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The European Medicines Agency (EMA) has started a review into the screening of patients before they begin treatment with certain drugs.

Most of the drugs in question are chemotherapies, and they include 5-fluorouracil (5-FU) and the related drugs capecitabine (Xeloda, Genentech) and tegafur, which are converted to fluorouracil in the body. These chemotherapies are very widely used in the treatment of a variety of cancer types, including colorectal, breast, and head and neck cancers.

This class of drugs also includes flucytosine (Ancobon, Valeant Pharmaceuticals), which is used for severe fungal infections.

The review will examine existing screening methods and their value in identifying patients who are at increased risk of severe side effects with these therapies, the agency notes. 

The screening methods aim to identify individuals who are deficient in the enzyme dihydropyrimidine dehydrogenase (DPD), which is needed to break down fluorouracil.

Without this enzyme, levels of the drug can build up in the body to toxic, even life-threatening levels, with side effects that include neutropenia, neurotoxicity, severe diarrhea, and stomatitis, the agency notes.

“Patients with a complete deficiency of DPD should therefore not be given fluorouracil, or medicines that can form it in the body,” the agency notes. The product information for most of these medicines states that they should not be used in patients with complete DPD deficiency, it adds.

Genetic testing for DPD deficiency is recommended for most medicines used in the treatment of cancer, but systematic screening for DPD deficiency before starting treatment is not mandatory. In addition, new data on genetic testing and other DPD screening methods have recently been published, and these may impact current recommendations, the agency notes.

Experts Debating the Issue

The EMA review comes just after several high-profile cases of fatal reactions.

In France, the families of four patients who died after fatal reactions to these chemotherapies have filed a lawsuit demanding to know why these patients had not been tested before treatment was initiated; the argument is that such testing may have prevented these deaths.

In the UK, a fatal reaction in a patient who was not tested was highlighted in the media.

This has led some European experts to openly question whether DPD testing should be incorporated into oncology practice in order to safeguard patients from the possible lethal consequences of fluoropyrimidine treatment.

In his Medscape video commentary, David Kerr, MD, professor of cancer medicine at the Oxford Cancer and Haematology Centre in Oxford, England, argues for germline testing for DPD deficiency, and discusses a recent study on the issue in The Lancet Oncology

However, another UK expert, Karol Sikora, PhD, MB BChir, professor of cancer medicine at the University of Buckingham, argues against such testing in his video commentary.

With the US medical community not immune to litigation, Medscape Medical News wanted to find out what oncology experts in the United States thought of the idea of screening every patient for DPD deficiency prior to initiating 5-FU/capecitabine.

The three US experts approached were against routine DPD testing, arguing that these are very widely used chemotherapies, that DPD deficiency is very rare, that patients sometimes react badly even if they are not deficient, and that there is an antidote to overdosages.

Review Carried Out by PRAC

In its announcement, the EMA said that it will now assess the available data in relation to existing screening methods to detect DPD deficiency, and will recommend whether any changes are needed to the way these medicines are used in order to ensure their safe use.

The review is being carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the EMA’s committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.

The PRAC recommendations will then be forwarded to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt an opinion.

The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all EU member states.

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