DRUG NAME: Fluorouracil
eneric available, ADRUCIL(r), EFUDEX(r) CREAM : g
antimetabolite, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
:
| Interpatient variability | variations in dihydropyrimidine dehydrogenase (DPD) activity result in differences in toxicity 6 (refer to the Dihydropyrimidine dehydrogenase (DPD) deficiency paragraph following the Side Effect table for more information) | |
| Oral Absorption | erratic; 28-100% | |
| Distribution | approximately 22% of total body water; penetrates extracellular fluid and third space fluids (e.g., malignant effusions and ascitic fluid) | |
| cross blood brain barrier? | yes | |
| volume of distribution 7 | 8-11 L/m 2 | |
| plasma protein binding 8 | 10% | |
| Metabolism | activated in target cells; 80% degraded in liver by DPD 7 | |
| active metabolite(s) | FdUMP, FUTP, and FdUTP | |
| inactive metabolite(s) | dihydrofluorouracil | |
| Excretion | 60-80% excreted as respiratory CO 2 ; 2-3% by biliary system | |
| urine | <10% as intact drug 7 | |
| terminal half life | IV bolus: 8-14 min (see also nonlinear pharmacokinetics in clearance below) | |
| clearance | IV bolus: 350-850 mL/min/m 2 ; dependent on dose, schedule, and route of administration; nonlinear pharmacokinetics due to saturable degradation 7 ; interference with fluorouracil degradation markedly prolongs its half-life 7 continuous infusion: clearance increases | |
| Ethnicity | DPD deficiency: caucasian (3-5%); African-American 0.1% 9 | |
Adapted from standard references10,11 unless specified otherwise.
| Primary uses: | Other uses: |
| *Actinic keratoses (topical fluorouracil) 12 | Cervical cancer 5 |
| *Bladder cancer | Esophageal cancer 5 |
| *Breast cancer | Renal cell cancer 5 |
| *Colorectal cancer | Skin cancer, Bowen's disease (topical fluorouracil) 13 |
| *Gastric cancer | Skin cancer, squamous cell (topical fluorouracil) 13 |
| *Head and neck cancer | |
| *Ovarian cancer | |
| *Pancreatic cancer | |
| *Prostate cancer | |
| *Skin cancer, basal cell (topical fluorouracil) 12 | |
*Health Canada approved indication
Nonlinear pharmacokinetics result in unpredictable plasma concentrations and toxicity at high doses.7 Elderly patients are at increased risk for developing toxicities, likely due to decreased bone marrow reserve.7 Female patients are at increased risk for developing toxicities.7,15,16
Carcinogenicity: Not yet studied.4
Fertility: The effects of fluorouracil on fertility have not been established.4
Pregnancy11: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding is not recommended due to the potential secretion into breast milk.10
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they
were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important17. When placebo-controlled trials are available, adverse events are included if the incidence is > 5% higher in the treatment group.
BC Cancer Agency Cancer Drug Manual(c) Page 2 of 11 Fluorouracil Developed: September 1994
Revised: June 2006 Limited revision: May 2007
Fluorouracil
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| allergy/immunology | anaphylaxis (rare) 4 | I | |||
| generalized allergic reactions (rare) 4 | I | ||||
| blood/bone marrow/ febrile neutropenia | myelosuppression *: onset: 7-10 days; nadir: 14 days; recovery: 30 days | I | |||
| cardiovascular (arrhythmia) | arrhythmias | I | |||
| cardiotoxicity * ( < 8%) 18 | E | ||||
| chest pain (< 1%); ranging from mild angina to crushing pain | I | ||||
| CHF (rare) 4 | E | ||||
| hypotension (< 1%) | I | ||||
| constitutional symptoms | somnolence (< 1%) | I | |||
| dermatology/skin | extravasation hazard: irritant 11,19,20 | ||||
| For more information on topical application see paragraph after this table. | |||||
| alopecia (> 10%) | E | ||||
| dermatitis * (>10%) | I | ||||
| dry skin and fissuring (1-10%) | E | ||||
| nail changes (< 1%); banding or loss of nails | E | ||||
| palmar-plantar erythrodysesthesia (PPE) * (<1%) | E | ||||
| photosensitivity (< 1%) | I | ||||
| vein hyperpigmentation (< 1%); proximal to injection sites | I | ||||
| gastrointestinal | emetogenic potential 21 : rare (< 10%) | ||||
| anorexia (> 10%) | I | ||||
| diarrhea * (> 10%) | I | ||||
| esophagitis (>10%) | I | ||||
| heart burn (>10%) | I | ||||
| nausea (< 10%) | I | ||||
| stomatitis * (> 10%) | I | ||||
| epithelial ulceration (1-10%) | E | ||||
| vomiting (< 10%) 21 | I | ||||
| hemorrhage | GI bleeding | E | |||
| hepatic | biliary sclerosis 7 | E | |||
| hepatic toxicity (< 1%) | E | ||||
| neurology | acute cerebellar ataxia (< 1%); increased with high doses or intensive regimens | E | |||
| neurotoxicities * (< 1%) | E | ||||
| ocular/visual | excessive lacrimation | I | |||
BC Cancer Agency Cancer Drug Manual(c) Page 3 of 11 Fluorouracil Developed: September 1994
Revised: June 2006 Limited revision: May 2007
Fluorouracil
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| ocular toxicities * | E | ||||
| pain | headache (< 1%) | I | |||
| pulmonary | dyspnea (< 1%) | I | |||
Adapted from standard references10,11 unless specified otherwise. *Severity varies with route of administration, refer to the following paragraph.
