Other safety alerts
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| Australia: Fluorouracil and capecitabine: DPD deficiency |
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Therapeutic Goods Administration (TGA) announces that 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.
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. 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.
A review of all adverse event reports submitted to the TGA for fluorouracil, capecitabine and flucytosine up to 20 Jul 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.
Please refer to the following website in TGA for details:
http://www.tga.gov.au/news/safety-updates/fluorouracil-and-capecitabine-dpd-deficiency
In Hong Kong, there are registered pharmaceutical products containing fluorouracil (4 products) and capecitabine (23 products). All products are prescription-only medicines. There is no registered pharmaceutical product containing flucytosine. So far, the Department of Health (DH) has received adverse drug reaction related to fluorouracil (102 cases) and capecitabine (70 cases; of which one case was related to DPD deficiency).
Related news was previously issued by EMA and the United Kingdom Medicines and Healthcare products Regulatory Agency, and was posted on the Drug Office website since 18 Mar 2019, with the latest update posted on 23 Oct 2020. Letters to inform local healthcare professionals were issued by the DH on 18 Mar 2019.
In Jun 2021, the Registration Committee of the Pharmacy and Poisons Board discussed the matter and decided that the package insert of products containing fluorouracil and capecitabine should include the relevant safety information (including the increased risk of severe and potentially life-threatening toxicity in patients with partial DPD deficiency and consideration for a reduced starting dose in these patients when using parenteral fluorouracil and capecitabine). The DH will remain vigilant on safety update of the drugs issued by other overseas drug regulatory authorities.
Ends/Friday, Sep 16, 2022
Issued at HKT 15:00
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