Fluorouracil

Pronunciation: FLURE-oh-UE-ra-sil
Class: Pyrimidine antimetabolite

Trade Names

Adrucil
- Injection, solution 50 mg/mL

Carac
- Cream 0.5%

Efudex
- Cream 5%

Fluorouracil
- Injection, solution 50 mg/mL
- Cream 5%
- Solution 2%
- Solution 5%

Fluoroplex
- Cream 1%

Pharmacology

The metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner, fluorouracil interferes with the synthesis of DNA and, to a lesser extent, inhibits the formation of RNA.

Pharmacokinetics

Distribution

Fluorouracil distributes into tumors, intestinal mucosa, bone marrow, liver, CSF, and brain tissue.

Metabolism

Metabolization takes place primarily in the liver; catabolic metabolism results in inactive degradation products.

Elimination

The parent drug is excreted unchanged (7% to 20%) in the urine in 6 h. The mean t _½ is about 16 min (range, 8 to 20 min) and is dose dependent.

Indications and Usage

Parenteral

Palliative management of colon, rectum, breast, gastric, and pancreatic carcinoma.

Topical Carac , Efudex , Fluoroplex

Multiple actinic or solar keratoses. Carac is only indicated for the face and anterior scalp areas.

Efudex 5%

Superficial basal cell carcinoma.

Unlabeled Uses

Condylomata acuminata (topical).

Contraindications

Hypersensitivity to any component of the product.

Parenteral

Depressed bone marrow function; poor nutritional status; potentially serious infections.

Topical

Pregnancy; dihydropyrimidine dehydrogenase enzyme deficiency (except for 1% cream).

Dosage and Administration

Colon, Rectum, Breast, Gastric, and Pancreatic Carcinomas
Adults

IV Individualize dosage based on actual body weight. Use lean body weight if patient is obese or has abnormal fluid retention.

Initial dose

12 mg/kg/day for 4 days. Do not exceed 800 mg/day. If no toxicity is observed, give 6 mg/kg on days 6, 8, 10, and 12. Give no therapy on days 5, 7, 9, or 11. Discontinue at end of day 12, even with no apparent toxicity.

In poor-risk patients and those with inadequate nutritional status

6 mg/kg/day for 3 days. If no toxicity is observed, give 3 mg/kg on days 5, 7, and 9. Give no therapy on days 4, 6, or 8. Do not exceed 400 mg/day.

Maintenance therapy

Start maintenance therapy 30 days after the last dose. If no toxicity is observed with the first course of therapy, repeat that dose of fluorouracil at 30-day intervals. If toxicity is observed with the first course of therapy, after the patient has recovered from initial toxicity, use a single weekly dose of 10 to 15 mg/kg. Do not exceed a weekly maintenance dose of 1,000 mg. Poor-risk patients may require a reduced maintenance dose.

Multiple Actinic or Solar Keratosis
Adults

Topical

Carac

Apply amount sufficient to cover the lesions once daily for up to 4 wk as tolerated. Healing generally occurs within 2 wk after therapy is stopped. The 0.5% cream is only indicated for the face and anterior scalp areas. Using fingertips, apply every day to cover lesions with a thin film. Do not apply near eyes, nostrils, or mouth. Apply 10 min after thoroughly washing, rinsing, and drying the entire area. After application, wash hands thoroughly. Continued treatment up to 4 wk results in greater lesion reduction.

Efudex

Apply amount sufficient to cover the lesions twice daily for 2 to 4 wk. Complete healing may not occur until 1 to 2 mo after therapy is stopped.

Fluoroplex

Apply amount sufficient to cover the entire face or other affected areas twice daily for 2 to 6 wk. When the inflammatory reaction reaches the erosion, ulceration, and necrosis stages, terminate use.

Superficial Basal Cell Carcinoma (5% Strength Only)
Adults

Topical Apply a sufficient amount to cover the lesions twice daily for 3 to 6 wk. Treatment may be required for 10 to 12 wk.

General Advice

• If a precipitate occurs in the injectable product because of exposure to low temperature, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

Storage/Stability

Injection

Store at 68° to 77°F.

Carac

Store at 68° to 77°F.

Efudex

Store at 59° to 86°F.

Fluoroplex

Store at 59° to 86°F. Avoid freezing.

Drug Interactions

The following drug interactions pertain to the injection doseform.

Cimetidine

May increase serum concentrations of fluorouracil and potentially increase toxicity.

Hydantoins (eg, phenytoin)

Hydantoin plasma levels may be elevated, increasing the risk of toxicity.

Leucovorin

Leucovorin may enhance GI toxicity of fluorouracil. Fatalities have occurred because of severe toxic enterocolitis.

Thiazide diuretics (eg, chlorothiazide)

Fluorouracil-induced leukopenia may be prolonged.

