Product Information (PI) documents for fluorouracil and capecitabine are being updated to expand the existing warning and information about dihydropyrimidine dehydrogenase (DPD) deficiency. Prescribers are advised to consider a reduced starting dose where partial DPD deficiency is detected.
The TGA is working with the sponsors of fluorouracil and its prodrugs capecitabine and flucytosine to include a new warning in the PI about the potential for severe and potentially life-threatening toxicity in patients with a partial DPD deficiency. The Australian PIs for fluorouracil and capecitabine already included a contraindication for patients with known complete DPD deficiency.
The PIs recommend that special attention be paid to patients’ DPD status before therapy or when evaluating patients experiencing fluorouracil-related toxicities.
Review and expert advice
A review by the TGA, which included advice from the Advisory Committee on Medicines (ACM), found that the Australian PIs for capecitabine and fluorouracil should be updated with advice to reduce the starting dose when partial DPD deficiency is detected. The updated warning for fluorouracil states:
'Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with fluorouracil injection (see section 4.3). Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction. Initial dose reduction may impact the efficacy of treatment. Consideration should be given to applicable clinical guidelines.'
The review also found that the capecitabine PIs should include the same warnings about DPD deficiency-related toxicity as the fluorouracil PIs, as well as further information that:
DPD deficiency-related toxicity usually occurs during the first cycle of treatment or after a dose increase.
fatal outcomes have been reported in some cases
laboratory testing for total or partial DPD deficiency should be considered before therapy is initiated or when evaluating patients experiencing related toxicities.
The TGA review followed strengthening of warnings and precautions about DPD deficiency for these products by the European Medicines Agency (EMA). The EMA recommended DPD testing prior to starting treatment and consideration of dose reduction and/or reduced starting dose for those with DPD deficiency. The ACM advised that DPD testing can be a reasonable clinical choice but need not be mandated. The treating team would consider the value of testing for the individual patient, taking into account test availability and cost and the potential for testing to delay treatment.
Adverse event reports
A review of all adverse event reports submitted to the TGA for fluorouracil, capecitabine and flucytosine up to 20 July 2022 found 11 cases where the reporter noted adverse events were possibly or likely due to DPD deficiency. In most of these cases DPD deficiency was not tested for or confirmed in the affected patients. A total of 6 cases were reported to have had a fatal outcome.
Fluorouracil is a prescription medicine indicated alone or in combination with other medicines for the palliative treatment of malignant tumours, particularly of the breast, colon or rectum. It is also used for the treatment of gastric, primary hepatic, pancreatic, uterine (particularly cervical), ovarian and bladder carcinomas.
Fluorouracil should only be used when other proven measures have failed or are considered impractical.
Capecitabine is indicated for the treatment of certain types of colon, colorectal, oesophagogastric and breast cancer.
What to report? You don't need to be certain, just suspicious!
The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.
We particularly request reports of:
all suspected reactions to new medicines (look for the Black Triangle in PI and CMI documents - this symbol identifies medicines that are new or being used differently)
all suspected medicines interactions
suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
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