STUDIES IN ADULT PATIENTS WITH SCHIZOPHRENIA

 

Pivotal 12-week Short-term Study

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

93.5% of patients were treated with an antipsychotic other than aripiprazole or no antipsychotic prior to study entry2

 

Percentages provided were patient-reported estimations. All patients underwent a 7-day washout period at trial entry.2

Patients without prior exposure received oral aripiprazole to establish tolerability1

  • In the short-term study of patients with schizophrenia, patients were given 10 mg of oral aripiprazole for 3 days for sensitivity purposes1
  • 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

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® (aripiprazole) (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 10
  • Safety was assessed throughout the duration of the study

CGI-S=Clinical Global Impression-Severity; PANSS=Positive and Negative Syndrome Scale.

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.

Pivotal 52-week Maintenance Study

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 treatment3‡
    • 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 relapse

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

DSM-IV-TR criteria.3

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

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.

Open-label Initiation Safety Study

4-week open-label clinical study evaluating the safety of initiating once-monthly ABILIFY MAINTENA in adult patients with schizophrenia4

Establish tolerability with oral aripiprazole before initiating therapy. For patients already stable on oral aripiprazole or another oral antipsychotic, after the first ABILIFY MAINTENA injection, continue treatment with the antipsychotic for 14 consecutive days.

Study Design

Open-label, 2-phase, multiple-site trial in adult patients with schizophrenia (n=60)4

  • Phase 1 screening (up to 30 days) included outpatients, aged 18 to 64 years with a DSM-IV-TR diagnosis of schizophrenia, a body mass index of 18 to 35 kg/m2
    • Patients had to have a history of aripiprazole tolerability
    • Patients had to be stabilized, as per the investigator’s judgment, for at least 14 days on risperidone, olanzapine, quetiapine, ziprasidone, or paliperidone
  • During the Phase 2 treatment period (up to 28 days), investigators were advised to reduce the oral antipsychotic dose following the administration of the ABILIFY MAINTENA injection
    • The suggested dose reduction was to be in the mid-to-lower range of recommended dosing, and the dose could be further adjusted at the investigator’s discretion
    • Patients received a single 400 mg dose of ABILIFY MAINTENA, which was coadministered with their current oral antipsychotic medication for a period of 14±1 days, at the investigator’s discretion
      • The duration of oral antipsychotic treatment during the study varied. Some patients discontinued their oral antipsychotic regimen earlier than the recommended 14±1 days, as per the investigator’s judgment
      • Benzodiazepine use was permitted to manage treatment-emergent adverse events (TEAEs), although not within 8 hours of rating scale assessments
      • A limited number of concomitant medications were permitted to manage specific TEAEs. There were no subjects enrolled on paliperidone

Primary endpoint: Assessment of safety during the 28-day treatment phase based on adverse events (AEs)4II

In this study, patients with a history of aripiprazole tolerability received a single injection of ABILIFY MAINTENA coadministered with their current therapy.

  • The 14-day overlap evaluated in this study with the patient’s current oral antipsychotic was considered sufficient when initiating ABILIFY MAINTENA
  • No unexpected AEs were observed in this open-label study
  • AEs were noted as similar, irrespective of the oral antipsychotic coadministered and the duration of overlap

IIAdverse events included treatment-emergent adverse events (TEAEs), clinical laboratory monitoring, extrapyramidal symptoms (EPS), and suicidality.

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

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. Potkin SG, Raoufinia A, Mallikaarjun S, et al. Safety and tolerability of once monthly aripiprazole treatment initiation in adults with schizophrenia stabilized on selected atypical oral antipsychotics other than aripiprazole. Curr Med Res Opin. 2013;29(10):1241-1251.

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RESOURCES

Susan's story

Hear from Kye and her daughter Susan, who is being treated for schizophrenia with ABILIFY MAINTENA® (aripiprazole). Individual results may vary.

Please see Full Prescribing Information, including BOXED WARNING.

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 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.

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

INDICATIONS

ABILIFY MAINTENA 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.