Dosing schedule and toxicity: The spectrum of toxicity associated with fluorouracil treatment varies with dose, schedule, route of administration, and whether the fluorouracil is being used with a biochemical modulator.7 The most commonly seen toxicities when standard doses are administered in the following schedules and routes are:
monthly bolus administration22: myelosuppression can be dose-limiting
daily bolus administration for 5 days22: diarrhea can be dose-limiting; myelosuppression, stomatitis, ocular, and dermatitis7
continuous infusion given over 24 hours to several weeks22: diarrhea, and stomatitis can be dose-limiting; myelosuppression, dermatitis, PPE, neurologic, ocular, and cardiotoxicity11
weekly bolus administration22: diarrhea can be dose-limiting; myelosuppression, stomatitis,7 and ocular23
topical daily7: local inflammation
Oral cryotherapy with bolus doses of fluorouracil: It is recommended that patients receiving bolus fluorouracil undergo 30 minutes of oral cryotherapy to decrease the incidence and severity of fluorouracil-induced stomatitis.24 The incidence can be reduced by 50%.25 Starting 5 minutes before the injection, the patient is asked to place ice chips into their mouth and swish for 30 minutes, replenishing the ice as it melts. This may cause numbness or headaches which subside quickly. This cooling of the oral cavity leads to vasoconstriction resulting in a lower concentration of fluorouracil reaching the oral mucosa.24 Oral cryotherapy is not used for infusional fluorouracil as this would be very inconvenient. It is also not used for bolus fluorouracil administered in combination with oxaliplatin. This is due to the concern with oxaliplatin and cold related laryngo-dysesthesias.17
Acute cerebellar syndrome can rarely occur and is characterized by an acute onset of ataxia, dysmetria, dysarthria, and nystagmus that develops weeks to months after beginning treatment.26 These symptoms usually resolve after discontinuation of fluorouracil.26 Cerebellar syndrome may be partly explained because fluorouracil
crosses the blood-brain barrier, and the highest concentrations are found in the cerebellum.26 Other rarer neurologic side effects include encephalopathy, optic neuropathy, eye movement abnormalities, focal dystonia, cerebrovascular disorders, parkinsonian syndrome, peripheral neuropathy, and seizures.26
Cardiotoxicity18: Fluorouracil has the second highest incidence of chemotherapy induced cardiotoxicity, after the anthracyclines.11 The incidence of fluorouracil induced cardiotoxicity can be as high as 8%.18 Within this group types of cardiotoxicity include27:
electrocardiographic changes, 69%
angina, 48%
myocardial infarction, 23%
acute pulmonary edema, 17%
arrhythmias,16%
elevated cardiac enzymes, 14%
cardiac arrest and pericarditis, 2%
Coronary vasospasm is thought to be the underlying mechanism of this toxicity.18,28 Although most patients who
experience fluorouracil-induced cardiotoxicity have no previous cardiac problems, history of preexisting coronary artery disease is a risk factor. Other risk factors include route of administration (refer to the Dosing schedule and toxicity paragraph following the Side Effect table) and the use of concurrent radiation or anthracyclines.18 Most cases
of fluorouracil-induced cardiotoxicities resolve after termination of fluorouracil infusion and/or administration of nitrates or calcium channel blockers.28 Rechallenging these patients remains controversial. If rechallenged, these
BC Cancer Agency Cancer Drug Manual(c) Page 4 of 11 Fluorouracil Developed: September 1994
Revised: June 2006 Limited revision: May 2007
Fluorouracil
patients needs careful observation during drug infusion and may benefit from treatment with calcium channel blockers or nitrates.28
Palmar-plantar erythrodysesthesia (PPE): also called hand-foot skin reaction, may occur in association with the continuous infusion of fluorouracil.19 PPE may gradually disappear over 5-7 days after discontinuance of fluorouracil therapy.4 PPE may be treated with oral pyridoxine 50-150 mg daily29,30; although efficacy has not been well established.4
Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare, inherited disorder of pyrimidine degradation. The frequency of low or deficient DPD activity in predominantly Caucasian and African-American populations is 3-5% and 0.1%, respectively.9 For patients with even a partial DPD deficiency, treatment with fluorouracil can lead to life-
