ask about your risk of VERY serious side effects before starting 5-FU Chemotherapy

The FDA's Response -- Partial Approval, Partial Denial of the Petitions

Docket Nos: FDA-2014-P-0405 and FDA-2014-P-0497

The complete response is available at:



Below are excerpts from the response: 

"We have carefully considered the information submitted in your Petitions and the comments and supplemental information submitted to the public dockets for your Petitions.  On March 25, 2015, FDA approved changes to the Xeloda prescribing information. Today (July 29, 2016), FDA approved changes to the fluorouracil prescribing information.  Although the changes do not include the prescreening and dose management provisions you requested, they do clarify the risk of severe toxic reactions in patients with impaired DPD activity as you sought. Accordingly, your Petitions are granted in part and denied in part." 


"We agree that changes to the language in the WARNINGS AND PRECAUTIONS sections of the fluorouracil and Xeloda prescribing information describing the risk of severe adverse reactions in patients with DPD deficiency were appropriate.  We have approved revisions to that language as follows to more clearly describe the risk of severe toxicity in patients with DPD deficiency: 

  • "Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g. mucositis, diarrhea, neutropenia, and neurotoxicity).  Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil/Xeloda." 
  • The changes: 
    • "...no longer describe the risk of severe toxicities as 'rare'. 
    • "...no longer describes the risk of severe toxicities as 'unexpected'.
    • "...fatalities have been added to the list of severe adverse outcomes for patients with DPD deficiency". 
    • "We [FDA], approved revisions that clarify the risk by removing language that unnecessarily qualified the risk." 

The response was signed by the Director of the FDA's Center for Drug Evaluation and Research


On Sept 8, 2016, I responded to the FDA's partial approval with the following:


September 8, 2016

Director, Center for Drug Evaluation and Research

Food and Drug Administration

White Oak 51, Room 6239

10903 New Hampshire Ave

Silver Spring, MD 20993-0002


Reference: Your reply of Jul 29, 2016 to Docket Nos. FDA-2014-P-0405 and FDA-2014-P-0497


Dear Dr. (redacted),


First I want to thank you and your staff for the thoughtful and thorough reply to my petitions.  Thank you of course for granting partial approval.   I am relieved to learn that the FDA acknowledges the risk now documented in many medical journals and has taken appropriate action.


With respect to your reply, I would like to comment on the parts of the petitions you approved and disapproved.


Concerning the partial approval:

·         How long before the revised WARNING AND PRECAUTIONS sections of the drug labels take effect?  Next, how is the change communicated so that care providers have their attention drawn to the changes?

·         In section I C, DPD Activity, of your reply, you acknowledge that “A person’s DPD activity is variable and influenced by several factors, including one’s ethnicity/race, gender, circadian rhythm, drug interactions, and genetics/epigenetics.”  You continue to add “…most known DPYD variants associated with decreased DPD activity are reported to be of low frequency, meaning that a significant proportion of cases of severe toxicity from fluoropyrimidine-based products are unrelated to genetic factors.”  Given that, why will the revised WARNINGS AND PRECAUTIONS statement indicate  “ … patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity….” instead of indicating genetic and non-genetic factors may contribute to a patient’s risk? 


As for the partial denial concerning my requests for pre-screening and dose management, your changes in the WARNINGS AND PRECAUTIONS serves to alert care providers of a risk consequence, a necessary step, but without providing them a guideline(s) for assessing the probability of risk for individual patients the change is insufficient.  It is fair to conclude that the perfect measure for guarding against this risk is unknown at this time, however, I still maintain that pre-screening and dose management practices can serve to provide patients better outcomes.  I offer the following for your further consideration:


·         Genetic pre-screening. Not all genetic variants are known as you indicate.  There are, however, known variants that are likely to place patients at risk of grade 3 or greater toxicity (see  “Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis” in the Journal of Clinical Oncology  (Jan H.M. Schellens et at), published on line Nov 16, 2015 and editorial “Is it Finally Time for a Personalized Medicine Approach for Fluorouracil-Based Therapies?” in the Journal of Clinical Oncology (Steven M. Offer and Robert B. Diasio), Jan 2016).  While we wait for the identification of every variant, we are failing to protect those we can readily identify as patients at risk.

·         “Functional” DPD pre-screening.  You concluded that pre-screening of this nature was “complex” and suffered from “a number of limitations”. I ask that you consider the contributions of Dr Joseph Ciccolini, Marseille FR. He has demonstrated great success at his institution by combining this type of pre-screening in combination with dose adjustment (refer to “Beating the Odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer” British Journal of Clinical Pharmacology, 22 Sep 2015, Joseph Ciccolini et al).  He performs this type of test routinely, at a low cost, with very good patient outcomes.

·         Dose management. 

o   It is true, I have not found a reference in a major oncological journal with a guideline for specific introductory dosing to safeguard against the onset of severe toxic reactions when patients are not first identified with a pre-screening test.  Nor has the NCCN recommended dose management measures for as you noted it dismisses impaired DPD activity as a “rare occurrence” (as a note, credit to the FDA for acknowledging the incidence of impaired DPD activity is not so “rare”; and yes I am quite familiar with the NCCN’s ruling on my petition to change its guidelines). 

o   As you noted, however, Dr. Gamelin et al, published in the Journal of Clinical Oncology, May 2008, and concluded “Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.”   This practice of dose management allows for the tailoring of treatment based on a patient’s ability to metabolize FU (dose increases or decreases as needed).


Once more, I wish to thank you for recognizing the need for change and for agreeing to revise the WARNINGS AND PRECAUTIONS section of the drug labels. I do ask that you consider how best to now help care providers identify at risk patients and to help them achieve desirable outcomes (e.g. pre-screening and dose management practices).  I would welcome the opportunity to discuss further with you how I might help regulatory bodies, care providers, and patients work together to achieve the best possible outcomes.




Ken Surprenant