Fluorouracil response

WARNINGS AND PRECAUTIONS: Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent [Dihydropyrimidine] Dehydrogenase (DPD) Activity

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD² 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 fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil.

Withhold or permanently discontinue fluorouracil 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 fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

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PATIENT COUNSELING INFORMATION

Advise patients to notify their healthcare provider if they have a known DPD deficiency.

Advise patients if they have complete or near complete absence of DPD activity, they are at an increased risk of severe and life-threatening mucositis, diarrhea, neutropenia and neurotoxicity.

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OVERDOSAGE

Administer uridine triacetate within 96 hours following the end of fluorouracil infusion for management of fluorouracil overdose.

Please review the complete therapeutic recommendations that are located here: (1).

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Table 2 summarizes the genetics-based dosing recommendations for fluoropyrimidines using the calculated DPYD activity score (DPYD-AS). The strength of the prescribing recommendations is based on the known impact of some variants (c.1905+1G>A, c.1679T>G, c.2846A>T, c.1129–5923C>G) on DPD activity, the demonstrated relationship between DPD activity and 5- fluorouracil clearance, and between 5-fluorouracil exposure and its toxic effects. Patients who are heterozygous for DPYD decreased/no function variants demonstrate partial DPD deficiency and should receive reduced starting doses. Prospective genotyping of c.1905+1G>A followed by a 50% dose reduction in heterozygous carriers resulted in a rate of severe toxicity comparable to noncarriers[see (9)]. This study thus demonstrated that DPYD genetic testing can reduce the occurrence of severe fluoropyrimidine-related toxicity, and that a dose reduction of 50% is suitable for heterozygous carriers of no function variants (DPYD-AS: 1). For decreased function variants, evidence is limited regarding the optimal degree of dose reduction. For c.2846A>T, a small retrospective study observed that the average capecitabine dose in heterozygous carriers was reduced by 25% compared to noncarriers. In a small prospective study, five patients carrying c.1236G>A (proxy for c.1129–5923C>G) were safely treated with a 25% reduced capecitabine starting dose. This suggests that heterozygous carriers of decreased function variants (DPYD-AS: 1.5) may tolerate higher doses com- pared to carriers of no function variants (DPYD-AS: 1). In patients with DPYD-AS of 1.5, the individual circumstances of a given patient should therefore be considered to determine if a more cautious approach (50% starting dose followed by dose titration), or an approach maximizing potential effectiveness with a potentially higher toxicity risk (25% dose reduction) is preferable. Of note, both studies indicating the suitability of a 25% dose reduction in decreased function variant carriers included only patients receiving capecitabine and no data are currently available for infusional 5-fluorouracil.

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. Similarly, doses should be decreased in patients who do not tolerate the starting dose.

In DPYD poor metabolizers (DPYD-AS: 0.5 or 0), it is strongly recommended to avoid use of 5-fluorouracil-containing regimens. However, if no fluoropyrimidine-free regimens are considered a suitable therapeutic option, 5-fluorouracil administration at a strongly reduced dose combined with early therapeutic drug monitoring may be considered for patients with DPYD-AS of 0.5. It should be noted, however, that no reports of the successful administration of low-dose 5-fluorouracil in DPYD poor metabolizers are available to date. Assuming additive effects of decreased and no function alleles (DPYD-AS: 0.5), it is estimated that a dose reduction of at least 75% would be required (i.e., starting dose <25% of normal dose). Furthermore, in such cases a phenotyping test is advisable to estimate DPD activity and a starting dose.

The US Food and Drug Administration (FDA) and the Health Canada Santé Canada (HCSC) have added statements to the drug labels for 5-fluorouracil and capecitabine that warn against use in patients with DPD deficiency, and prescribing recommendations for 5-fluorouracil, capecitabine, and tegafur are also available from the Dutch Pharmacogenetics Working Group.

