In a 32-week, open-label, multiple-dose, randomized, parallel-arm, pharmacokinetic bridging study
ABILIFY ASIMTUFII® (aripiprazole): TWO MONTHS of sustained therapeutic concentrations with ONE DOSE
The aripiprazole concentrations of ABILIFY ASIMTUFII were explored in a pharmacokinetic bridging study, which was a 32-week, open-label, multiple-dose, randomized, parallel-arm, multicenter study (N=266) in patients living with schizophrenia or bipolar I disorder.1
Primary objectives included1:
- To establish the similarity of aripiprazole plasma concentrations and exposure following ABILIFY ASIMTUFII and ABILIFY MAINTENA® (aripiprazole) administration
- To establish the safety and tolerability of multiple-dose administrations of ABILIFY ASIMTUFII
Mean plasma concentrations of ABILIFY ASIMTUFII following the fourth administration were compared to concentrations following the seventh and eighth administrations of ABILIFY MAINTENA in adult patients living with schizophrenia or bipolar I disorder.
Mean aripiprazole plasma concentrations assessed after the fourth dose of ABILIFY ASIMTUFII
vs the seventh and eighth doses of ABILIFY MAINTENA1
*Day 0 corresponds to the 24th week of the 32-week study.
ABILIFY ASIMTUFII 960 mg demonstrated comparable aripiprazole concentrations, and thus comparable efficacy, to ABILIFY MAINTENA 400 mg throughout the two-month dosing interval.1
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 aripiprazole. 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 aripiprazole, intensive symptomatic treatment, and monitoring.
Comparable efficacy over 32 weeks
Change from baseline in PANSS (schizophrenia) and YMRS (bipolar I disorder) total scores1
Schizophrenia1
Mean PANSS total scores were comparable
for ABILIFY ASIMTUFII and ABILIFY MAINTENA groups for the duration of the 32-week trial.
ABILIFY ASIMTUFII1:
Baseline (n=92): 62.0
Week 32 (n=89): 59.4
ABILIFY MAINTENA1:
Baseline (n=93): 61.8
Week 32 (n=85): 60.1
Bipolar I Disorder1
Mean YMRS total scores were comparable
for ABILIFY ASIMTUFII and ABILIFY MAINTENA groups for the duration of the 32-week trial.
ABILIFY ASIMTUFII1:
Baseline (n=40): 6.7
Week 32 (n=39): 4.8
ABILIFY MAINTENA1:
Baseline (n=41): 9.4
Week 32 (n=40): 4.7
PANSS=Positive and Negative Syndrome Scale; YMRS=Young Mania Rating Scale.
Patients treated with ABILIFY ASIMTUFII 960 mg remained clinically stable over the 32-week study period, comparable to those treated with ABILIFY MAINTENA 400 mg.1
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.
The safety profile of ABILIFY ASIMTUFII was comparable to that seen with ABILIFY MAINTENA.
The efficacy of ABILIFY ASIMTUFII® (aripiprazole) is based on the adequate and well-controlled studies of ABILIFY MAINTENA® (aripiprazole)
Schizophrenia efficacy data
12-week study design
Primary endpoint: Mean change in PANSS total score from baseline to Week 101
A 12-week, randomized, double-blind, placebo-controlled study in which acutely relapsed adult patients* living with schizophrenia were randomized to either ABILIFY MAINTENA or intramuscular placebo.1 Safety was assessed throughout the duration of the study.
*Baseline characteristics: PANSS total score ≥80 and PANSS score >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, and unusual thought content).1
PANSS=Positive and Negative Syndrome Scale.
ABILIFY MAINTENA showed a statistically significant reduction in PANSS total score vs placebo as early as Week 1 through Week 121
*Baseline characteristics: PANSS total score ≥80 and PANSS score >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, and unusual thought content).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
| 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 | 22.0% |
| No antipsychotic | 26.5% |
†Percentages provided were patient-reported estimations. All patients underwent a seven-day washout period at trial entry.
Screening phase
93.5% of patients were treated with an antipsychotic other than aripiprazole or no antipsychotic prior to study entry2
Patients without prior exposure received oral aripiprazole to establish tolerability.1
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.
CGI-S=Clinical Global Impressions-Severity of Illness.
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
In a 52-week, multiphase maintenance study of adult patients living 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
The hazard ratio was used to calculate the reduction in risk of relapse for patients on ABILIFY MAINTENA vs placebo.
‡DSM-IV-TR criteria.
§Relapse was defined as one or more of the following: clinical worsening, psychiatric hospitalization, risk of suicide, or violent behavior.
||This figure is based on a total of 80 relapse events.
CI=confidence interval; DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; HR=hazard ratio; IM=intramuscular.
ABILIFY MAINTENA (n=269) significantly delayed time to relapse§ vs placebo (n=134) in a 52-week study (HR=0.199 [95% CI, 0.1-0.3], P<0.0001)3,4||
Primary endpoint:
Time from randomization to relapse
‡DSM-IV-TR criteria.
§Relapse was defined as one or more of the following: clinical worsening, psychiatric hospitalization, risk of suicide, or violent behavior.
||This figure is based on a total of 80 relapse events.
CI=confidence interval; DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; HR=hazard ratio; IM=intramuscular.
