Adult: As part of chemotherapeutic regimen (usually in combination with leucovorin alone or with either oxaliplatin or irinotecan): 200-600 mg/m2, depending on the administration (as bolus or infusion). Dosing frequency (either weekly, bimonthly or monthly) and the number of cycles may vary based on the treatment regimen used and on treatment success and tolerability.
Intravenous Pancreatic carcinoma
Adult: As part of chemotherapeutic regimen (usually in combination with folinic acid or gemcitabine): 200-500 mg/m2 via bolus inj or via infusion, depending on the regimen used and repeated cyclically.
Intravenous Gastric cancer
Adult: As part of platinum-containing multidrug chemotherapeutic regimen: 200-1,000 mg/m2 via continuous infusion over 24 hours. Dosing frequency and the length of each cycle depends on fluorouracil dose and the regimen used.
Intravenous Breast cancer
Adult: As part of chemotherapeutic regimen (usually in combination with either cyclophosphamide and methotrexate, epirubicin and cyclophosphamide or methotrexate and leucovorin: 500-600 mg/m2 via bolus inj repeated every 3-4 weeks as necessary.
Adult: As 5% cream: Apply to lesions 1-2 times daily. As 5% solution: Apply to lesions bid. Treatment duration: 3-6 weeks (may be up to 10-12 weeks as required).
Topical/Cutaneous Actinic keratoses
Adult: As 0.5% cream: Apply a thin film once daily to the affected area for up to 4 weeks as tolerated. As 1% cream: Apply to lesions bid for 2-6 weeks. As 4% cream: Apply to lesions once daily for 4 weeks, as tolerated. As 5% cream or solution (2% or 5%): Apply to lesions 1-2 times daily for 2-4 weeks.
Special Patient Group
Pharmacogenomics:
The DPYD gene encodes the enzyme dihydropyrimidine dehydrogenase (DPD), which catalyses the first and the rate-limiting step in the breakdown of the pyrimidine nucleotides thymine and uracil. DPD also catalyses the rate-limiting step in the breakdown of fluoropyrimidines.
DPYD alleles are classified according to activity status, functional allele type (e.g. *1, *4, *5, *6, *9A) and no function allele type (e.g. *2A, *13, rs67376798). No function DPYD variants have been related to low DPD activity and an increased risk of toxicity with fluoropyrimidines. Individuals who carry combinations of normal function, decreased function DPYD alleles are known as poor metabolisers. Approx 3-5% of Caucasians have partial DPD deficiency and 0.2% have complete DPD deficiency. The NIH Genetic Testing Registry (GTR) demonstrates genetic tests that are currently available for DPYD gene and fluorouracil drug response. The DPYD*2A is the most well-studied and most commonly tested variant. Biochemical tests that assess the level of the DPD enzyme include biochemical assays such as analyte testing (e.g. measuring the amount of thiamine and uracil in the urine or blood) or an enzyme assay (e.g. directly measuring the activity of DPD using RNA extracted from blood cells and measuring the DPD mRNA copy number).
CPIC and DPWG cited some guidelines on DPYD phenotype and fluoropyrimidine dosing.
CPIC Guideline (2017 update) DPYD normal metaboliser (Activity score 2; carriers of 2 normal function alleles)
Normal DPD activity. No dosage adjustment required, follow recommended dosing.
DPYD intermediate metaboliser (Activity score 1 or 1.5; carrier of 1 normal function allele and 1 no function allele; or 1 decreased function allele; or carriers of 2 decreased function alleles)
Decreased DPD activity resulting in increased risk of severe or life-threatening drug toxicity. Reduce initial dose by 50% (activity score 1) or 25-50% (activity score 1.5) followed by dose titration according to toxicity and therapeutic drug monitoring.
