Janssen News Release Understanding CATIE: Some thoughts about the Clinical Antipsychotic Trials of Intervention Effectiveness

For Healthcare Professionals Statement for Media Regarding CATIE Trial NIMH Perspective

As many of you are aware, results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study were published in this week's issue of The New England Journal of Medicine. This study of five antipsychotic medications over an 18-month period was intended to compare all atypical antipsychotic drugs available at the time of the study and one older conventional medication in the treatment of patients with chronic schizophrenia. The publication drew certain conclusions about treatment choices for schizophrenia, based on the study results. We at Janssen would also like to share some information about the study with you and give you some important thoughts about the results to help place the study in context. This study underscores that people with schizophrenia need many medication options, because what works well for one patient may not work as well for another. CATIE confirms what physicians have long understood -- that frequent discontinuation (switching) is a problem with all prescription treatments for schizophrenia. The primary measure used in this trial was length of time to drug discontinuation (switch), which is not the typical measure used in this patient group. Typically, efficacy (e.g., relapses or symptom scores) and/or safety measures (e.g., weight gain, sedation, movement disorders, or cardiac effects) are used as primary measures in schizophrenia research. Using the time to discontinuation (switch) measure, the study found a short time to a drug switch for all treatments, reflected by the observation that around half of patients switched medicines by 6 months and almost three fourths switched treatments during phase 1. This frequent switching means that schizophrenia patients need access to many medication choices to help them through a lifetime of treatment. The "efficacy" (time to discontinuation) results for RISPERDAL® (risperidone) did not demonstrate the full efficacy of RISPERDAL® because many patients in the CATIE trial received doses that were too low. The authors acknowledge that dose could have been a factor in the performance of the studied medications. Based on the reported average dose and the dosage strengths of capsules made available in the study, the many patients receiving RISPERDAL® (risperidone) in this trial were treated with sub-therapeutic (1.5mg/day) or less effective (3mg/day) doses . Based on over 15 years of published studies involving RISPERDAL®, the lower efficacy observed in this trial would be expected because of low dosing. This large body of peer-review literature, dozens of studies in many thousands of patients, has well characterized use of RISPERDAL® for treating schizophrenia. For example, one large study previously published in the NEJM demonstrated the benefits of RISPERDAL® and a commonly used conventional antipsychotic in the treatment of schizophrenia . An even larger study of RISPERDAL® and conventional antipsychotics also showed that under naturalistic "real world" conditions, the decision to treat with RISPERDAL® had many benefits. In the CATIE study, Zyprexa (olanzapine) appeared to demonstrate better "efficacy" (time to discontinuation (switching) drugs) and worse tolerability than other medications; however, it also was the only drug given in excess of labeled maximum doses. The appearance of an "efficacy" advantage accompanied by poor tolerability must be considered in light of the fact that the average dose of olanzapine that patients received the most often was higher than the FDA-approved maximum dose. Doses above the FDA-approved maximum may be associated with risks and/or benefits that have not been sufficiently characterized to allow treatment to be recommended. Any single study, including CATIE, has limitations. RISPERDAL® has been widely available to doctors and patients since 1994, has been studied in many controlled trials in thousands patients, and has been used by millions of patients over the past 11 years. This extensive experience has created a large body of information that extends far beyond any single study. The study further highlights the need for newer therapies that can improve adherence to medication and address other unmet needs of these patients who battle this lifelong disease. The CATIE study reinforces the overwhelming need for greater medication compliance in the chronic treatment of schizophrenia. As a long-time leader in providing prescription medications that address the unmet needs of chronic schizophrenia, we recognized this unmet need. And in 2003, subsequent to the initiation of the CATIE study, we introduced the first atypical long-acting injectable treatment, RISPERDAL® CONSTA® (risperidone) long-acting injection. A long-acting, professionally administered medication, while not guaranteeing compliance, allows you to recognize and intervene when a patient misses a dose. We would like to thank you for your interest in Janssen and our mission over the years. The company founded by Dr. Paul Janssen, now the world's largest company dedicated solely to the needs of psychiatry, has brought many different treatments to schizophrenia patients worldwide over the decades since it was founded. The people of Janssen remain committed to the millions of patients with schizophrenia; their families; their caregivers; and the healthcare professionals who work so hard to help them. The unmet needs remain great, but with continued focus and commitment, together we will achieve ever better outcomes for patients with schizophrenia. As always, if you have any questions or want to request further information about RISPERDAL®, you are welcome to call our Medical Communications Contact Center, at 1-800-526-7736.

IMPORTANT SAFETY INFORMATION

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Neither RISPERDAL® nor RISPERDAL® CONSTA® (risperidone) is approved for the treatment of patients with Dementia-Related Psychosis

Commonly observed events RISPERDAL ORAL®: In short-term trials, the most commonly observed adverse events associated with RISPERDAL at an incidence of > 5% and at least 2x placebo were: anxiety, somnolence, extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia. Commonly observed events RISPERDAL® CONSTA®: Treatment-emergent adverse events with an incidence of 5% or greater in at least one of the RISPERDAL® CONSTA® groups (25 mg or 50 mg) and at least twice that of placebo were: somnolence, akathisia, parkinsonism, dyspepsia, constipation, dry mouth, fatigue and weight increase. Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL®. Patients starting treatment with APS who have or are at risk for diabetes, should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. Tardive Dyskinesia (TD): As with all antipsychotic medications, prescribing should be consistent with the need to minimize the risk of TD; if its signs and symptoms appear, discontinuation of RISPERDAL® should be considered. Elderly patients appeared to be at increased risk for TD. Neuroleptic malignant syndrome (NMS): NMS has been reported rarely with this class of medications, including RISPERDAL® and appropriate management should be employed. Cerebrovascular adverse events (CAEs): CAEs, including fatalities, have been reported in elderly patients with dementia-related psychosis taking risperidone in clinical trials. The incidence of CAEs with risperidone was significantly higher than with placebo. RISPERDAL®, is not approved for treating these patients. Somnolence: Incidence of adverse events in short-term trials was somnolence at 3% for <10 mg/day and 8% for 16 mg/day vs. 1% for placebo. Other disorders related to sedation, such as sleepiness, increased duration of sleep, lassitude, and increased fatigability, were uncommon but dose related. For more information, read the full U.S. Prescribing Information including the Boxed Warning for RISPERDAL and RISPERDAL CONSTA Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. ###