Flucytosine (Ancotil): new contraindication in patients with DPD deficiency

Flucytosine is a prodrug of 5-fluorouracil used to treat systemic yeast and fungal infections and can cause life-threatening and severe toxicity in patients with complete and partial dihydropyrimidine dehydrogenase (DPD) deficiency. Although pre-testing of DPD status before flucytosine treatment is not required, a new contraindication for patients with complete DPD deficiency has been introduced.

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

Advice for healthcare professionals:

  • flucytosine should not be used in patients with known complete dihydropyrimidine dehydrogenase (DPD) deficiency due to the risk of life-threatening toxicity

  • patients with a partial DPD deficiency are also at increased risk of severe toxicity

  • do not delay antimycotic therapy with flucytosine for pre-treatment testing of DPD deficiency; however, consider determination of DPD activity if drug toxicity is confirmed or suspected

  • in cases of drug toxicity, consider stopping treatment with flucytosine

  • report suspected adverse drug reactions associated with flucytosine on a Yellow Card

New recommendations following review

Flucytosine is an antifungal drug authorised to treat systemic yeast and fungal infections. It is typically used in combination with amphotericin to treat cryptococcal meningitis, severe systemic candidiasis, and other long-standing fungal infections. Flucytosine is a 5-fluorouracil prodrug, and systemic exposure of 5-fluorouracil has been observed in patients treated with flucytosine.

Following a European review of fluorouracil and related medicines, treatment with flucytosine is now contraindicated in patients with known complete DPD deficiency. A letter has been sent to healthcare professionals to inform of this new contraindication.

In order to avoid a delay in starting antimycotic therapy, testing for DPD deficiency is not required before treatment with flucytosine. However, determination of DPD activity should be considered when there is a confirmed or suspected drug toxicity. In case of suspected drug toxicity, consideration should be given to stopping treatment with flucytosine.

For recommendations for oncological medicines in which screening patients for DPD deficiency before treatment is recommended, see recommendation to identify patients at increased risk of severe and fatal toxicity.

About DPD deficiency

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

Patients with known complete DPD deficiency are at higher risk of developing life-threatening toxicity and must not be treated with flucytosine. In patients with partial DPD deficiency, the risk of severe drug toxicity is increased, with the level of toxicity correlating with the extent of DPD deficiency.

The majority of data on the frequency of DPD deficiency are in Caucasian people. The European review considered that complete DPD deficiency is rare (0.01–0.5% of Caucasian people). Partial DPD deficiency is estimated to affect 3–9% of Caucasian people.

Report on a Yellow Card

Please continue to report suspected adverse drug reactions (ADRs) on a Yellow Card. Reporting suspected ADRs, even those known to occur in association with the medicine, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.

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: 2.

Updates to this page

Published 22 October 2020
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