Page 110 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
SPC Xeloda (capecitabine) 26-07-16.
gene act. 0: CTC- AE 5
gene act. 0.5-1.5: CTC-AE 4
Warning: Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity. Patients with low or absent DPD activity, an enzyme involved in 5-FU degradation, are at increased risk for severe, life-threatening, or fatal adverse reactions caused by 5-FU. Although DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus, which can cause complete or near complete absence of DPD enzymatic activity (as determined from laboratory assays), have the highest risk of life- threatening or fatal toxicity and should not be treated with Xeloda. No dose has been proven safe for patients with complete absence of DPD activity. For patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the benefits of Xeloda are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution and frequent monitoring with dose adjustment according to toxicity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by specific test. In patients with unrecognised DPD deficiency treated with capecitabine, life-threatening toxicities manifesting as acute overdose may occur. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately.
Warning:
Based on post-marketing 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 of toxicity and severe, life-threatening, or fatal adverse reactions caused by 5-FU (e.g., mucositis, diarrhoea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by 5-FU.
Withhold or permanently discontinue 5-FU based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No 5-FU dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in
ref. 40 – FU SPC Fluorouracil 29-07-16 (USA) and othera
Level of evidence score: 0
gene act. 0: CTC- AE 5
gene act. 0.5-1.5: CTC-AE 5
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