DPYD poor metaboliser (Activity Score of 0 or 0.5; carriers of 2 no function alleles; or carriers of 1 no function allele and 1 decreased function allele)
Complete DPD deficiency resulting in increased risk of severe or life-threatening toxicity. Activity score 0.5: Avoid fluorouracil or use an alternative. If alternative agents are not considered, fluorouracil should be administered at a strongly reduced dose with early therapeutic drug monitoring. Activity score 0: Avoid fluorouracil or fluorouracil prodrug-based regimens.
DPWG Guideline (November 2018 update)
DPYD Activity Score 0 (cutaneous)
Genetic variation increases the risk of severe, life-threatening toxicity. Reduced conversion of fluorouracil to inactive metabolites means that the standard dose is an overdose. Use an alternative drug.
DPYD Activity Score 0 (systemic)
Genetic variation increases the risk of severe, life-threatening toxicity. Reduced conversion of fluorouracil to inactive metabolites means that the standard dose is a more than 100-fold overdose. Use an alternative drug; if not possible, determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly, or adjust the initial dose based on efficacy and toxicity.
DPYD Activity Score 0.5
Genetic variation increases the risk of severe, life-threatening toxicity. Reduced conversion of fluorouracil to inactive metabolites means that the normal dose is an overdose. Start with 25% of the standard dose or use an alternative. Initial dose adjustment should be guided by toxicity and effectiveness. Tegafur is not an alternative, as it is also metabolised by DPD.
DPYD Activity Score 1
Genetic variation increases the risk of severe, life-threatening toxicity. Reduced conversion of fluorouracil to inactive metabolites means that the normal dose is an overdose. Start with 50% of the standard dose or use an alternative. Initial dose adjustment should be guided by toxicity and effectiveness. Tegafur is not an alternative, as it is also metabolised by DPD.
DPYD Activity Score 1.5
Genetic variation increases the risk of severe, life-threatening toxicity. Reduced conversion of fluorouracil to inactive metabolites means that the normal dose is an overdose. Start with 75% of the standard dose or use an alternative. Initial dose adjustment should be guided by toxicity and effectiveness. Tegafur is not an alternative, as it is also metabolised by DPD.
Renal Impairment
Intravenous: Dose reduction may be required.
Hepatic Impairment
Intravenous:
Dose reduction may be required.
Incompatibility
Avoid admixture with acidic drugs or drugs that decompose in an alkaline environment. Incompatible with cytarabine, diazepam, methotrexate, platinum compounds (e.g. carboplatin, cisplatin), doxorubicin and other anthracyclines, folinic acid/leucovorin, droperidol, filgrastim, gallium nitrate, metoclopramide, morphine, ondansetron, parenteral nutrition and vinorelbine; do not administer in the same IV line.
Contraindications
Near-complete or total absence of dihydropyrimidine dehydrogenase (DPD) activity. Bone marrow depression (after treatment with radiotherapy or other antineoplastic agents); serious infections (e.g. Herpes zoster, chickenpox). Seriously debilitated patients. Concomitant use with antiviral nucleoside drugs (e.g. brivudine, sorivudine and analogues) and live vaccines. Pregnancy and lactation.
Special Precautions
Patients with history of heart disease, partial DPD deficiency. Renal and hepatic impairment.
