October 6, 2010
Otsuka Pharmaceutical Co., Ltd.
OTSUKA ANNOUNCES PHASE 3 ARIPIPRAZOLE INTRAMUSCULAR (IM) DEPOT TRIAL INTERIM ANALYSIS REVEALS EFFICACY CRITERIA MET
OTSUKA TO FILE NDA FOR ITS NEW INVESTIGATIONAL ONCE MONTHLY IM DEPOT FORMULATION FOR THE MAINTENANCE TREATMENT OF SCHIZOPHRENIA
TOKYO, JAPAN and PRINCETON, NJ, October 5, 2010 - Otsuka Pharmaceutical Co., Ltd. (OPC) and Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) announced today that an independent data monitoring committee (IDMC) has recommended the early termination of its Phase 3, 52-week, placebo-controlled, intramuscular depot aripiprazole trial. This is due to the study successfully meeting efficacy criteria at a protocol-specified interim analysis. The Aripiprazole Intramuscular Depot Study in Schizophrenia-U.S., evaluated the efficacy and safety of this investigational once-monthly IM depot formulation for the maintenance treatment of schizophrenia.
"The study successfully achieved its efficacy criteria ahead of schedule," said William H. Carson, M.D., President & CEO, OPDC. "According to the IDMC, the interim efficacy analyses met the pre-specified termination rules of the protocol."
Based on the successful interim analysis, OPDC anticipates filing a New Drug Application during fiscal year 2011. "This is an important milestone in our clinical development of aripiprazole," said Dr. Carson. "This will allow us to provide patients with schizophrenia in the U.S. another treatment option."
About aripiprazole IM depot
Aripiprazole IM depot is a sterile lyophilized cake that when reconstituted with sterile water for injection forms an injectable suspension. The current study evaluated this formulation as a once-monthly injection for the maintenance treatment of schizophrenia.
Otsuka's Aripiprazole Intramuscular Depot Study in Schizophrenia-U.S. is a Phase 3 clinical study of the IM depot formulation of aripiprazole that was designed to evaluate the efficacy, safety and tolerability of the intramuscular formulation as a maintenance treatment in patients with schizophrenia. The U.S. registrational study (31-07-246) was a multicenter, randomized, double-blind, placebo-controlled study and originally scheduled for a duration of 52 weeks. The study incorporated two interim analyses, at 50% and 75% of the 125 events needed to complete the study. It was determined that 50% of the events were achieved in June, seven months ahead of schedule, and the independent data monitoring committee determined that the interim analysis met the established termination criteria and recommended that the study be stopped.
Oral formulations of aripiprazole (including tablets, orally disintegrating tablets and oral solution) are co-marketed by Otsuka and Bristol-Myers Squibb under the brand name, ABILIFY. It is indicated for the treatment of schizophrenia in adults and in adolescents 13 to 17 years of age in the United States. In addition, ABILIFY (aripiprazole) Injection is also co-marketed by Otsuka and Bristol-Myers Squibb for treatment of agitation in schizophrenia in adults. See attached safety information for ABILIFY (aripiprazole).
IMPORTANT SAFETY INFORMATION for ABILIFY® (aripiprazole)
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. ABILIFY is not approved for the treatment of patients with dementia-related psychosis.
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of adjunctive ABILIFY or another antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increased risk of suicidality in adults beyond age 24. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ABILIFY is not approved for use in pediatric patients with depression.
See Full Prescribing Information for complete Boxed WARNINGS
Contraindication - Known hypersensitivity reaction to ABILIFY. Reactions have ranged from pruritus/urticaria to anaphylaxis.
- Cerebrovascular Adverse Events, Including Stroke- Increased incidence of cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY
- Neuroleptic Malignant Syndrome (NMS) - As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with ABILIFY. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems
- Tardive Dyskinesia (TD) -The risk of developing TD and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn
- Hyperglycemia and Diabetes Mellitus - Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including ABILIFY. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for 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
Orthostatic Hypotension - ABILIFY may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.
Leukopenia, Neutropenia, and Agranulocytosis - Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics, including ABILIFY. Patients with history of a clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC count in the absence of other causative factors.
Seizures/Convulsions - As with other antipsychotic drugs, ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold (eg, Alzheimer's dementia)
Potential for Cognitive and Motor Impairment - Like other antipsychotics, ABILIFY may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain ABILIFY does not affect them adversely.
Body Temperature Regulation - Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.
Suicide - The possibility of a suicide attempt is inherent in psychotic illnesses, Bipolar Disorder, and Major Depressive Disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Dysphagia - Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY; use caution in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia.
Physicians should advise patients to avoid alcohol while taking ABILIFY.
Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine) inhibitors will increase ABILIFY drug concentrations; reduce ABILIFY dose by one-half when used concomitantly, except when used as adjunctive treatment with antidepressants in adults with Major Depressive Disorder.
CYP3A4 inducers (eg, carbamazepine) will decrease ABILIFY drug concentrations; double ABILIFY dose when used concomitantly.
Commonly observed adverse reactions (=5% incidence and at least twice the rate of placebo for ABILIFY vs placebo, respectively):
- Adult patients with Schizophrenia: akathisia (8% vs 4%)
- Pediatric patients (13 to 17 years) with Schizophrenia: extrapyramidal disorder (17% vs 5%), somnolence (16% vs 6%), and tremor (7% vs 2%)
Dystonia is a class effect of antipsychotic drugs. Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.
Please see accompanying FULL PRESCRIBING INFORMATION, including Boxed WARNINGS, and Medication Guide for ABILIFY® (aripiprazole) or visit www.abilify.com.
Information in this news release was current as of the original release date.