBO10%40%
RELAPSED WITHABILIFY MAINTENARELAPSED WITHPLACEBO10%40%

 

††Relapse was defined as one or more of the following: clinical worsening, psychiatric hospitalization, risk of suicide, or violent behavior.3

 

Important Warning and Precaution Regarding 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.

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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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References: 1. 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. 2. Data on file. ABIMAI-122. 3. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73(5):617-624. 4. Data on file. ABIMAI-027.

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.