www.know_the_risk_of_5fu_chemotherapy.com
November 2020
The newest petition to the FDA, accepted for review in Nov 2020, is available to review/comment at: https://www.regulations.gov/document/FDA-2020-P-2213-0001
The petition asks the FDA to revise the Drug Label inserts for Fluorouracil and Xeloda (Capecitabine) by:
1) Recommending Pre-Treatment Testing to Identify Patients with Dihydropyrimidine Dehydrogenase (DPD) Deficiency and include the recommendation in the content of the drug labels dealing
with:
a. Patient Counseling
b. Dosage and Administration
c. Box Warning.
2) Revising the Patient Counseling Information content to: Shift responsibility for identifying DPD deficiency from the patient to the prescribing physicians who should also discuss with patients
the risk associated with DPD deficiency before the start of treatment.
3) Revising the Dosage and Administration content to: Recommend treating physicians pre-screen patients for DPD deficiency and adapt the treatment plan if partial or complete DPD deficiency is
identified.
4) Adding a Box Warning that:
a. Highlights the risk of severe toxicity when treating patients with DPD deficiency, and
b. Recommends screening for DPD deficiency prior to the start of treatment and prior to resuming treatment after an adverse event that necessitated treatment modification.
========================================================
Citizen's Petition to the US Food and Drug Administration (FDA) -- April 2014
You may also read and comment on the petitions at the FDA's site:
Fluorouracil -- https://www.regulations.gov/search?filter=FDA-2014-P-0405
Xeloda -- https://www.regulations.gov/search?filter=FDA-2014-P-0497
April 6, 2014
Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, rm. 1061
Rockville, MD 20852.
Subject: Citizen Petition Concerning the FDA Drug Label Insert for Fluorouracil
The undersigned submits this petition to request the Commissioner of Food and Drugs to revise the package insert for Fluorouracil (see attached).
.
A. Action requested
Recommend revisions to the Contraindications, Warnings, and Precautions sections of the insert. See the existing and proposed wording of each section below:
Contraindications
Warnings
Precautions
B. Statement of grounds
(A full statement, in a well organized format, of the factual and legal grounds on which the petitioner relies, including all relevant information and views on which the petitioner relies, as well as representative information known to the petitioner which is unfavorable to the petitioner's position.)
Care providers are making great advances in personalizing cancer treatment with the genetic assessment of tumors. The medical profession should now make advances in personalizing treatment by assessing each patient’s ability to tolerate proposed treatment options.
Patients with impaired DPD activity (due to genetic or non-genetic factors) are unable to metabolize fluorouracil and therefore are at risk of severe toxic reaction – compromised DPD activity is the single point of failure for this course of treatment. Pre-screening patients will improve patient care, treatment efficacy, and significantly reduce grade 3 and 4 toxic reactions and fatalities (instances of severe toxicity range from 10-40%).
Medical journal articles report that severe reactions are far from rare (estimated 500-1000 fatalities/year in the US) and demonstrate that pre-treatment screening and dose management of fluorouracil and fluoropyrimidines can effectively reduce the incidence of severe toxic and fatal reactions. (See the attached Recommendation to the National Comprehensive Cancer Network Guideline Panel that includes specific medical journal references that report toxicity frequencies and pre-screening – this includes the citations of the authors referenced below).
Medical studies (e.g. Ciccolini et, al) have found that dihydropyrimidine dehydrogenase (DPD) deficiency is not just a genetic condition, environmental factors may contribute to compromised DPD activity. Given this, two medical institutes in France (see Gamelin in Angiers and Ciccolini in Marseilles) employ “functional”, not genetic, tests to detect at-risk patients. Dr. Ciccolini successfully employs tests to measure the dihydrouracil/uracil ratio to identify individuals with impaired dihydropyrimidine dehydrogenase (DPD) activity for whom the fluoropyrimidine dosage should be reduced to avoid severe toxic reactions; his institute in Marseilles also uses pharmacokinetic follow-up to indicate more precisely recommended dosage levels (see the DPD Testing for Dummies poster attached).
Despite the successes of the pioneering efforts in Marseilles and Angiers France, there is no consensus in the US on pre-screening procedures. Because of this, Caudle and Diasio recommend reducing initial doses 50% followed by different dose levels based on a patient’s ability to tolerate the fluorouracil treatment. Until such time as test protocols are commonly adopted, the reduced initial dose level may help reduce severe toxicities and improve patient outcomes.
C. Environmental impact
None
D. Economic impact
None
E. Certification
The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.
(Signature)
Ken Surprenant
==================
April 19, 2014
Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, rm. 1061
Rockville, MD 20852
Subject: Citizen Petition Concerning the FDA Drug Label Insert for Xeloda.
The undersigned submits this petition to request the Commissioner of Food and Drugs to revise the package insert for Xeloda (see attached).
.
A. Action requested
Recommend revisions to the Warnings and Precautionssection of the insert. See the existing and proposed wording of each section below:
Warnings and Precautions
B. Statement of grounds
Care providers are making great advances in personalizing cancer treatment with the genetic assessment of tumors. The medical profession should now make advances in personalizing treatment by assessing each patient’s ability to tolerate proposed treatment options.
Patients with impaired DPD activity (due to genetic or non-genetic factors) are unable to metabolize fluorouracil based products, to include Xeloda, and therefore are at risk of severe toxic reaction – compromised DPD activity is the single point of failure for this course of treatment. Pre-screening patients will improve patient care, treatment efficacy, and significantly reduce grade 3 and 4 toxic reactions and fatalities (instances of severe toxicity range from 10-40%).
Medical journal articles report that severe reactions are far from rare (estimated 500-1000 fatalities/year in the US) and demonstrate that pre-treatment screening and dose management of fluorouracil and fluoropyrimidines can effectively reduce the incidence of severe toxic and fatal reactions. (See the attached Recommendation to the National Comprehensive Cancer Network Guideline Panel that includes specific medical journal references that report toxicity frequencies and pre-screening – this includes the citations of the authors referenced below).
Medical studies (e.g. Ciccolini et, al) have found that dihydropyrimidine dehydrogenase (DPD) deficiency is not just a genetic condition, environmental factors may contribute to compromised DPD activity. Given this, two medical institutes in France (see Gamelin in Angiers and Ciccolini in Marseilles) employ “functional”, not genetic, tests to detect at-risk patients. Dr. Ciccolini successfully employs tests to measure the dihydrouracil/uracil ratio to identify individuals with impaired dihydropyrimidine dehydrogenase (DPD) activity for whom the fluoropyrimidine dosage should be reduced to avoid severe toxic reactions; his institute in Marseilles also uses pharmacokinetic follow-up to indicate more precisely recommended dosage levels (see the DPD Testing for Dummies poster attached).
Despite the successes of the pioneering efforts in Marseilles and Angiers France, there is no consensus in the US on pre-screening procedures. Because of this, Caudle and Diasio recommend reducing initial doses 50% followed by different dose levels based on a patient’s ability to tolerate the fluorouracil treatment. Until such time as test protocols are commonly adopted, the reduced initial dose level may help reduce severe toxicities and improve patient outcomes.
C. Environmental impact
None
D. Economic impact
None
E. Certification
The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.