A Call to Action: Data Presented at the Annual Meeting of the American Society of Clinical Oncology Confirms Standard Cremophor-Based Paclitaxel Associated with High Rate of Serious Allergic Reaction Despite Prophylactic Medication

Los Angeles, CA – The Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program today announced a review of adverse-events reports submitted to global regulatory agencies, including the U.S. Food and Drug Administration’s (FDA) Adverse Event Report System (AERS), which found many cancer patients treated with Cremophor EL-containing paclitaxel experienced hypersensitivity reactions despite prophylaxis prior to paclitaxel therapy.

Investigators lead by Dr. Charles Bennett from Northwestern University and Dr. Dennis Raisch from the University of New Mexico identified 287 unique cases of Cremophor-based paclitaxel-associated hypersensitivity reactions between 1997 and 2007, with 109 fatalities (38 percent). RADAR investigators also found that 22 percent of all fatalities occurred in patients who had received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

As a result of these findings, investigators recommend that the FDA and other international regulatory agencies consider mandating the development of Risk Evaluation and Mitigation Strategy (REMS) to address the toxicity issue. The report, “Cremophor EL-containing paclitaxel-associated anaphylaxis: a call to action” (Abstract #6589), was presented recently in a poster session at the 45thAnnual Meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Fla.

Cremophor EL-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor EL-containing paclitaxel includes a black box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivy reactions.

“The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment,” says Charles Bennett, M.D., Ph.D., RADAR program coordinator and Professor, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine. “Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, and physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring chemotherapy regimes that do not include Cremophor in the administration process and eliminates the need for premedications.”

A subset analysis of the adverse event reports found that patients with early-stage breast cancer treated with Cremophor EL-containing paclitaxel in the adjuvant setting were particularly affected by hypersensitivity reactions. Two fatalities associated with hypersensitivity reactions were reported in this group of patients, and both of these patients received prophylactic medications. An additional four patients also experienced life-threatening anaphylaxis recommendations, three of whom received prior medication.

“The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent,” says Dennis Raisch, Ph.D., MS, professor, Pharmacoeconomics, Epidemiology, Public Policy and Outcomes Research, College of Pharmacy, University of New Mexico. “This report suggests that physicians should carefully monitor patients who receive Cremophor EL-containing paclitaxel in the adjuvant setting. Physicians should also be diligent about providing complete reporting of adverse events to better equip regulatory agencies with information about the relative risks and benefits of Cremophor EL-containing medicines for these patients.”

About the Review

Cremophor®EL-Containing Paclitaxel-Associated Anaphylaxis: A Call to Action (Abstract #6589-Poster Presentation)

RADAR investigators Dr. Bennett and Dr. Raisch reviewed case reports of Cremophor EL-containing paclitaxel-induced hypersensitivity reactions submitted to regulatory agencies in the U.S., Europe and Japan to: assess the quality and timing of individual case reports of serious or fatal paclitaxel hypersensitivity reactions; evaluate whether any of these events occurred despite the use of pre-medication prophylaxis; and assess whether these events occurred in breast cancer patients who received adjuvant chemotherapy treatment.

Investigators gathered 287 case reports submitted to these regulatory agencies between 1997 and 2007. For adverse event reports submitted to regulatory agencies in the United States, Europe and Japan the most common cancer diagnoses were lung cancer (in the US), breast cancer (in Europe) and ovarian cancer (in Japan). Overall, the most common diagnosis among the three regions was lung cancer.

The median duration of time between the date of the event to regulatory notification to the FDA varied between regions, with Japan being the fastest, followed by the United States and Europe (21 days for survivable events and 52 days for fatal events, 62 and 45, and 56 and 63, respectively). Despite a substantial number of deaths from serious anaphylactic reactions to Cremophor EL-containing paclitaxel, the quality of case reports in the US, Europe and Japan was poor especially with regard to important clinical information describing the anaphylactic event including anaphylaxis, duration of symptoms and time to onset of symptoms.

About RADAR

Research on Adverse Drug events And Reports (RADAR) is a pharmacovigilance team of 25 doctors who receive calls about possible adverse drug reactions and investigate. RADAR is based out of the Northwestern University Feinberg School of Medicine and the VA Center for Management of Complex Chronic Care at the Jesse Brown VA Medical Center, Chicago.

Additionally, RADAR collaborates with researchers at the University of New Mexico and the VA Center for Medication Safety at Edward Hines, Jr. VA Hospital. Though it was without funding for its first four years, RADAR has raised about $12 million through grants from the National Institutes of Health and other such institutions. RADAR was founded by Charles L. Bennett, M.D., Ph.D.

Contact: Lauren Cruse, 505/272-3690; cell 505/220-1093 Luke Frank, 505/272-3679; cell 505/907-9525