Loading
Before your first dose of fluorouracil (5-FU) given into a vein, capecitabine tablets or tegafur, you should have a blood test for DPD deficiency. A few people break these drugs down very slowly, and a normal dose can make them seriously ill. If the test finds this, the dose is lowered or a different drug is chosen. A normal result does not rule out side effects, so still report them quickly.
Fluoropyrimidines are cleared by dihydropyrimidine dehydrogenase (DPD). The EU review of 2020 recommends phenotype and/or genotype testing before systemic fluorouracil, capecitabine or tegafur, contraindicates them in known complete deficiency and advises a reduced starting dose in partial deficiency; the MHRA adopted the same advice for the UK in October 2020 ('test all patients'). Since October 2025 the US capecitabine label also tells prescribers to test for DPYD variants before starting unless treatment is urgent, while noting no FDA-authorised test exists.
There are two ways to test. Genotyping reads the four DPYD variants named in the EU product information (c.1905+1G>A, c.1679T>G, c.2846A>T, c.1236G>A/HapB3), which are considered virtually absent in people of African or Asian ancestry. Phenotyping measures plasma uracil: the EU product information treats 16 to under 150 ng/mL as indicative of partial and 150 ng/mL or more as indicative of complete deficiency, to be read with caution when kidney function is impaired.
Dosing by genotype uses an activity score. CPIC (2017 update) recommends a 50% reduction at activity score 1 (strong) and 25 to 50% at 1.5 (moderate), avoiding fluorouracil and its prodrugs at 0 or 0.5, with the dose raised in later cycles if the first two are tolerated. DPWG (2020) recommends 50% at both 1 and 1.5 and avoiding tegafur below 2, and calls testing 'essential'. Every source says severe toxicity can still occur with a normal result, most often in the first cycle or after a dose increase.
Why: In people of European ancestry, up to half of one per cent lack the enzyme completely and three to nine per cent have a partial lack (MHRA figures); at a normal dose they can have severe or fatal side effects.
“test all patients for DPD deficiency before initiation of treatment with these products”
Medicines and Healthcare products Regulatory Agency (UK) 2020
Why: A known family history can identify a risk the standard test misses, and the result already known in a relative can speed the decision.
“ask patients whether they or their family members have history of complete or partial DPD deficiency”
Medicines and Healthcare products Regulatory Agency (UK) 2020
Why: The EU recommends testing without fixing the method: genotyping reads inherited variants, while a uracil level measures how well the enzyme is working.
“Phenotype and/or genotype testing prior to the initiation of treatment with Xeloda is recommended despite uncertainties regarding optimal pre-treatment testing methodologies.”
Why: A high uracil level suggests the enzyme is not working, but poor kidney function can also raise it and give a false alarm.
“Despite uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥ 16 ng/mL and < 150 ng/mL should be considered indicative of partial DPD deficiency and associated with an increased risk for fluoropyrimidine toxicity.”
Why: Without the enzyme the drug builds up to dangerous levels; no dose has been shown to be safe.
“Treatment with fluorouracil, capecitabine or tegafur-containing medicines is contraindicated in patients with known complete DPD deficiency.”
Why: A lower first dose brings the risk of severe side effects in carriers close to that of non-carriers.
“Activity score 1: Reduce dose by 50% Activity score 1.5: Reduce dose by 25% to 50%”
CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018 · Activity score 1: Strong Activity score 1.5: Moderate
Why: Some carriers tolerate a full dose, and staying on a reduced dose without need may make the treatment less effective.
“Given that some patients carrying decreased or no function variants tolerate normal doses of 5-fluorouracil, to maintain effectiveness, doses should be increased in subsequent cycles in patients experiencing no or clinically tolerable toxicity in the first two chemotherapy cycles or with subtherapeutic plasma concentrations.”
CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018
Why: Most severe reactions from DPD deficiency appear in the first cycle, and the test does not find every person at risk.
“monitor all patients for toxicity particularly during the first cycle of treatment or after a dose increase”
Medicines and Healthcare products Regulatory Agency (UK) 2020
Why: Severe diarrhoea, mouth sores, fever or infection still need same-day contact with the team.
“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”
Medicines and Healthcare products Regulatory Agency (UK) 2020
Why: Uridine triacetate is an antidote that limits the damage fluorouracil does when there is too much of it.
“Administer uridine triacetate within 96 hours for management of XELODA overdose.”
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
Test before the first systemic dose, act on the result, and keep watching. Europe and the UK test every patient (EMA 2020, MHRA 2020), by genotype, uracil level or both; the US label has since October 2025 told prescribers to genotype before capecitabine unless treatment is urgent. Avoid fluoropyrimidines in complete deficiency. For partial deficiency by genotype, the two pharmacogenetic guidelines differ at activity score 1.5: CPIC (2017) allows a 25 to 50% reduction (moderate) and DPWG (2020) recommends 50%; both reduce by 50% at activity score 1 (CPIC strong). CPIC adds titration upwards after two tolerated cycles. DPWG alone recommends phenotyping where the genotype cannot give a score, and avoiding tegafur in any carrier. A normal result does not remove the need to monitor the first cycle.
European Medicines Agency 2020 · Medicines and Healthcare products Regulatory Agency (UK) 2020 · European Medicines Agency (EPAR product information) 2026 · US Food and Drug Administration label (DailyMed) 2025 · CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018 · DPWG, Royal Dutch Pharmacists Association (European Journal of Human Genetics, Lunenburg et al.) 2020
Where it differs: Measures plasma uracil before treatment rather than reading DPYD variants; France is the country best known for it, and the EU product information gives the thresholds (16 to under 150 ng/mL partial, 150 ng/mL or more complete deficiency).
