Les renseignements du Formulaire de médicaments s’adressent aux professionnels de la santé. Il ne s’agit pas d’un avis médical. Certains des renseignements, y compris ceux sur le financement des médicaments anticancéreux, ne s’appliquent pas à tous les patients. Les plans de traitement du cancer sont propres à chaque patient. Si vous êtes un patient, veuillez parler avec votre équipe soignante pour comprendre comment ces renseignements s’appliquent à vous.
fluorouracil
fluorouracil
SYNONYM(S): 5-fluorouracil; 5-FU
COMMON TRADE NAME(S): Efudex® Cream; IV generic brands available
Fluorouracil was developed based on the observation that some tumour cells utilized the base pair uracil for DNA synthesis more efficiently than did normal cells. It is a fluorinated pyrimidine antimetabolite that is metabolized intracellularly to its active form, fluorouridine monophosphate (FdUMP), which then inhibits DNA synthesis by inhibiting thymidylate synthetase and the normal production of thymidine. Effects on RNA (incorporation into RNA and RNA inhibition) also occur. Fluorouracil is cell cycle phase-specific (S-phase).
| Bioavailability |
Topical: Insignificant (<5-10%) |
Into all body water by passive diffusion, crosses placenta, high and persistent levels in malignant effusions.
| Cross blood brain barrier? | yes |
| PPB | 10 % |
Activated in target cells, 80% of dose degraded in liver by dihydropyrimidine dehydrogenase (DPD).
| Active metabolites |
FdUMP, FdUTP, FUTP |
| Inactive metabolites | yes |
60-80% excreted as respiratory CO2, 2-3% by biliary system. Higher clearance occurs in IV infusions than IV injections, due to saturation of metabolic or transport processes at higher drug concentrations.
| Urine | 15-20% as intact drug within 6 hours. |
| Half-life | 6-20 minutes; dose-dependent. |
- Breast cancer (adjuvant/palliative)
- Gastrointestinal cancer (adjuvant/palliative colorectal, gastric, pancreatic - palliative)
- Genitourinary cancer (bladder, prostate - palliative)
- Head and neck cancer (palliative)
- Gynecological (ovarian; palliative)
- Premalignant keratoses (topical)
- Superficial basal cell carcinoma (topical)
Other Uses:
- Gastrointestinal cancer (hepatobiliary, neuroendocrine tumours, small bowel and appendix, esophageal, anal)
- Genitourinary cancer (penile, renal cell)
- Gynecological cancer (vulvar)
- Primary unknown
- Skin (squamous cell)
- Lung (neuroendocrine)
Emetogenic Potential:
Minimal (CIV)
Extravasation Potential: Irritant
The following table lists side effect incidences reported from the fluorouracil arm (IV infusion on days 1 and 2) in a phase III study in advanced colorectal cancer patients. Incidences marked with "^" were reported from other sources, including severe adverse effects from other studies or post-marketing
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (<10%) ^ | I | |||
| Arterial/venous thromboembolism (6%) | E | ||||
| Cardiotoxicity (<10%) ^ | D | ||||
| ECG changes (69%) (asymptomatic; severe in rare cases)^ | I | ||||
| Dermatological | Alopecia (17%) (mild) | E | |||
| Erythema (including necrosis, with topical application) | I E | ||||
| Hand-foot syndrome (13%) | E | ||||
| Nail disorder (occasional) | E | ||||
| Photosensitivity (occasional) | E | ||||
| Radiation recall reaction (rare) | I E | ||||
| Rash (20%) (extremities, sometimes on trunk) / dry skin (may be severe) | E | ||||
| Gastrointestinal | Anorexia (19%) | E | |||
| Diarrhea (45%) (6% severe) | E | ||||
| GI ulcer or bleeding (rare) | E | ||||
| Mucositis (29%) (3% severe) | E | ||||
| Nausea, vomiting (55%) (4% severe) | I | ||||
| Hematological | Anemia (91%) (2% severe) | E | |||
| Hemolysis (rare) | E | ||||
| Myelosuppression ± infection, bleeding (48%) (13% severe) | E | ||||
| Hepatobiliary | ↑ Bilirubin (36%) (11% severe) | D | |||
| Hepatic necrosis (rare; may be fatal) | D | ||||
| Hypersensitivity | Hypersensitivity (rare; including anaphylaxis) | I | |||
| Injection site | Vein discolouration (occasional) | I | |||
| Nervous System | Ataxia / acute cerebellar syndrome (rare, reversible, but may persist following discontinuation of treatment) | E D | |||
| Confusion | E D | ||||
| Extrapyramidal disorder or cortical dysfunction (rare; usually reversible) | E D | ||||
| Leukoencephalopathy (rare) | E D | ||||
| Optic neuritis , oculomotor disturbance (rare) | E D | ||||
| Ophthalmic | Conjunctivitis (25%) and/or tearing^ | I E | |||
| Other - tear duct fibrosis (rare, reversible) | E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for fluorouracil include ECG changes, nausea/vomiting, myelosuppression ± infection (including anemia), bleeding, diarrhea, ↑ bilirubin, mucositis, conjunctivitis, rash and anorexia.
