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This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
Fluorouracil may be confused with flucytosine
Efudex® may be confused with Efidac (Efidac 24®), Eurax®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
International issues:
Carac™ may be confused with Carace® which is a brand name for lisinopril in Ireland and Great Britain
Pronunciation
(flure oh YOOR a sil)
U.S. Brand Names
Index Terms
Generic Available
Yes: Injection, topical solution
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of carcinomas of the breast, colon, head and neck, pancreas, rectum, or stomach; topically for the management of actinic or solar keratoses and superficial basal cell carcinomas
Pregnancy Risk Factor
D (injection); X (topical)
Pregnancy Considerations
There are no adequate and well-controlled studies in pregnant women, however, fetal defects and miscarriages have been reported following use of topical and intravenous products. Use is contraindicated during pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to fluorouracil or any component of the formulation; dihydropyrimidine dehydrogenase (DPD) enzyme deficiency; pregnancy
Warnings/Precautions
Boxed warnings:
• Experienced physician: See “Other warnings/precautions” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Hand-foot syndrome: Palmar-plantar erythrodysesthesia (hand-foot) syndrome has been associated with use.
• Toxicity: Discontinue if intractable vomiting, diarrhea, precipitous fall in leukocyte or platelet counts, myocardial ischemia, hemorrhage, or stomatitis occur.
Disease-related concerns:
• Dihydropyrimidine dehydrogenase deficiency (DPD): Administration to patients with genetic DPD has been associated with increased toxicity following administration (diarrhea, neutropenia, and neurotoxicity). Systemic toxicity normally associated with parenteral administration has also been associated with topical use, particularly in patients with DPD; discontinue if symptoms of DPD occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Alkylating agents: Use with caution in patients who have had previous use of alkylating agents.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
• Pelvic radiation recipients: Use with caution in patients who have had high-dose pelvic radiation.
Dosage form specific issues:
• Topical: Avoid topical application to mucous membranes due to potential for local inflammation and ulceration. The use of occlusive dressings with topical preparations may increase the severity of inflammation in nearby skin areas. Avoid exposure to ultraviolet rays during and immediately following therapy.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
Toxicity depends on route and duration of treatment
I.V.:
Cardiovascular: Angina, myocardial ischemia, nail changes
Central nervous system: Acute cerebellar syndrome, confusion, disorientation, euphoria, headache, nystagmus
Dermatologic: Alopecia, dermatitis, dry skin, fissuring, palmar-plantar erythrodysesthesia syndrome, pruritic maculopapular rash, photosensitivity, vein pigmentations
Gastrointestinal: Anorexia, bleeding, diarrhea, esophagopharyngitis, nausea, sloughing, stomatitis, ulceration, vomiting
Hematologic: Agranulocytosis, anemia, leukopenia, pancytopenia, thrombocytopenia
Myelosuppression:
Onset: 7-10 days
Nadir: 9-14 days
Recovery: 21-28 days
Local: Thrombophlebitis
Ocular: Lacrimation, lacrimal duct stenosis, photophobia, visual changes
Respiratory: Epistaxis
Miscellaneous: Anaphylaxis, generalized allergic reactions, nail loss
Topical: Note: Systemic toxicity normally associated with parenteral administration (including neutropenia, neurotoxicity, and gastrointestinal toxicity) has been associated with topical use particularly in patients with a genetic deficiency of dihydropyrimidine dehydrogenase (DPD).
Central nervous system: Headache, insomnia, irritability
Dermatologic: Alopecia, photosensitivity, pruritus, rash, scarring, telangiectasia
Gastrointestinal: Medicinal taste, stomatitis
Hematologic: Leukocytosis, thrombocytopenia
Local: Application site reactions: Allergic contact dermatitis, burning, crusting, dryness, edema, erosion, erythema, hyperpigmentation, irritation, pain, soreness, ulceration
Ocular: Eye irritation (burning, watering, sensitivity, stinging, itching)
Miscellaneous: Birth defects, herpes simplex, miscarriage
Drug Interactions
Coumarin Derivatives: Antineoplastic Agents may enhance the anticoagulant effect of Coumarin Derivatives. Antineoplastic Agents may diminish the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy
Coumarin Derivatives: Fluorouracil may enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Gemcitabine: May increase the serum concentration of Fluorouracil. Risk C: Monitor therapy
Leucovorin-Levoleucovorin: May enhance the adverse/toxic effect of Fluorouracil. This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Sorafenib: May decrease the serum concentration of Fluorouracil. Sorafenib may increase the serum concentration of Fluorouracil. Risk C: Monitor therapy
Vaccines (Dead Organisms): Immunosuppressants may diminish the therapeutic effect of Vaccines (Dead Organisms). Risk C: Monitor therapy
Vaccines (Live Organisms): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live Organisms). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Herb/Nutraceutical: Avoid black cohosh, dong quai in estrogen-dependent tumors.