Evidence: The EU review accepted both methods because the best one is uncertain. A uracil test can find deficiency from causes other than the four common variants, but kidney impairment raises uracil and can mislead. DPWG recommends phenotyping where a genotype cannot be scored, and for any homozygous carrier.
European Medicines Agency (EPAR product information) 2026 · Medicines and Healthcare products Regulatory Agency (UK) 2020 · DPWG, Royal Dutch Pharmacists Association (European Journal of Human Genetics, Lunenburg et al.) 2020
Where it differs: The Dutch guideline starts every heterozygous carrier at half dose of fluorouracil or capecitabine, recommends avoiding tegafur at any activity score below 2, and avoids systemic and cutaneous fluorouracil at a score of 0.
Evidence: The DPWG text compares itself with CPIC: CPIC allows 25 to 50% at a score of 1.5 on the basis of small capecitabine studies and makes no tegafur recommendation because evidence is too limited.
DPWG, Royal Dutch Pharmacists Association (European Journal of Human Genetics, Lunenburg et al.) 2020 · CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018
Where it differs: The US label (boxed warning and section 2.1, revised 10/2025) tells prescribers to test for DPYD variants before capecitabine unless immediate treatment is necessary, says no FDA-authorised test is available, and gives no dose for partial deficiency beyond individualising it.
Evidence: Regulatory labelling, not a graded guideline. The label notes that available tests vary in which variants they detect.
Where it differs: Laboratories test a defined minimum set of DPYD variants (tier 1) and an extended list (tier 2) rather than only the four variants named in the EU product information.
Evidence: A 2024 joint consensus of AMP, ACMG, CPIC, CAP, DPWG and others sets out the tiers for laboratory assays; only its abstract was read, and it states its recommendations are a reference guide, not prescriptive.
Where it differs: Adjusts the dose of an infusional fluorouracil regimen by the measured blood level rather than by body surface area alone.
Evidence: The EU review says it may improve clinical outcomes as a complement to pre-treatment testing; the MHRA gives the target area under the curve as 20 to 30 mg x h/L.
European Medicines Agency 2020 · Medicines and Healthcare products Regulatory Agency (UK) 2020
A cheap gene test for DPYD, UGT1A1 and TPMT or NUDT15 before fluoropyrimidines, irinotecan or thiopurines identifies people at risk of severe or fatal toxicity so their dose can be lowered. The EMA has recommended DPD testing since 2020; US uptake remains partial.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Phenotype and/or genotype testing before fluoropyrimidines “Phenotype and/or genotype testing is therefore recommended before starting treatment with fluoropyrimidines.” | Regulatory recommendation (not graded) | European Medicines Agency 2020 |
| Test for DPYD variants before capecitabine unless immediate treatment is necessary (US label) “Prior to initiating XELODA, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary.” | Boxed warning (10/2025) | US Food and Drug Administration label (DailyMed) 2025 |
| Normal metabolisers: label dose “Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage and administration.” | Strong | CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018 |
| Activity score 1: reduce the starting dose by 50%; 1.5: by 25 to 50% | Activity score 1: Strong Activity score 1.5: Moderate | CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018 |
| Activity score 0: avoid fluorouracil and its prodrugs “Activity score 0: Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.” | Strong | CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018 |
| Tegafur: no CPIC recommendation “As such, tegafur is rated as a CPIC “no recommendation” (see Supplement for definition).” | no recommendation | CPIC (Clinical Pharmacology & Therapeutics, Amstutz et al.) 2018 |
| DPYD genotyping before fluoropyrimidines “This score dictates that DPYD genotyping prior to treatment must be performed for all patients initially being prescribed therapy with 5-FU, capecitabine or tegafur with DPD inhibitors, to optimize the initial dose and to prevent potentially fatal toxicity.” | Clinical implication score: essential | DPWG, Royal Dutch Pharmacists Association (European Journal of Human Genetics, Lunenburg et al.) 2020 |
Shares Pharmacogenomic testing before chemotherapy, DPYD genotyping and DPD phenotyping before fluoropyrimidines, Dose reduction, interruption and discontinuation, Neutropenia.
Shares Uridine triacetate, Fluorouracil (5-FU), Capecitabine.
Shares Pharmacogenomic testing before chemotherapy, DPYD genotyping and DPD phenotyping before fluoropyrimidines, Dose reduction, interruption and discontinuation, Neutropenia.
Shares Living with FOLFIRINOX, NALIRIFOX and gemcitabine with nab-paclitaxel, Fluorouracil (5-FU).
Shares Uridine triacetate, Fluorouracil (5-FU), Capecitabine.
Shares Living with FOLFIRINOX, NALIRIFOX and gemcitabine with nab-paclitaxel, Living with FOLFOX, CAPOX, FOLFIRI and the EGFR antibodies, DPYD genotyping and DPD phenotyping before fluoropyrimidines, Dose reduction, interruption and discontinuation.
Shares Living with FOLFIRINOX, NALIRIFOX and gemcitabine with nab-paclitaxel, Test DPYD, UGT1A1 and TPMT/NUDT15 before the first dose, everywhere, Living with FOLFOX, CAPOX, FOLFIRI and the EGFR antibodies.