Following longer IV infusions, mucositis, hand-foot syndrome and diarrhea occur most commonly. Diarrhea may be profuse and life-threatening following administration of leucovorin with fluorouracil. Leukopenia is the usual dose-limiting toxicity after IV bolus administration
Patients with dihydropyrimidine dehydrogenase deficiency (DPD) are at risk of severe life-threatening toxicity with fluorouracil. While severe deficiency is rare, 3-4% of the population has some degree of DPD deficiency. No dose has been proven safe for patients with complete absence of DPD activity.
Excessive lacrimation can occur. Transient blurring of vision, eye irritation and excessive nasal discharge have also been reported. The onset of eye symptoms may occur at any time during treatment. Fluorouracil has been demonstrated in tear fluid causing acute and chronic conjunctivitis that can lead to tear duct fibrosis.
Acute cerebellar syndrome is manifested as ataxia of the trunk or extremities, disturbance of gait and speech, coarse nystagmus and dizziness. The ataxia syndrome is related to peak plasma levels of the drug rather than to cumulative dose, and is therefore more common with bolus doses than with infusions. It usually resolves after treatment is discontinued, but may persist in some cases. Leukoencephalopathy has been reported with symptoms such as decreased alertness, agitation, and disorientation memory deficit. This usually resolves within a few days of discontinuing fluorouracil.
Palmar-plantar erythrodysesthesia or hand-foot syndrome has been noted with protracted and high dose continuous infusion. The syndrome begins with dysesthesias of the palms and soles that progress to pain and tenderness. There is associated symmetrical swelling and erythema of the hand and foot. The syndrome resolves gradually over 5 to 7 days with cessation of drug infusion.
Cardiotoxicity has been reported and may be caused by coronary vasospasm, endothelial cell damage or increased thrombogenicity. It occurs in less than 10% of patients, of which up to 8% may be fatal. Cardiac effects include ECG changes, angina, arrhythmias, myocardial infarction, heart failure and are usually reported within 72 h of the first cycle of fluorouracil. Cardiotoxicity is independent of dose or underlying cardiac risk factors, but may be more common with infusions. Patients should be rechallenged only when there are no other treatment options.
Fluorouracil has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the fluorouracil. Recurrent injury to a previously radiated site may occur weeks to months following radiation.
Hemolytic-uremic syndrome has been reported when used in combination with mitomycin C.
Topical use:
When applied to a lesion, the following occurs: Erythema, usually followed by vesiculation, erosion, ulceration, necrosis and epithelization. The lower frequency and intensity of activity in adjacent normal skin indicates a selective cytotoxic property. An occlusive dressing is not essential, and may increase the incidence of inflammatory reactions in adjacent normal skin. Therapy is usually continued to reach the erosion, necrosis and ulceration stage (2-4 weeks), after which healing occurs over 4-8 weeks. The most frequent local reactions are pain, pruritus, hyperpigmentation and burning at the application site. Avoid prolonged exposure to sunlight or ultraviolet light during treatment and 1-2 months after ending treatment as the intensity of the reaction may be increased.
Refer to protocol by which patient is being treated.
Patients should be tested for DPD deficiency before starting treatment with fluorouracil. Refer to the DPD Deficiency Guidance for Clinicians for more information.
In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; if acute grade 2-4 toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.
Consider a reduced starting dose for patients who are heavily pretreated, malnourished or have poor performance status, or in patients with large third space collections or edema.
IV bolus:
- q4w: 425 mg/m2 day x 5 days
- q4w: 500-600 mg/m2 days 1 & 8
IV infusion:
- q3w: 200 mg/m2/day on days 1-21 as continuous infusion
- q3-4w: 750-1000 mg/m2/day x 4-5 days as continuous infusion
- q2w: 600 mg/m2/day x 22 hours on days 1 and 2
- q2w: 2400 mg/m2 over 46 hours starting on day 1
Topical:
- Twice daily: x 1-4 weeks. Stop when erosion evident, usually 2-4 weeks. Allow 1-2 months for healing. Total area treated at one time should not exceed 500 cm2 (23x23 cm). Larger areas should be treated one section at a time.