Adverse Reactions
Significant: Hand-and-foot syndrome/palmar-plantar erythrodysaesthesia syndrome, hyperammonemic encephalopathy (e.g. altered mental status, confusion, disorientation, coma, ataxia), mucositis, neurologic toxicity (e.g. confusion, disorientation, ataxia, visual disturbance. Topical: Hypersensitivity (e.g. severe pruritus or eczema, allergic contact dermatitis), local skin reactions (e.g. erythema followed by vesiculation, desquamation, erosion; local oedema, irritation, pain, pruritus, scaling, scarring, soreness, stinging, ulceration), photosensitivity. Blood and lymphatic system disorders: Pancytopenia, febrile neutropenia, thrombophlebitis. Cardiac disorders: Angina. Eye disorders: Lacrimal duct stenosis, visual changes, excessive lacrimation, photophobia, eye movement disturbance, optic neuritis, diplopia, decreased visual acuity, conjunctivitis, blepharitis. Gastrointestinal disorders: Gastrointestinal ulceration and bleeding, sloughing, nausea, vomiting, watery diarrhoea, dehydration sepsis. General disorders and administration site conditions: Delayed wound healing, fatigue, weakness, fever. Immune system disorders: Anaphylaxis, generalised allergic reactions. Infections and infestations: Infections. Metabolism and nutrition disorders: Hyperuricaemia, anorexia. Nervous system disorders: Headache, dizziness, somnolence. Psychiatric disorders: Euphoria. Respiratory, thoracic and mediastinal disorders: Bronchospasm, epistaxis. Skin and subcutaneous tissue disorders: Dry skin, fissuring, vein pigmentation, alopecia. Potentially Fatal: Bone marrow suppression (e.g. neutropenia, thrombocytopenia, anaemia), gastrointestinal toxicity (e.g. stomatitis, diarrhoea), cardiotoxicity (e.g. angina, MI, arrhythmia, heart failure, cardiogenic shock).
This drug may cause visual changes, if affected do not drive or operate machinery. Avoid prolonged exposure to UV radiation (e.g. natural sunlight, tanning salon). Avoid topical application to mucous membranes.
Monitoring Parameters
Monitor CBC with differential and platelet count, renal function tests, LFTs, INR and prothrombin time (in patients receiving concomitant-coumarin derivative anticoagulants). Monitor for signs and symptoms of palmar-plantar erythrodysesthesia syndrome, cardiotoxicity, CNS toxicity, stomatitis, diarrhoea and hyperammonemic encephalopathy.
Overdosage
Symptoms: Nausea, vomiting, diarrhoea, gastrointestinal ulcers, haemorrhage and bone marrow depression (e.g. thrombocytopenia, leucopenia, agranulocytosis). Management: Symptomatic and supportive treatment.
Drug Interactions
Increased INR with warfarin. May increase the plasma concentration of phenytoin. Cimetidine may increase the plasma concentration of fluorouracil. May increase risk of toxicity with other cytotoxic agents used in combination with chemotherapy or in radiation therapy. Anti-tumour efficacy or toxicity may be altered by metronidazole, allopurinol. Increased risk of agranulocytosis with clozapine. Potentially Fatal: Nucleoside analogues (e.g. brivudine, sorivudine) increases plasma concentration of fluorouracil, resulting in toxicological reactions. Concurrent administration of live vaccines may potentially cause serious infections.
Action
Description: Mechanism of Action: Fluorouracil is a pyrimidine analogue that interferes with DNA synthesis by blocking the conversion of deoxyuridylic acid to thymidylic acid resulting to inhibition of cell proliferation of fast-growing cells and causes cell death. It also interferes with RNA synthesis. Pharmacokinetics: Absorption: Approx 6% of topical dose is absorbed systemically (5% cream). Time to peak plasma concentration: Approx 1 hour (topical, 4% cream). Distribution: Distributed throughout the body including brain tissue, CSF, bone marrow, intestinal mucosa and liver. Metabolism: Metabolised in the liver by dehydrogenase enzyme to form active metabolites 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2’-deoxyuridine-5’-O-monophosphate (F-dUMP). Excretion: Via urine (5-20% as unchanged drug; as metabolites urea and α-fluoro-β-alanine over 3-4 hours); via lungs (large amount as carbon dioxide). Elimination half-life: 8-20 minutes (bolus); approx 16 minutes (IV).
Chemical Structure
Fluorouracil Source: National Center for Biotechnology Information. PubChem Database. 5-Fluorouracil, CID=3385, https://pubchem.ncbi.nlm.nih.gov/compound/5-Fluorouracil (accessed on Jan. 21, 2020)
Storage
Store between 20-25°C. Do not freeze. Protect from light. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
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