threatening complications. Fluorouracil clearance is dependent on DPD as fluorouracil is enzymatically inactivated to dihydrofluorouracil by DPD.31 There is no evidence of fluorouracil degradation in DPD-deficient patients.32 Toxicities can include severe diarrhea, stomatitis, and myelosuppression.9 Nausea, vomiting, rectal bleeding, volume
depletion, skin changes, and neurologic abnormalities (cerebellar ataxia, changes in cognitive function, changes in the level of consciousness) may also occur.9 Management should include aggressive supportive care with hemodynamic support, parenteral nutrition, antibiotics, and hematopoietic colony stimulating factors.9 Tests for the diagnosis of DPD deficiency are not readily available and as a result most cases are diagnosed long after the
administration of fluorouracil.9
Ocular toxicity: Fluorouracil-induced ocular toxicities result primarily from ocular surface problems, such as excessive lacrimation, blurred vision, photophobia, and eye irritation.22 Excessive lacrimation is the most frequent ocular symptom and can be quite dramatic; it may occur any time during treatment and possibly accompanied with
pruritus and burning.7 Fluorouracil has been found in tear fluid and can cause acute and chronic conjunctivitis
leading to tear duct fibrosis. Ocular toxicities can also include epiphora, blepharitis, conjunctivitis, tear duct stenosis, and sclerosing canaliculitis. Applying ice packs to the eyes before, during, and for 30 minutes after fluorouracil injection may decrease ocular toxicity.22
Topical application leads to the following sequence12: 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. The most frequent local reactions are pain, pruritus, hyperpigmentation, and burning at the application site. Other local reactions include dermatitis, scarring, soreness, and tenderness.
Insomnia, stomatitis, suppuration, scaling, swelling, irritability, medicinal taste, photosensitivity, and lacrimation have also been reported.33
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| cimetidine 34 | delayed, moderate, possible; fluorouracil efficacy and toxicity may be increased | unknown | monitor for fluorouracil toxicity; discontinue cimetidine if necessary |
| fosphenytoin 34 | delayed, moderate, possible; fosphenytoin efficacy and toxicity may be increased | inhibition of hydantoin metabolism (CYP2C9) by fluorouracil suspected | monitor fosphenytoin plasma levels; observe clinical response when starting or stopping fluorouracil |
| gemcitabine 35 | fluorouracil efficacy and toxicity may be increased | unknown | some protocols are designed to take advantage of this effect; monitor toxicity closely |
| leucovorin 22 | increased 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 |
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| metronidazole 36 | fluorouracil efficacy and toxicity may be increased | metronidazole may decrease the metabolism of fluorouracil | monitor for fluorouracil toxicity |
| oxaliplatin 37 | no influence on fluorouracil pharmacokinetics | ||
| phenytoin 34 | delayed, moderate, | inhibition of hydantoin | monitor phenytoin plasma |
| possible; phenytoin | metabolism (CYP2C9) by | levels; observe clinical | |
| efficacy and toxicity may | fluorouracil suspected | response when starting or | |
| be increased | stopping fluorouracil | ||
| thiazides 34 (e.g., chlorthalidone, hydrochlorothiazide) | delayed, moderate, possible; thiazides may prolong fluorouracil- induced leukopenia | unknown | consider alternative antihypertensive therapy |
| warfarin 11,34,38 | delayed, moderate, documented 39 ; increased effect and toxicity of warfarin | possibly protein displacement, inhibition of warfarin metabolism, or inhibition of clotting factor synthesis | check baseline INR; monitor weekly INR during, and for one month after, fluorouracil therapy; increase frequency and duration of monitoring if INR unstable; adjust warfarin dose as needed; anticoagulation with LMWH may be considered |
Topical33: Supplied as fluorouracil 5% in a vanishing cream base. Non-medicinal ingredients: white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, and parabens. Store in a dry location at room temperature, away from heat and direct light.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
Diluted solution for infusion40: The following solutions are compatible with fluorouracil at certain concentrations: D5W; NS; Dextrose 5% in Lactated Ringer's; Dextrose 3.3% in NS 0.3%; Plasmalyte 3G5.
