Important Safety Concerns re Use of Propofol for Sedation in Pediatric Patients

Date: 2001-05-01

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Therapeutic Products Directorate
Direction des produits thérapeutiques

Notice to Hospitals

from the Therapeutic Products Directorate

IMPORTANT SAFETY CONCERNS re Use of PROPOFOL for sedation in pediatric patients

May 1, 2001

To: Hospital Chief of Medical Staff

Please forward the following information to involved professional staff in Departments such as Pharmacy, Intensive Care Units (ICUs) and Anaesthesiology.

The Canadian approved Product Monograph states in the INDICATIONS section: "Propofol is not recommended for sedation in children under the age of 18, either during surgical / diagnostic procedures or in the Intensive Care Unit (ICU), as safety and efficacy have not been established."

Health Canada is re-emphasizing the importance of strict adherence to the current Canadian approved Product Monograph. This recommendation is based on newly-obtained clinical trial information reviewed by the U.S. FDA

Therapeutic Products Directorate (TPD) wishes to draw your attention to a warning letter addressed to Health Professionals in the U.S. regarding important safety concerns when propofol is used for sedation in the ICU in pediatric patients. This letter was posted on the Food and Drug Administration (FDA) web site on April 25, 2001. http://www.fda.gov/medwatch/safety/2001/diprivan_deardoc.pdf

March 26,2001

Dear Health Care Provider,

I am writing to inform you that based on a recent review of new clinical trial data, the Food and Drug Administration (FDA) has determined that there may be important safety concerns when propofol, marketed by AstraZeneca as DIPRIVAN . (propofol) Injectable Emulsion, is used for sedation in the Intensive Care Unit (ICU) in pediatric patients. I would like to remind you that propofol is not approved in the US for sedation in pediatric ICU patients and should not be used for this purpose.

The FDA s determination was made based on the review of data from a randomized, controlled, clinical trial that evaluated the safety and effectiveness of DIPRIVAN versus standard sedative agents (SSA)in pediatric ICU patients. In that study a total of 327 pediatric patients were randomized to receive either DIPRIVAN 2% (113 patients), DIPRIVAN 1% (109 patients),or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with DIPRIVAN as compared to SSAs. A total of 25 patients died during the trial or within the 28-day follow-up period:12 (11%) in the DIPRIVAN 2%treatment group, 9 (8%) in the DIPRIVAN 1%treatment group, and 4 (4%) in the SSA treatment group. In the opinion of FDA, careful review of the deaths failed to reveal a correlation with underlying disease status, nor did the review reveal a definite pattern to the causes of death. In order to better understand this potential safety issue AstraZeneca will initiate a new clinical trial designed specifically to evaluate any differences in adverse events and deaths in pediatric patients randomized to propofol or SSAs for ICU sedation. If you would like additional information related to the trial, please call the AstraZeneca Information Center. Sincerely,

We would like to reemphasize that propofol is currently not approved for sedation in pediatric ICU patients in the US and should not be used for this purpose. It is important that you forward any adverse event information involving propofol to AstraZeneca (for DIPRIVAN) at the Information Center 1-800-236-9933,8 am -7 pm or to the FDA via the MedWatch system. Copies of the MedWatch form are available on the FDA web site (http://www.fda.gov/medwatch/index.html or  http://www.fda.gov/medwatch/safety.htm) as listed.

David Goodale,DDS,PhD
Medical Leader for Pain,Anesthesia and Infection Products
AstraZeneca LP
Enclosure

AstraZeneca Pharmaceuticals LP Tel 302 886 3000
1800 Concord Pike PO Box 15437 Wilmington DE 19850-5437  www.astrazeneca-us.com