5-fluorouracil (intravenous), capecitabine, tegafur: DPD testing recommended before initiation to identify patients at increased risk of severe and fatal toxicity

Patients with complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency are at increased risk of severe and fatal toxicity during treatment with these medicines. All patients should be tested for DPD deficiency before initiation to minimise the risk of these reactions.

From:
Medicines and Healthcare products Regulatory Agency
Published
22 October 2020
Therapeutic area:
Cancer

Advice for healthcare professionals:

  • patients with complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency are at increased risk of severe and fatal toxicity during treatment with medicines containing 5-fluorouracil (intravenous), capecitabine, and tegafur
  • DPD deficiency is most often caused by inherited variants of the DYPD gene
  • test all patients for DPD deficiency before initiation of treatment with these products
  • ask patients whether they or their family members have history of complete or partial DPD deficiency
  • do not treat patients with known complete DPD deficiency with these medicines
  • for patients with partial DPD deficiency, consider a reduced starting dose
  • monitor all patients for toxicity particularly during the first cycle of treatment or after a dose increase
  • advise patients that despite negative test results for DPD deficiency, severe toxicity may still occur and ensure they have a copy of the patient information leaflet
  • report suspected adverse drug reactions associated with medicines to the Yellow Card scheme

Review of DPD testing prior to treatment

Fluoropyrimidines are a group of anti-cancer medicines including 5-fluorouracil and its prodrugs capecitabine and tegafur – see Background.

The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), a key enzyme involved in catabolism of 5-fluorouracil. DPD deficiency is most often caused by inherited variants of the DYPD gene. Treatment of patients with DPD deficiency with these medicines increases risk of serious and fatal toxicities (see Characteristics of reactions).

Complete DPD deficiency is rare (0.01–0.5% of Caucasian people), but partial DPD deficiency is estimated to affect 3–9% of Caucasian people.[footnote 1] Most data on the frequency of DPD deficiency are in Caucasian people and rates may differ in other ethnic groups.

A recent European safety review has recommended that, despite uncertainties in the optimal pre-treatment testing methodologies, all patients should undergo testing for DPD deficiency prior to the initiation of these treatments. A letter has been sent to healthcare professionals to inform of these requirements. Safety warnings will also be updated in the Summary of Product Characteristics and Patient Information Leaflets (product information).

The review also considered and made recommendations for flucytosine, indicated for severe systemic fungal infections.

Fluorouracil is also available in topical formulations. Due to very low systemic absorption via this route, DPD testing is not required prior to initiation of topical treatment. For topical 5-fluorouracil (5%), if systemic drug toxicity is confirmed or suspected, determination of DPD activity should be considered in line with existing UK product information.

Characteristics of reactions

DPD activity is rate limiting in the catabolism of 5-fluorouracil. Patients with DPD deficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia, and neurotoxicity.

DPD-deficiency-related toxicity usually occurs during the first cycle of treatment or after dose increase.

Treatment considerations in patients with DPD deficiency

Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated systemically with fluoropyrimidines.

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 the risk of severe 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 and so, in the absence of serious toxicity, subsequent doses may be increased with careful monitoring.

Despite negative test results for DPD deficiency, severe toxicity may still occur and patients should be counselled on the benefits and risks of their cancer treatments and provided with the patient information leaflet.

Reports in the UK

Up to 17 June 2020, the Yellow Card scheme has received 30 reports associated with a fatal outcome that describe a known or suspected DPD deficiency with fluorouracil and capecitabine. These include reports of testing and confirmation of DPD deficiency after patients were treated with capecitabine and developed severe and fatal toxicity.

Caution should be exercised in interpreting the Yellow Card data as they may be affected by under-reporting.

Genotyping and phenotyping

Consider clinical and other applicable guidelines before starting patients on these medicines.

The European review considered that pre-treatment genotype testing for mutations of the DPYD gene can identify patients with DPD deficiency. The review described four DPYD variants that can cause complete absence or reduction of DPD enzymatic activity (see details of specific genotype advice in the amended product information). However, other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.

Data on the frequency of the four DPYD variants in populations other than Caucasian people are limited but their frequency is considered to vary between different ethnic groups.

The European review recommended that phenotyping can also be used to test for DPD deficiency through the measurement of pre-therapeutic blood levels of the endogenous DPD substrate uracil in plasma. There are uncertainties regarding uracil thresholds to define complete and partial DPD deficiency, however, indicative blood uracil cut-off levels are provided in the amended product information for these medicines.

Therapeutic drug monitoring of continuous 5-fluorouracil infusions

The European review considered that complementary to DPD deficiency testing before initiation of treatment, therapeutic drug monitoring of 5-fluorouracil may improve clinical outcomes in patients treated with continuous 5-fluorouracil infusions by reducing toxicities and improving efficacy. The target area under the curve (AUC) is between 20 and 30 mg x h/L.

Background

These measures affect the following medicines:

  • Parenteral 5-fluorouracil: a component of the standard therapy for a variety of malignancies, including colorectal, pancreatic, gastric, breast and head and neck cancer, mostly used in combination with other anticancer agents

  • Capecitabine: an oral prodrug of 5-fluorouracil, indicated for the treatment of colorectal, gastric and breast cancer

  • Tegafur: an oral prodrug of 5-fluorouracil, available in combination with two modulators of 5-fluorouracil metabolism, gimeracil, and oteracil for the treatment of gastric cancer

Report on a Yellow Card

Please report suspected serious adverse drug reactions (ADRs) associated with medicines containing 5- fluorouracil, capecitabine or tegafur to the MHRA via the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, treatment dates, and product brand name.

Article citation: Drug Safety Update volume 14, issue 3: October 2020: 1.

 

  1. European Medicines Agency. ‘Public Assessment Report. Fluorouracil and fluorouracil related substances (capecitabine, tegafur and flucytosine) containing medicinal products’. 27 March 2020. ↩

Updates to this page

Published 22 October 2020
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