Modify according to protocol by which patient is being treated.
|
Toxicity or Counts (x 109/L) |
During Cycle |
For Next cycle
|
|
Platelets < 80 or ANC < 1.5 |
Hold* |
May consider ↓ |
|
Bleeding, febrile neutropenia |
Hold* |
↓ by 25% |
|
≥ grade 3 GI |
Hold* |
↓ by 25% |
| ≥ grade 3 Hand-Foot Syndrome | Hold* | ↓ by 25% |
|
CNS |
Hold* |
↓ by 25% |
|
Cardiac |
Hold* |
Consider discontinuing |
|
* Do not retreat until ANC ≥ 1.5 x 109/L , platelets ≥ 100 x 109/L and organ toxicity ≤ grade 2. With severe toxicity, consider testing for DPD deficiency prior to rechallenge. |
||
Consider dose reduction with moderate to severe hepatic impairment.
Suggested:
|
Bilirubin
|
|
AST/ALT
|
Fluorouracil (% previous dose)
|
|
< 2 x ULN |
and
|
3-5 x ULN |
75 % |
|
2-4 x ULN |
or
|
5-10 x ULN |
50-75%
|
|
> 4 x ULN |
or
|
> 10 x ULN |
Discontinue
|
No adjustment required, although reduction may be considered with severe renal insufficiency.
Elderly patients are at a higher risk of developing toxicities, likely due to lower bone marrow reserve.
IV Push or Intermittent Infusion:
- Slow push through sidearm of free-flowing IV (5% Dextrose, Normal Saline)
- May be mixed in 50mL minibag (NS or D5W); infuse over 15 min.
- Store unopened vials at 15ºC to 25ºC. Protect from light.
IV Continuous Infusion:
- Refer to local guidelines on preparation of fluorouracil IV infusion for central or peripheral lines. A lower concentration is usually used for peripheral IV infusions to prevent vein irritation.
- Continuous infusion using CADD infusion pump, or similar device
- Infusion volume, duration and administration via central or peripheral line depend on the regimen used.
- If given peripherally, inspect peripheral infusion sites daily and replace if evidence of irritation or extravasation.
- Incompatible with doxorubicin, epirubicin, diazepam, methotrexate and cytarabine; line must be flushed between administrations of fluorouracil and these agents.
- Store at room temperature (15 to 25ºC). Protect from light.
Topical:
- Glove or non-metal applicator preferred. If fingertips used, wash hands immediately afterward.
- Exercise care when applying the cream near the eyes, nostrils and mouth.
Antidote for Fluorouracil Overdose:
Uridine triacetate is a prodrug of uridine and is a specific antidote for treating fluorouracil overdose or severe early onset toxicities. If available, consider administering as soon as possible (i.e. within 96 hours) for suspected overdose. If not available, treatment is symptomatic and supportive.
For usage approval and supply, contact Health Canada’s Special Access Program (SAP) (Phone: 613-941-2108. On-call service is available for emergencies). Uridine triacetate (Vistogard®) is supplied by its manufacturer in the United States.
The recommended dosing and administration for uridine triacetate in patients ≥18 years is:
- 10 grams (1 packet of coated granules) orally every 6 hours for 20 doses in total, without regards to meals.
- Granules should not be chewed. They should be mixed with 3 to 4 ounces of soft foods such as applesauce, pudding or yogurt.
- The dose should be ingested within 30 minutes of preparation, followed by at least 4 ounces of water.
- Refer to the prescribing information on dose preparation for NG-tube or G-tube use.
Additional resources on the management of fluorouracil infusion overdose:
- Management of Fluorouracil Infusion Overdose Guideline (Alberta Health Services)
- Management of Fluorouracil Infusion Overdose at the BCCA - Interim Guidance (BC Cancer Agency)
- patients with poor nutritional state
- patients with depressed bone marrow function (prior pelvic irradiation / marrow infiltration)
- patients with potentially serious infections
- patients with known hypersensitivity to the drug or any of its excipients
- patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. Refer to the DPD Deficiency Guidance for Clinicians for more information.
- Fluorouracil should not be used within 4 weeks of treatment with brivudine, sorivudine or their chemically related analogues.
- Use with extreme caution in patients who:
- have undergone recent major surgery,
- have renal or hepatic impairment,
- have widespread bone marrow involvement,
- have previous use of other myelosuppressive chemotherapeutic agents,
- have a history of high dose irradiation to bone marrow-bearing areas,
- have a history of heart disease,
- or are suspected to have DPD deficiency. Refer to the DPD Deficiency Guidance for Clinicians for more information.
- Avoid the use of live vaccines.