November 2018 Update:

The current DPYD guideline recommends to reduce the dose of fluoropyrimidines by 25-50% (from the full standard dose) in DPYD Intermediate Metabolizers with an activity score of 1.5. At the time of the guideline publication, this dose range was recommended due to limited evidence for genotype-guided dosing of decreased function alleles/variants. However, a recent prospective study (PMID: 30348537) provides evidence to support a recommendation for a 50% dose reduction in heterozygous carriers of the decreased function variants c.2846A>T (rs67376798) or c.1129–5923C>G (rs75017182; HapB3 or its tagging SNP c.1236G>A; rs56038477). These data suggest that all Intermediate Metabolizers with an activity score of 1.5 should receive a 50% dose reduction.

Therefore CPIC revises its recommendation such that all DPYD Intermediate Metabolizers should receive a 50% dose reduction from the full standard starting dose, whether the activity score is 1 or 1.5 followed by dose titration, based on clinical judgement and ideally therapeutic drug monitoring.

In addition, recent case reports from patients who are homozygous for c.2846A>T (activity score of 1) indicate that a dose reduction of more than 50% may be required in some carriers of this genotype. Therefore, in patients with an activity score of 1 due to a homozygous c.[2846A>T];[2846A>T] genotype, clinicians should be aware that a >50% reduction in starting dose might be warranted.

Please review the complete therapeutic recommendations that are located here: (2, 3)

DPD Gene Activity Score 0

The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the standard dose is a more than 100-fold overdose.

• Avoid fluorouracil and capecitabine

Tegafur is not an alternative, as this is also metabolized by DPD.

• If it is not possible to avoid fluorouracil and capecitabine: determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly.

A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard dose (150 mg capecitabine every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard dose (150 mg capecitabine every 5 days with every third dose skipped)

DPD [PHENO] [phenotyping indicates reduced function]

The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.

It is not possible to recommend a dose adjustment for this patient based on the genotype only.

• determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose based on phenotype and genotype, or avoid fluorouracil and capecitabine.

Tegafur is not an alternative, as this is also metabolized by DPD.

DPD Gene Activity Score 1

The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.

• Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

Adjustment of the subsequent dose should be guided by toxicity and effectiveness. However, in one study involving 17 patients with gene activity 1, the average dose after titration was 57% of the standard dose.

Tegafur is not an alternative, as this is also metabolized by DPD.

DPD Gene Activity Score 1.5

The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.

• Start with 50% of the standard dose or avoid fluorouracil and capecitabine.

After starting treatment, the dose should be adjusted based on toxicity and effectiveness. In a study involving 17 patients with genotype 1/2846T, the average dose after titration was 64% of the standard dose. For 51 patients with genotype 1/1236A, the average dose after titration was 74% of the standard dose. Tegafur is not an alternative, as this is also metabolized by DPD.

DPD Gene Activity Score 0 (Cutaneous fluorouracil)

The gene variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of fluorouracil/capecitabine to inactive metabolites means that the normal dose is an overdose.

• avoid fluorouracil

NOTE: If a patient has two different genetic variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the variations are on a different allele. If both variations are on the same allele, this patient actually has a gene activity score 1, for which no increased risk of severe, potentially fatal toxicity has been found with cutaneous use. These two situations can only be distinguished by determining the enzyme activity (phenotyping). This recommendation only applies if the patient has virtually no enzyme activity.

Background Information - Mechanism

Fluorouracil is mainly (> 80%) converted by dihydropyrimidine dehydrogenase (DPD) to inactive metabolites. Lower metabolic activity of DPD leads to increased intracellular concentrations of fluorodeoxyuridine monophosphate, the active metabolite of fluorouracil and its prodrug capecitabine. This leads to an increased risk of adverse events such as neutropenia, thrombopenia and hand-foot syndrome.

For more information about the phenotype gene activity score: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for DPD).

Please review the complete therapeutic recommendations that are located here: (5) .