Yes: Injection

Antineoplastic Agent, Antimetabolite

Treatment of carcinoma of stomach, colon, rectum, breast, and pancreas; also used topically for management of multiple actinic keratoses and superficial basal cell carcinomas

D (injection); X (topical)

Hypersensitivity to fluorouracil or any component, poor nutritional status, bone marrow depression, or potentially serious infections; pregnancy with topical product

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution in patients with impaired kidney or liver function. The drug should be discontinued if intractable vomiting or diarrhea, precipitous falls in leukocyte or platelet counts, stomatitis, hemorrhage, or myocardial ischemia occurs. Use with caution in patients who have had high-dose pelvic radiation or previous use of alkylating agents. Patient should be hospitalized during initial course of therapy.

Toxicity depends on route and duration of infusion

Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia

Irritant chemotherapy

Gastrointestinal (route and schedule dependent): Heartburn, nausea, vomiting, anorexia, stomatitis, esophagitis, anorexia, stomatitis, and diarrhea; bolus dosing produces milder GI problems, while continuous infusion tends to produce severe mucositis and diarrhea; vomiting is moderate, occurring in 30% to 60% of patients, and responds well to phenothiazines and dexamethasone

Emetic potential:

<1000 mg: Moderately low (10% to 30%)

greater than or equal to 1000 mg: Moderate (30% to 60%)

Hematologic: Myelosuppressive: Granulocytopenia occurs around 9-14 days after 5-FU and thrombocytopenia around 7-17 days. The marrow recovers after 22 days. Myelosuppression tends to be more pronounced in patients receiving bolus dosing of 5-FU.

WBC: Moderate

Platelets: Mild to moderate

Onset (days): 7-10

Nadir (days): 14

Recovery (days): 21

1% to 10%:

Dermatologic: Dry skin

Gastrointestinal: GI ulceration

<1%: Hypotension, chest pain, EKG changes similar to ischemic changes, and possibly cardiac enzyme abnormalities. Usually occurs within the first two days of therapy, and may resolve with nitroglycerin and calcium channel blockers. May be due to coronary vessel vasospasm induced by 5-FU.

Cerebellar ataxia, headache, somnolence, ataxia are seen primarily in intracarotid arterial infusions for head and neck tumors. This is believed to be caused by fluorocitrate, a neurotoxic metabolite of the parent compound.

Pruritic maculopapular rash, alopecia, hyperpigmentation of nailbeds, face, hands, and veins used in infusion; photosensitization with UV light; palmar-plantar syndrome (hand-foot syndrome); coagulopathy, hepatotoxicity, conjunctivitis, tear duct stenosis, excessive lacrimation, visual disturbances, shortness of breath

Symptoms of overdose include myelosuppression, nausea, vomiting, diarrhea, alopecia

No specific antidote exists; monitor hematologically for at least 4 weeks; supportive therapy

Methotrexate: This interaction is schedule dependent; 5-FU should be given following MTX, not prior to

If MTX is given first: The cells exposed to MTX before 5-FU have a depleted reduced folate pool which inhibits the binding of the 5dUMP to TS. However, it does not interfere with FUTP incorporation into RNA. Polyglutamines, which accumulate in the presence of MTX may be substituted for the folates and allow binding of FdUMP to TS. MTX given prior to 5-FU may actually activate 5-FU due to MTX inhibition of purine synthesis.

If 5-FU is given first: 5-FU inhibits the TS binding and thus the reduced folate pool is not depleted, thereby negating the effect of MTX

Increased effect: Leucovorin: the folate pool and in certain tumors, may promote TS inhibition and 5-FU activity. Must be given before or with the 5-FU to prime the cells; it is not used as a rescue agent in this case.