Storage
Injection: Store intact vials at room temperature and protect from light; slight discoloration does not usually denote decomposition. If exposed to cold, a precipitate may form; gentle heating to 60°C will dissolve the precipitate without impairing the potency. Solutions in 50-1000 mL NS or D5W, or undiluted solutions in syringes are stable for 72 hours at room temperature.
Topical: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F).
Reconstitution
Dilute in 50-1000 mL NS, D5W, or bacteriostatic NS for infusion.
Compatibility
Stable in D5LR, D5W, NS, bacteriostatic NS; incompatible with concentrations >25 mg/mL of fluorouracil and >2 mg/mL of leucovorin (precipitation occurs).
Y-site administration: Compatible: Allopurinol, amifostine, aztreonam, bleomycin, cefepime, cisplatin, cyclophosphamide, doxorubicin, doxorubicin liposome, etoposide phosphate, fludarabine, furosemide, gatifloxacin, gemcitabine, granisetron, heparin, hydrocortisone sodium succinate, leucovorin, linezolid, mannitol, melphalan, methotrexate, metoclopramide, mitomycin, paclitaxel, piperacillin/tazobactam, potassium chloride, propofol, sargramostim, teniposide, thiotepa, vinblastine, vincristine, vitamin B complex with C. Incompatible: Amphotericin B cholesteryl sulfate complex, droperidol, filgrastim, ondansetron, topotecan, vinorelbine.
Compatibility in syringe: Compatible: Bleomycin, cisplatin, cyclophosphamide, furosemide, heparin, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine. Incompatible: Droperidol, epirubicin. Variable (consult detailed reference): Doxorubicin.
Compatibility when admixed: Compatible: Bleomycin, cyclophosphamide, cyclophosphamide with methotrexate, etoposide, floxuridine, hydromorphone, ifosfamide, methotrexate, mitoxantrone, vincristine. Incompatible: Carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, fentanyl, leucovorin, metoclopramide, morphine.
Mechanism of Action
A pyrimidine antimetabolite that interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid; fluorouracil inhibits thymidylate synthetase (TS), or is incorporated into RNA. The reduced folate cofactor is required for tight binding to occur between the 5-FdUMP and TS.
Pharmacodynamics/Kinetics
Duration: ?3 weeks
Distribution: Vd: ?22% of total body water; penetrates extracellular fluid, CSF, and third space fluids (eg, pleural effusions and ascitic fluid)
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; FU must be metabolized to be active
Bioavailability: <75%, erratic and undependable
Half-life elimination: Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP and FUTP, have prolonged half-lives depending on the type of tissue
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) in 6 hours
Dosage
Adults:
Refer to individual protocols:
I.V. bolus: 500-600 mg/m2 every 3-4 weeks or 425 mg/m2 on days 1-5 every 4 weeks
Continuous I.V. infusion: 1000 mg/m2/day for 4-5 days every 3-4 weeks or
2300-2600 mg/m2 on day 1 every week or
300-400 mg/m2/day or
225 mg/m2/day for 5-8 weeks (with radiation therapy)
Actinic keratoses: Topical:
Carac™: Apply thin film to lesions once daily for up to 4 weeks, as tolerated
Efudex®: Apply to lesions twice daily for 2-4 weeks; complete healing may not be evident for 1-2 months following treatment
Fluoroplex®: Apply to lesions twice daily for 2-6 weeks
Superficial basal cell carcinoma: Topical: Efudex® 5%: Apply to affected lesions twice daily for 3-6 weeks; treatment may be continued for up to 10-12 weeks
Dosage adjustment for renal impairment: The FDA-approved labeling does not contain specific dosing adjustment guidelines; however, it is stated that extreme caution should be used in patients with renal impairment.
Hemodialysis: Administer dose following hemodialysis.
Aronoff (2007): Recommends that dosage adjustment is not needed in adult patients with Clcr <50 mL/minute and patients receiving hemodialysis should be administered 50% of dose.
Dosage adjustment for hepatic impairment: The FDA-approved labeling does not contain specific dosing adjustment guidelines; however, it is stated that extreme caution should be used in patients with hepatic impairment. The following guidelines have been used by some clinicians:
Floyd, 2006: Bilirubin >5 mg/dL: Avoid use.
Koren, 1992: Hepatic impairment (degree not specified): Administer <50% of dose, then increase if toxicity does not occur.