Compatibility of selected drugs 40: The following are compatible with fluorouracil via Y-site injection: bleomycin; cisplatin; cyclophosphamide; doxorubicin; fludarabine; furosemide; gemcitabine; granisetron; heparin;
Incompatibility of selected drugs 40: The following are incompatible with fluorouracil via Y-site injection: droperidol; filgrastim; ondansetron; vinorelbine.
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous | not used due to corrosive nature |
| Intramuscular | not used due to corrosive nature |
| * Direct intravenous | over 1-3 minutes |
| * Intermittent infusion | can be used (e.g., dilute in 50 mL and infuse for up to 15 minutes) 11 |
| *Continuous infusion | over 24 hours or greater; may be given via an ambulatory infusion device |
| Intraperitoneal 41 | 15 mg/kg and 50 mEq sodium bicarbonate to 1000 mL 1.5% dextrose dialysis solution; dwell for 23 hours then drain for one hour |
| Intrapleural | no information found |
| Intrathecal 2 | contraindicated due to neurotoxicity |
| Intra-arterial 2 | hepatic artery |
| Intravesical 4 | portal vein infusion |
*Doses prescribed for continuous infusion can be FATAL when given as direct intravenous or intermittent
infusion.
Adults:
Intravenous: 1 week42,43: 1000 mg/m2 IV over 24 hours for 2 consecutive days starting on day 1
(total dose per cycle 2000 mg/m2) (maximum dose is 5000 mg/48 h)
weeks44-48: 400 mg/m2 IV for one dose on day 1 immediately followed by 2400-3000 mg/m2 IV over 46 hours
(total dose per cycle 2800-3400 mg/m2)
weeks49-57: 500-600 mg/m2 IV for one dose on day 1 (total dose per cycle 500-600 mg/m2)
weeks58: 1000 mg/m2IV over 24 hours for 3 consecutive days starting on day 1
(total dose per cycle 3000 mg/m2)
weeks59,60: 425 mg/m2 IV once daily for 5 consecutive days starting on day 1
(total dose per cycle 2125 mg/m2)
4 weeks61,62: when given as a dose-dense regimen with filgrastim (G- CSF) support:
500 mg/m2 IV for one dose on days 1 and 8 (total dose per cycle 1000 mg/m2)
4 weeks63-65: 500-600 mg/m2 IV for one dose on days 1 and 8 (total dose per cycle 1000-1200 mg/m2)
4 weeks66-69: when given as a dose-dense regimen with filgrastim (G- CSF) support:
500 mg/m2 IV for one dose on days 1 and 15 (total dose per cycle 1000 mg/m2)
4 weeks70,71: 1000 mg/m2 IV over 24 hours for 4 consecutive days starting on day 1
(total dose per cycle 4000 mg/m2)
6 weeks72: 400-500 mg/m2 IV on day 1, 8, 15 and 22 (total dose per cycle 1600-2000 mg/m2)
6 weeks73: 1000 mg/m2 IV over 24 hours for 4 consecutive days starting on day 1
(total dose per cycle 4000 mg/m2)
Concurrent radiation74-81: can be used with variable schedules and dosing; specific treatment protocols
Dosage in myelosuppression:
Dosage in obesity10: if patient is obese or there has been a spurious weight gain because of edema,
Dosage in renal failure:
Dosage in hepatic failure11: bilirubin > 86 umol/L omit dose
Topical12: apply twice daily x 2-4 weeks. See Topical Administration for more information.
Children:
Topical 33: use and dose as determined by physician
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BC Cancer Agency Breast Tumour Group. BCCA Protocol summary for Inflammatory Breast Cancer using Cyclophosphamide, Epirubicin and Fuorouracil. Vancouver: BC Cancer Agency; BRINFCEF, 2005. BC Cancer Agency Breast Tumour Group. BCCA Protocol summary for Locally Advanced Breast Cancer using Cyclophosphamide, Doxorubicin, Fuorouracil. Vancouver: BC Cancer Agency; BRLA2, 2004. BC Cancer Agency Gastrointestinal Tumour Group. BCCA Protocol summary for Palliative Therapy of Pancreatic Endocrine Tumours using Carmustine and Fluorouracil. Vancouver: BC Cancer Agency; GIENDO1, 2006. BC Cancer Agency Gastrointestinal Tumour Group. BCCA Protocol summary for Adjuvant Therapy for Stage III and High Risk Stage II Colon Cancer using Leucovorin and Fluorouracil. Vancouver: BC Cancer Agency; GIFFAD, 2006. BC Cancer Agency Gastrointestinal Tumour Group. BCCA Protocol summary for Adjuvant Therapy for Resected Pancreatic Cancer using Leucovorin and Fluorouracil. Vancouver: BC Cancer Agency; GIPAJFF, 2006. 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