Increased toxicity:

Allopurinol: Inhibits thymidine phosphorylase (an enzyme that activates 5-FU). The antitumor effect of 5-FU appears to be unaltered, but decreases toxicity

Cimetidine: Results in increased plasma levels of 5-FU due to drug metabolism inhibition and reduction of liver blood flow induced by cimetidine

Store intact vials at room temperature and protect from light; slight discoloration does not usually denote decomposition

Further dilution in D₅W or NS at concentrations of 0.5-10 mg/mL are stable for 72 hours at 4°C to 25°C

Incompatible with cytarabine, diazepam, doxorubicin, methotrexate; concentrations of >25 mg/mL of fluorouracil and >2 mg/mL of leucovorin are incompatible (precipitation occurs)

Compatible with vincristine, methotrexate, potassium chloride, magnesium sulfate

Standard I.V. dilution: I.V. push: Dose/syringe (concentration: 50 mg/mL)

Maximum syringe size for IVP is a 30 mL syringe and syringe should be <75% full

CIV/IVPB: Dose/50-1000 mL D₅W or NS

Syringe and solution are stable for 72 hours at 4°C to 25°C

A pyrimidine antimetabolite that interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid; 5-FU rapidly enters the cell and is activated to the nucleotide level; there it inhibits thymidylate synthetase (TS), or is incorporated into RNA (most evident during the GI phase of the cell cycle). The reduced folate cofactor is required for tight binding to occur between the 5-FdUMP and TS.

Duration: ~3 weeks

Absorption: Oral: Erratic and rarely used

Distribution: V_d: ~22% of total body water; penetrates the extracellular fluid, CSF, and third space fluids (such as pleural effusions and ascitic fluid)

Metabolism: 5-FU must be metabolized to be active. 90% metabolized; accomplished by a dehydrogenase enzyme primarily found in the liver; dose may need to be omitted in patients with liver failure (bilirubin >5 mg/dL)

Bioavailability: <75%, erratic and undependable

Half-life (biphasic): Initial: 6-20 minutes; doses of 400-600 mg/m² produce drug concentrations above the threshold for cytotoxicity for normal tissue and remain there for 6 hours; 2 metabolites, FdUMP and FUTP, have prolonged half-lives depending on the type of tissue; the clinical effect of these metabolites has not been determined

Elimination: 5% of dose excreted as unchanged drug in the urine in 6 hours, and a large amount excreted as CO₂ from the lung

Refer to individual protocols

Children and Adults:

I.V.: Initial: 400-500 mg/m²/day (12 mg/kg/day; maximum: 800 mg/day) for 4-5 days either as a single daily I.V. push or 4-day CIV

I.V.: Maintenance dose regimens:

200-250 mg/m² (6 mg/kg) every other day for 4 days repeated in 4 weeks

500-600 mg/m² (15 mg/kg) weekly as a CIV or I.V. push

I.V.: Concomitant with leucovorin:

370 mg/m²/day x 5 days

500-1000 mg/m² every 2 weeks

600 mg/m² weekly for 6 weeks

Although the manufacturer recommends no daily dose >800 mg, higher doses of up to 2 g/day are routinely administered by CIV; higher daily doses have been successfully used

Hemodialysis: Administer dose posthemodialysis

Dosing adjustment/comments in hepatic impairment: Bilirubin >5 mg/dL: Omit use

Topical:

Actinic or solar keratosis: Apply twice daily for 2-6 weeks

Superficial basal cell carcinomas: Apply 5% twice daily for at least 3-6 weeks and up to 10-12 weeks

Use of acidic solutions such as orange juice or other fruit juices to dilute 5-FU for oral administration may result in precipitation of the drug and decreased absorption; increase dietary intake of thiamine

CBC with differential and platelet count, renal function tests, liver function tests

Fecal discoloration

May cause drowsiness

Myelosuppression is common; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Avoid alcohol and all OTC drugs unless approved by your oncologist. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) and nutrition (small frequent meals may help). You may experience sensitivity to sunlight (use sunblock, wear protective clothing, or avoid direct sunlight); susceptibility to infection (avoid crowds or infected persons or persons with contagious diseases); nausea, vomiting, diarrhea, or loss of appetite (frequent small 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); 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.

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.

Cool to body temperature before using; after vial has been entered, any unused portion should be discarded within 1 hour; wash hands immediately after topical application of the 5% cream; I.V. formulation may be given orally mixed in water, grape juice, or carbonated beverage

Cream, topical:

Efudex®: 5% (25 g)

Fluoroplex®: 1% (30 g)

Injection (Adrucil®): 50 mg/mL (10 mL, 20 mL, 50 mL, 100 mL)

Solution, topical:

Efudex®: 2% (10 mL); 5% (10 mL)

Fluoroplex®: 1% (30 mL)

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