Dosage: Combination Regimens
Breast cancer:
CAF
CEF
CFP
CMF
CMF-IV
CMFP
CMFVP (Cooper Regimen, VPCMF)
CNF
Docetaxel-FEC
Docetaxel-Trastuzumab-FEC
Dox-CMF (Sequential)
FAC
FEC
MF
NFL
Vinorelbine-FEC
Vinorelbine-Trastuzumab-FEC
Cervical cancer: Cisplatin-Fluorouracil
Colorectal cancer:
Bevacizumab-Fluorouracil-Leucovorin
Bevacizumab-Irinotecan-Fluorouracil-Leucovorin
Bevacizumab-Oxaliplatin-Fluorouracil-Leucovorin
Cetuximab-FOLFOX4
FLOX (Nordic FLOX)
Fluorouracil-Leucovorin
Fluorouracil-Leucovorin-Irinotecan (Saltz Regimen)
FOIL
FOLFOX 2
FOLFOX 3
FOLFOX 4
FOLFOX 7
FU-LV-CPT-11
PFL (Colorectal Cancer)
Esophageal cancer: TCF
Gastric cancer:
Docetaxel-Cisplatin-Fluorouracil (Gastric Cancer)
ECF
EFP
ELF
FAM
FAMe
FAP
FAMTX
FUP
Head and neck cancer:
CF
Docetaxel-Cisplatin-Fluorouracil (Head and Neck Cancer)
Fluorouracil + Carboplatin
FU HURT
PFL (Head and Neck Cancer)
PFL + IFN
Neuroblastoma: N4SE Protocol
Pancreatic cancer: FAM
Renal cell cancer: Interleukin 2-Interferon Alfa-2-Fluorouracil
Administration: Oral
I.V. formulation may be given orally mixed in water, grape juice, or carbonated beverage. It is generally best to drink undiluted solution, then rinse the mouth. CocaCola® has been recommended as the “best chaser” for oral fluorouracil.
Administration: I.V.
Irritant. Direct I.V. push injection (50 mg/mL solution needs no further dilution) or by I.V. infusion. Doses >1000 mg/m2 are usually administered as a 24-hour infusion. Toxicity may be reduced by giving the drug as a constant infusion. Bolus doses may be administered by slow IVP or IVPB.
Administration: Topical
Topical: Apply 10 minutes after washing, rinsing, and drying the affected area. Apply using fingertip (wash hands immediately after application) or nonmetal applicator. Do not cover area with an occlusive dressing. Wash hands immediately after topical application of the 5% cream. Topical preparations are for external use only; not for ophthalmic, oral, or intravaginal use
Administration: I.V. Detail
After vial has been entered, any unused portion should be discarded within 1 hour. Continuous infusions may be administered in D5W or NS. Solution should be protected from direct sunlight. Fluorouracil may also be administered intra-arterially or intrahepatically (refer to specific protocols).
pH: 9.2 (adjusted)
Monitoring Parameters
CBC with differential and platelet count, renal function tests, liver function tests
Dietary Considerations
Increase dietary intake of thiamine.
Patient Education
Do not take any new medication during therapy without consulting prescriber. Follow exact directions for use (oral solution or topical application). Avoid excessive alcohol (may increase gastrointestinal irritation). Maintain adequate nutrition and hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause sensitivity to sunlight (use sunblock, wear protective clothing, and avoid direct sunlight); susceptibility to infection (avoid crowds and exposure to infection); nausea, vomiting, diarrhea, or loss of appetite (small frequent meals may help; request medication); weakness, lethargy, dizziness, decreased vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or headache (request medication). Report signs and symptoms of infection (eg, fever, chills, sore throat, burning urination, vaginal itching or discharge, fatigue, mouth sores); bleeding (eg, black or tarry stools, easy bruising, unusual bleeding); vision changes; unremitting nausea, vomiting, or abdominal pain; CNS changes; respiratory difficulty; chest pain or palpitations; severe skin reactions to topical application; or any other adverse reactions.
Topical: Use as directed; do not overuse. Wash hands thoroughly before and after applying medication. Avoid contact with eyes, nostrils, and mouth. Avoid occlusive dressings; use a porous dressing. May cause local reaction (pain, burning, or swelling); if severe, contact prescriber.
Oral solution: May be mixed in water, grape juice, or carbonated beverage. It is generally best to drink undiluted solution, then rinse mouth thoroughly. CocaCola® has been recommended as the best rinse following oral fluorouracil.
Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a pregnancy. Male/female: Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Breast-feeding is not recommended.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness
Mental Health: Effects on Psychiatric Treatment
Myelosuppression is common; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other pharmacological agents or herbal products patient may be taking. Assess results of laboratory tests prior to each infusion and regularly with all formulations, including topical use. Assess patient response (eg, cardiovascular, respiratory, and renal function) prior to each infusion and on a regular basis throughout therapy. Note: Inform prescriber if intractable vomiting or diarrhea, precipitous fall in leukocyte or platelet counts, or myocardial ischemia occurs (drug may be discontinued). Teach patient proper use (topical application [avoid application to mucous membranes]; oral solution [rinse mouth thoroughly]), possible side effects/appropriate interventions (eg, importance of adequate hydration), and adverse symptoms to report. Pregnancy risk factor D/X: Determine that patient is not pregnant before starting therapy. Do not give to females of childbearing age unless patient is capable of complying with contraceptive use. Male/female: Advise patient about contraceptive measures as appropriate.
