Archived – Important Drug Safety Information: Risperdal (Risperidone) and Cerebrovascular Adverse Events in Placebo-Controlled Dementia Trials – Janssen-Ortho Inc.

Important Drug Safety Information

October 11, 2002

Subject: Risperdal* (risperidone) and Cerebrovascular Adverse Events in Placebo-controlled Dementia Trials

Dear Healthcare Professional:

Janssen-Ortho Inc., following discussions with Health Canada, would like to inform you of emerging important safety information pertaining to cerebrovascular adverse events, that have occurred in elderly patients treated with Risperdal (risperidone) in Dementia Trials.

Cerebrovascular Adverse Events

Recent analysis of some clinical trials in elderly patients with dementia suggests that the use of Risperdal in dementia patients may be associated with an increased incidence of reports of cerebrovascular adverse events (CVAEs) such as stroke and transient ischemic attacks (TIAs), including fatalities.

While elderly patients are at an increased risk of CVAEs, the above clinical trial data reflect an increased incidence of such adverse events in patients taking Risperdal compared with age-matched, placebo-treated dementia patients.

Physicians are advised to reassess the risks and benefits of the use of Risperdal in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient.

Physicians should counsel their patients/caregivers to immediately report signs and symptoms of potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems, so that diagnosis can be made and treatment options considered, including discontinuation, without delay.

There is insufficient information to determine whether CVAEs in elderly patients with dementia are associated specifically with Risperdal, all antipsychotic agents or any particular type of Dementia.

Summarized clinical trial data are provided in the "Background Information" section of this letter.

An ongoing safety trial aims to characterize patients at risk. Further information on this trial and other data will be provided as it becomes available.

Background Information

Clinical Trial Data Available to Date:

Four patients died in the Risperdal group versus 1 patient in the placebo group.

Recently, an Australian trial (AUS-5; Table 1) comparing Risperdal with placebo in patients who presented with dementia and behavioural problems (age range: 56-100 years; average age 84 years) was analyzed. It was found that 15 of the 167 Risperdal-treated patients suffered cerebrovascular adverse events (CVAEs) whereas only 3 of the 170 placebo-treated patients experienced CVAEs.

In light of these observations, 3 additional completed double-blind, placebo-controlled studies in patients with dementia were examined for the presence of CVAEs. In the total dementia clinical trial database of 4 placebo-controlled studies (see Table 1), 29 cases of CVAEs occurred in the Risperdal-treated patients (N = 764) versus 7 cases of CVAEs in the placebo-treated patients (N = 466). Of these cases, 4 patients died in the Risperdal group versus 1 patient in the placebo group.

A further 8 cases of CVAEs, including 2 fatalities, were reported in open-label safety trials in dementia patients (N = 454), studied for up to one year.

The above-cited clinical trials included differing proportions of patients with pure Alzheimer's dementia (AD), pure vascular dementia (VaD) and mixed AD-VaD. The number of patients to date is too small to allow for further interpretation.

Spontaneous Post-marketing Reports:

Review of the global post-marketing database for the elderly dementia population, representing over 2.4 million patient years, identified 37 cases of CVAEs (including 1 case from Canada). Of these 37 cases, 16 were fatal (one in Canada). Note that due to varied regulations in some jurisdictions, numbers of officially reported adverse events represent only a small fraction of actual events. As only a small proportion of suspected adverse events are usually reported, caution should be exercised in estimating the incidence of adverse events.

Janssen-Ortho Inc. will continue to monitor ongoing clinical trials, and worldwide pharmacovigilance reports. Janssen- Ortho Inc. is committed to providing you with the most current and complete product information available for the management of patients receiving Risperdal.

Janssen-Ortho Inc. is working with Health Canada to update the Canadian Prescribing Information. In the interim, Janssen-Ortho Inc. would like to remind you of the current wording in the "Warnings" section of the Canadian Risperdal (risperidone) Prescribing Information which refers to cerebrovascular disease:

Risperdal should be used with caution in patients with cardiovascular diseases (e.g., heart failure, history of myocardial infarction or ischemia, cerebrovascular disease, conduction abnormalities) and other conditions such as dehydration and hypovolemia. Special care should be taken to avoid hypotension in patients with a history of cerebrovascular insufficiency or ischemic heart disease, and in patients taking medications to lower blood pressure.

A copy of the revised Prescribing Information will be sent to you for insertion into your CPS, as soon as it becomes available.

The identification, characterization and management of drug-related adverse events are dependent on the active participation of Healthcare Professionals in adverse event reporting programs. Healthcare Professionals are asked to report any suspected adverse events in patients receiving Risperdal (risperidone) to Janssen-Ortho Inc. at the following address:

Janssen-Ortho Inc.
Drug Safety and Surveillance
19 Green Belt Drive
Toronto, ON M3C 1L9 or call toll free at 1-800-567-3331

Your professional commitment in this matter has an important role in protecting the well-being of your patients by contributing to early signal detection and informed use of drugs.

Should you have any questions or require additional information regarding the use of Risperdal (risperidone), please contact Janssen-Ortho Inc. Medical Information Department at 1-800-567-3331 from 9:00 a.m. to 5:00 p.m., Monday through Friday, EST.

Sincerely,

original signed by

Wendy Arnott, Pharm.D.
Vice-President
Medical, Regulatory, Quality and Linguistics

* All trademark rights used under license

Any suspected adverse drug reactions can also be reported to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
Health Canada
Address Locator: 0201C2
Ottawa, Ontario, K1A 1B9
Tel: (613) 957-0337 or Fax: (613) 957-0335
Toll free for consumers and health professionals:
Tel: 866 234-2345, Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The ADR Reporting Form can be found in The Canadian Compendium of Pharmaceuticals and Specialties, or on the TPD web site, along with the ADR Guidelines.