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/docket?D=FDA-2020-P-2213

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.

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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:

http://www.regulations.gov/#!docketDetail;D=FDA-2014-P-0405

http://www.regulations.gov/#!docketDetail;D=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

• Current: Fluorouracil therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function, those with potentially serious infections or those with a known hypersensitivity to fluorouracil.

• Proposed: Fluorouracil therapy is contraindicated for patients in a poor nutritional state, those with depressed bone marrow function, those with potentially serious infections, those with a known hypersensitivity to fluorouracil, and those with impaired dihydropyrimidine dehydrogenase (DPD) activity.

Warnings

• Current:
• • THE DAILY DOSE OF FLUOROURACIL IS NOT TO EXCEED 800 MG. IT IS RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST COURSE OF TREATMENT.
  • Fluorouracil should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function.
  • Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity. A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity. Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil.

• Proposed:
• • THE DAILY DOSE OF FLUOROURACIL IS NOT TO EXCEED 800 MG. IT IS RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST COURSE OF TREATMENT.
  • Fluorouracil should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function.
  • Rarely, unexpected, Severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) and fatalities associated with 5-fluorouracil have been attributed to deficiency of dihydopyrimidine dehydrogenase activity. Estimates of the frequency of severe (grade 3, 4) toxicities range from 10-40%.  A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity. Absence of this catabolic enzyme, or compromised activity levels,  appears to results in prolonged clearance of 5-fluorouracil  and places patients at grave risk.

Precautions

• Current:
• • General: Fluorouracil is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully supervised, since therapeutic response is unlikely to occur without some evidence of toxicity. Severe hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of fluorouracil despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good condition.
  • Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears:
  • • Stomatitis or esophagopharyngitis, at the first visible sign.
    • Leukopenia (WBC under 3500) or a rapidly falling white blood count.
    • Vomiting, intractable.
    • Diarrhea, frequent bowel movements or watery stools.
    • Gastrointestinal ulceration and bleeding.
    • Thrombocytopenia (platelets under 100,000).
    • Hemorrhage from any site.

• Proposed:
• • General: Fluorouracil is a highly toxic drug with a narrow margin of safety. Therefore, patients should be carefully supervised, since therapeutic response is unlikely to occur without some evidence of toxicity. Severe hematological toxicity, gastrointestinal hemorrhage and even death may result from the use of fluorouracil despite meticulous selection of patients and careful adjustment of dosage. Although severe toxicity is more likely in poor risk patients, fatalities may be encountered occasionally even in patients in relatively good condition.
  • Pre-screening patients can serve to identify at-risk patients with a compromised dihydropyrimidine dehydrogenase (DPD) activity level who will require adjusted dosages or who must avoid treatment entirely.  Measuring the dihydrouracil/uracil ratio will identify individuals with impaired dihydropyrimidine dehydrogenase (DPD) activity for whom the fluoropyrimidine dosage should be reduced to avoid severe toxic reactions; treatments should also rely upon pharmacokinetic follow-up to indicate more precisely recommended dosage levels.
  • Therapy is to be discontinued promptly whenever one of the following signs of toxicity appears:
  • • Stomatitis or esophagopharyngitis, at the first visible sign.
    • Leukopenia (WBC under 3500) or a rapidly falling white blood count.
    • Vomiting, intractable.
    • Diarrhea, frequent bowel movements or watery stools.
    • Gastrointestinal ulceration and bleeding.
    • Thrombocytopenia (platelets under 100,000).
    • Hemorrhage from any site.

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

• Current:
• • Diarrhea: May be severe. Interrupt XELODA treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.1)
  • Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. (5.2)
  • Cardiotoxicity: Common in patients with a prior history of coronary artery disease. (5.3)
  • Pregnancy: Can cause fetal harm. Advise women of the potential risk to the fetus. (5.6, 8.1)
  • Hand-and-Foot Syndrome (Grade 2 or 3): Interrupt XELODA treatment until the event resolves or decreases in intensity. (5.7)
  • Hyperbilirubinemia (Grade 2 to 4): Interrupt XELODA treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8)
  • Hematologic: Do not treat patients with neutrophil counts <1.5 x 109/L or thrombocyte counts <100 x 109/L. If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9)

• Proposed (add the following):
• • Severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) and fatalities associated with fluorouracils, such as Xeloda, have been attributed to deficiency of dihydopyrimidine dehydrogenase (DPD)activity. Absence of this catabolic enzyme (DPD), or compromised activity levels,  results in prolonged clearance of fluorouracil based products, e.g. Xeloda, and places patients at grave risk.
  • Pre-screening patients can serve to identify at-risk patients with a compromised dihydropyrimidine dehydrogenase (DPD) activity level who will require adjusted dosages or who must avoid treatment entirely.  Measuring the dihydrouracil/uracil ratio will identify individuals with impaired dihydropyrimidine dehydrogenase (DPD) activity for whom the fluoropyrimidine dosage should be reduced to avoid severe toxic reactions; treatments should also rely upon pharmacokinetic follow-up to indicate more precisely recommended dosage levels.

 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.