The placebo-controlled, 52-week maintenance study evaluated the time
to relapse for adult patients with schizophrenia
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 treatment.3¶
PHASE 1
4-6 weeks
ORAL ARIPIPRAZOLE
PHASE 2
2-8 weeks
ORAL ARIPIPRAZOLE
15 mg to 30 mg
once daily
PHASE 3
12-36 weeks
ABILIFY MAINTENA® (aripiprazole)
400 mg
Patients continued on oral aripiprazole 10 mg to 20 mg for the first 14 days following the initial ABILIFY MAINTENA dose.
PLACEBO-CONTROLLED, RANDOMIZED
PHASE 4
Up to 52 weeks
Patients were randomized at baseline to receive either ABILIFY MAINTENA or placebo.
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 the 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
- CGI-Improvement score ≥5 and an increase on any of the 4 specific PANSS# items to a score >4:
- 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.
#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.
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 aripiprazole. 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 aripiprazole, intensive symptomatic treatment, and monitoring.
Bipolar I disorder efficacy data
52-week study design
In a 52-week multiphase maintenance study of adult patients living with bipolar I disorder with a history of ≥1 manic or mixed episode with manic symptoms that required hospitalization and/or treatment with either a mood stabilizer and/or antipsychotic (N=266).5
The placebo-controlled, 52-week maintenance study evaluated the time to recurrence for adult patients living with bipolar I disorder.5
Maintenance study of adult patients living with bipolar I disorder consisted of four phases.5
**Including those patients entering the trial on oral aripiprazole.
IM=intramuscular.
Recurrence was defined as one or more of the following5:
Clinical worsening
- YMRS total score ≥15
OR - MÅDRS total score ≥15
OR - CGI-BP-S overall score >4
OR - Serious AE of worsening BP-I
OR - Discontinuation due to lack of efficacy or due to an AE of worsening BP-I
OR - Clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, and/or increase greater than the allowed benzodiazepine doses for treatment of symptoms of an underlying mood disorder
Psychiatric hospitalization
- For any mood episode
Increased risk of suicide
- Score ≥4 on the MÅDRS item 10
OR - Answer of YES on question 4 or 5 on the C-SSRS
AE=adverse event; BP-I=bipolar I disorder; CGI-BP-S=Clinical Global
Impression-Bipolar Version-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; MÅDRS=Montgomery-Åsberg Depression Rating Scale; YMRS=Young Mania Rating Scale.
ABILIFY MAINTENA significantly delayed time to recurrence†† of any mood episode vs placebo over one year (HR=0.45 [95% CI, 0.30-0.68], P<0.0001)5‡‡
Significantly delayed time to recurrence for a manic episode (52 episodes; P<0.0001) and mixed episodes (11 episodes; P=0.06). No substantial difference in the time to a depressive episode (39 episodes; P=0.864).6
††Recurrence was defined as clinical worsening, psychiatric hospitalization, or increased risk of suicide.5
‡‡This figure is based on a total of 103 recurrences.
CI=confidence interval; HR=hazard ratio.
ABILIFY MAINTENA significantly delayed time to recurrence†† of any mood episode vs placebo over one year (HR=0.45 [95% CI, 0.30-0.68], P<0.0001)5‡‡
Primary endpoint: Time from randomization to recurrence††
of any mood episode5
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.
ABILIFY MAINTENA significantly reduced the risk of recurrence of manic or mixed mood episodes over one year vs placebo6
No substantial difference in the time to a depressive episode (HR=0.932 [95% CI, 0.497-1.747], P=0.8247)6
The HR was used to calculate the reduction in risk of recurrence for patients on ABILIFY MAINTENA vs placebo.
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.
The safety profile of ABILIFY ASIMTUFII was comparable to that seen with ABILIFY MAINTENA.
Non-pivotal analyses
ABILIFY MAINTENA® (aripiprazole) exposure response analysis
ABILIFY MAINTENA treatment in adult patients living with schizophrenia1*
The exposure-response analysis reported below was funded by Otsuka Pharmaceutical Development & Commercialization, Inc.
The exposure-response time to relapse analysis used data from two Phase 3 clinical studies and included 615 subjects living with schizophrenia. Of these subjects, 120 were administered oral aripiprazole only, and 495 subjects were administered ABILIFY MAINTENA gluteally. Patients receiving ABILIFY MAINTENA also received 14 days of oral aripiprazole at initiation. Exposure-response analysis of time to relapse included 85 impending relapse events (48 events for placebo and 37 events for ABILIFY MAINTENA) and 530 censored subjects (72 subjects for placebo and 458 subjects for ABILIFY MAINTENA).1
Median pharmacokinetic data were studied in ABILIFY MAINTENA and oral aripiprazole. Caution should be taken in the interpretation of these data.
Predicted minimum
aripiprazole concentration
*Adapted from Wang X, et al. Clinical Pharmacology in Drug Development. 2022;11(2):150-164.
†Subjects with Cmin ≥95 ng/mL are 4.41 times less likely to relapse vs subjects with a predicted Cmin <95 ng/mL with the use of ABILIFY MAINTENA.1
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. (cont'd)
32-week pharmacokinetic simulation
From initiation, ABILIFY ASIMTUFII showed similar aripiprazole concentrations to ABILIFY MAINTENA
Median simulated aripiprazole plasma concentrations were similar
to ABILIFY MAINTENA from initiation through 32 weeks2‡
IMPORTANT WARNING AND PRECAUTION REGARDING METABOLIC CHANGES (cont'd)
Atypical antipsychotic drugs have caused metabolic changes including:
- 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.
‡Based on a simulation population of N=1000.
The safety profile of ABILIFY ASIMTUFII was comparable to that seen with ABILIFY MAINTENA.