Other Drug Properties:
-
Carcinogenicity:
Probable
-
Mutagenicity:
Yes
-
Embryotoxicity:
Yes
-
Teratogenicity:
Yes
-
Crosses placental barrier:
Yes
Fluorouracil is contraindicated in pregnancy. Appropriate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (generic recommendation).
-
Breastfeeding:
Contraindicated
-
Fertility effects:
Probable
Laboratory tests for bilirubin (icteric index) and urinary 5-HIAA may increase or have false positive results. Increases in T3 and T4 levels have been reported in euthyroid, advanced breast cancer patients treated with single agent fluorouracil, and these changes were reversible within 4 weeks after the end of treatment.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Brivudine, sorivudine and chemically related analogues | Significant ↑ in 5-FU exposure and toxicities | Irreversible DPD inhibition | CONTRAINDICATED Use alternative antiviral therapy or allow at least 4 weeks washout period between brivudine/ sorivudine/ analogues and starting 5-FU treatment. Immediate hospitalization with measures to reduce 5-FU toxicity is recommended, in case of accidental use of nucleoside analogues that inhibit DPD in 5-FU treated patients . |
| mitomycin | ↑ incidence of hemolytic-uremic syndrome with long-term usage | Unknown | Caution |
| cimetidine | ↑ serum concentrations of fluorouracil; fatal cases have been reported | appears to interfere with fluorouracil metabolism (e.g. by inhibiting hepatic enzymes and reducing hepatic blood flow) | Caution; observe for increased toxicity of fluorouracil |
| leucovorin | ↑ cytotoxic and toxic effects of fluorouracil | Leucovorin stabilizes the bond to thymidylate synthetase | Some protocols are designed to take advantage of this effect; monitor toxicity closely |
| metronidazole | ↑ serum concentration and/or toxicity of fluorouracil; fatal cases have been reported | ↓ clearance of fluorouracil | Avoid if possible |
| phenytoin | ↑ phenytoin levels and toxicity | Possible inhibition or decreased synthesis of CYP2C9 by fluorouracil | Monitor phenytoin levels and patient |
| Thiazide diuretics | ↑ myelosuppression | ↓ renal excretion of fluorouracil | Consider an alternative antihypertensive |
| warfarin | ↑ effects of warfarin; fatal cases have been reported | ↓ CYP2C9 enzymes for metabolism; reduced warfarin clearance | Monitor INR closely; adjust warfarin doses accordingly |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each cycle |
Liver function tests |
Baseline and before each cycle |
Renal function tests |
Baseline and before each cycle |
Clinical assessment and grading of stomatitis, diarrhea, bleeding, infection, local site toxicity, skin effects (rash or hand-foot-syndrome), cardiovascular, ophthalmic effects, and neurotoxicity |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
INR in patients taking warfarin |
Baseline and as clinically indicated |
Budd GT, Fleming TR, Bukowski RM et al. 5-fluorouracil and folinic Acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest oncology group study. J Clin Oncol 1987;5:272-7.
Fluorouracil: ASHP's Interactive Handbook on Injectable Drugs.
Fluorouracil drug monograph Cancer Drug Manual. British Columbia Cancer Agency (BCCA). Accessed November 21, 2018.
Gradishar WJ, Vokes EE, et al. 5-Fluorouracil cardiotoxicity: A critical review. Annals of Oncology 1990;1: 409-14.
Griffin JD, Garnick MB. Eye toxicity of cancer chemotherapy: a review of the literature. Cancer 1981;48(7):1539-49.
Health Canada's Special Access Programs, Health Canada. Accessed May 26, 2021.
Management of Fluorouracil Infusion Overdose Guideline. Alberta Health Services, Feb 2016.
Management of Fluorouracil Infusion Overdose at the BCCA - Interim Guidance. BC Cancer Agency, May 2015.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1074-8.
Prescribing Information: Uridine triacetate (Vistogard®). Wellstat Therapeutics (US), Feb 2017.
Product Monograph: Fluorouracil. Sandoz Canada, April 3, 2012.
Product Monograph: Fluorouracil. Biolyse Pharma Corp., March 7, 2018.
Product Monograph: Irinotecan. Pfizer Canada Inc., Feb 11, 2015.
Product Monograph: Efudex® (fluorouracil topical). Valeant Canada Limited. December 15, 2004.
Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf 2009; 8(2): 191-202
Sara JD, Kaur J, Kodhadadi R, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol 2018;10:1-18.
Sorrentino MF, Kim J, Foderaro AE, et al. Fluorouracil induced cardiotoxicity: review of the literature. Cardiol J 2012;19(5):453-8.
Summary of Product Characteristics: Efudix®. Meda Pharmaceuticals (UK), March 2014.
April 2024 Removed previous manufacturer name from antidote information
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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