Oncology: Emetic Potential
Low (10% to 30%)
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Cream, topical:
Carac™: 0.5% (30 g)
Efudex®: 5% (40 g)
Fluoroplex®: 1% (30 g) [contains benzyl alcohol]
Injection, solution: 50 mg/mL (10 mL, 20 mL, 50 mL, 100 mL)
Adrucil®: 50 mg/mL (10 mL, 50 mL, 100 mL)
Solution, topical: 2% (10 mL); 5% (10 mL)
Efudex®: 2% (10 mL); 5% (10 mL)
Fluorouracil®: 5% (10 mL)
Pricing: U.S. (www.drugstore.com)
Cream (Carac)
0.5% (30): $163.48
Cream (Fluoroplex)
1% (30): $158.72
Solution (Efudex)
2% (10): $87.07
5% (10): $125.83
Solution (Fluorouracil)
5% (10): $101.99
50 mg/mL (50): $25.99
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 100.
Balis FM, Holcenberg JS, and Bleyer WA, “Clinical Pharmacokinetics of Commonly Used Anticancer Drugs,” Clin Pharmacokinet, 1983, 8(3):202-32.
Curran CF and Luce JK, “Fluorouracil and Palmar-Plantar Erythrodysesthesia,” Ann Intern Med, 1989, 111(10):858.
Diasio RB and Harris BE, “Clinical Pharmacology of 5-Fluorouracil,” Clin Pharmacokinet, 1989, 16(4):215-37.
Diasio RB and Johnson MR, “The Role of Pharmacogenetics and Pharmacogenomics in Cancer Chemotherapy With 5-Fluorouracil,” Pharmacology, 2000, 61(3):199-203.
Floyd J, Mirza I, Sachs B, et al, "Hepatotoxicity of Chemotherapy," Semin Oncol, 2006, 33(1):50-67.
Grem JL, “5-Fluorouracil: Forty-Plus and Still Ticking. A Review of its Preclinical and Clinical Development,” Invest New Drugs, 2000, 18(4):299-313.
Grem JL, “Systemic Treatment Options in Advanced Colorectal Cancer: Perspectives on Combination 5-Fluorouracil Plus Leucovorin,” Semin Oncol, 1997, 24(5 Suppl 18):13-8, 18.
Iyer L and Ratain MJ, “5-Fluorouracil Pharmacokinetics: Causes for Variability and Strategies for Modulation in Cancer Chemotherapy,” Cancer Invest, 1999, 17(7):494-506.
Kleiman NS, Lehane DE, Geyer CE Jr, et al, “Prinzmetal's Angina During 5-Fluorouracil Chemotherapy,” Am J Med, 1987, 82(3):566-8.
Koren G, Beatty K, Seto A, et al, “The Effects of Impaired Liver Function on the Elimination of Antineoplastic Agents,” Ann Pharmacother, 1992, 26(3):363-71.
Kuhn JG, “Fluorouracil and the New Oral Fluorinated Pyrimidines,” Ann Pharmacother, 2001, 35(2):217-27.
Macdonald JS, “Toxicity of 5-Fluorouracil,” Oncology, 1999, 13(7 Suppl 3):33-4.
Machover D, “A Comprehensive Review of 5-Fluorouracil and Leucovorin in Patients With Metastatic Colorectal Carcinoma,” Cancer, 1997, 80(7):1179-87.
Mainwaring P and Grygiel JJ, “Interaction of 5-Fluorouracil With Folates,” Aust N Z J Med, 1995, 25(1):60.
Milano G and Chamorey AL, “Clinical Pharmacokinetics of 5-Fluorouracil With Consideration of Chronopharmacokinetics,” Chronobiol Int, 2002, 19(1):177-89.
Parker WB and Cheng YC, “Metabolism and Mechanism of Action of 5-Fluorouracil,” Pharmacol Ther, 1990, 48(3):381-95.
Pottage A, Holt S, Ludgate S, et al, “Fluorouracil Cardiotoxicity,” Br Med J, 1978, 1(6112):547.
Schalhorn A and Kuhl M, “Clinical Pharmacokinetics of Fluorouracil and Folinic Acid,” Semin Oncol, 1992, 19(2 Suppl 3):82-92.
Schilsky RL, “Biochemical and Clinical Pharmacology of 5-Fluorouracil,” Oncology, 1998, 12(10 Suppl 7):13-8.
Trissel LA, Martinez JF, and Xu QA, “Incompatibility of Fluorouracil With Leucovorin Calcium or Levoleucovorin Calcium,” Am J Health Syst Pharm, 1995, 52(7):710-5.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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