Warfarin

Anticoagulant effect of warfarin may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Parenteral

Angina, myocardial ischemia, thrombophlebitis.

CNS

Parenteral

Acute cerebellar syndrome, confusion, disorientation, euphoria, headache.

Topical Carac

Headache (3%).

Efudex

Emotional upset, insomnia, irritability.

Dermatologic

Parenteral

Alopecia, dermatitis (often presenting as a pruritic, maculopapular rash), dry skin, fissuring, nail changes (including loss of nails), palmar-plantar erythrodysethesia syndrome, photosensitivity, vein pigmentation.

Topical Carac

Application-site reaction (95%); erythema (93%); dryness (83%); burning (75%); erosion, pain (44%); irritation (1%).

Efudex

Allergic contact dermatitis, alopecia, blistering, bullous pemphigoid, burning, crusting, discomfort, erosions, erythema, hyperpigmentation, ichthyosis, irritation, pain, photosensitivity, pruritus, rash, scaling, scarring, soreness, suppuration, swelling, telangiectasias, tenderness, ulceration, urticaria.

Fluoroplex

Allergic contact dermatitis, burning, hyperpigmentation, inflammation, irritation, pain, pruritus, scarring, telangiectasias.

EENT

Parenteral

Epistaxis, lacrimal duct stenosis, lacrimation, nystagmus, photophobia, visual changes.

Topical Carac

Eye irritation (5%); sinusitis (2%).

Efudex

Conjunctival reaction, corneal reaction, lacrimation, nasal irritation.

GI

Parenteral

Anorexia, diarrhea, emesis, esophagopharyngitis, nausea, stomatitis, ulceration and bleeding.

Topical Efudex

Medicinal taste, stomatitis.

Hematologic-Lymphatic

Parenteral

Agranulocytosis, anemia, leukopenia, pancytopenia, thrombocytopenia.

Topical Efudex

Eosinophilia, thrombocytopenia, toxic granulation.

Hypersensitivity

Parenteral

Anaphylaxis, generalized allergic reactions.

Miscellaneous

Topical Efudex

Herpes simplex.

Carac

Edema (35%); common cold (5%); allergy (1%).

Precautions

Warnings Hospitalize for first course of injection therapy because of the possibility of severe toxic reactions.

Monitor Before each injection dose, obtain WBC with differential. Biopsy solar keratosis, which do not respond, to confirm the diagnosis. Perform follow-up biopsies as indicated in the management of superficial basal cell carcinoma.

Pregnancy

Category D (injection); Category X (topical).

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hypersensitivity

The potential for delayed hypersensitivity exists (topical).

Special Risk Patients

Use with extreme caution in poor-risk patients who have had high-dose pelvic irradiation or previous use of alkylating agents, have widespread involvement of bone marrow by metastatic tumors, or have hepatic or renal function impairment.

Photosensitivity

Avoid exposure to ultraviolet (UV) rays because the intensity of the reaction may be increased.

Discontinue use

Discontinue if the following signs of toxicity occur: diarrhea or frequent bowel movements, GI ulceration and bleeding, hemorrhage, intractable vomiting, leukopenia (WBC less than 3,500/mm ³ ), rapidly falling WBC count, stomatitis or esophagopharyngitis (at first visible sign), or thrombocytopenia (platelets less than 100,000/mm ³ ).

Dihydropyrimidine dehydrogenase deficiency ( Carac )

Rarely, severe toxicity (eg, diarrhea, neurotoxicity, neutropenia, stomatitis) has been attributed to dihydropyrimidine dehydrogenase deficiency.

Extravasation

Can cause local irritation or phlebitis. Refer to institution-specific protocol.

Hand-foot syndrome (injection)

May occur; characterized as a tingling sensation of hands and feet that progresses over the next few days to pain when holding objects or walking. Interruption of therapy is followed by gradual resolution over 5 to 7 days.

Obese/Edematous patients

Base dose on lean body mass in obese or edematous patients.

Topical use

Avoid application to mucous membranes because of the possibility of local inflammation and ulceration. Occlusive dressing may increase the incidence of inflammatory reactions.

Toxicity

Severe toxicity, including hematologic, GI hemorrhage, and death, has occurred.

Overdosage

Symptoms

Symptoms for the injection doseform may include agranulocytosis, bone marrow depression (including leukopenia, thrombocytopenia), diarrhea, GI ulceration and bleeding, nausea, vomiting.

Patient Information

• Caution women of childbearing potential to avoid becoming pregnant while being treated.

• Injection
• Advise patient that medication will usually be prepared and administered by health care provider in a health care setting but that home administration may be possible in some situations.
• If administering at home, ensure that the patient or caregiver understands how to store, prepare, and administer the dose and dispose of used equipment and supplies.
• Advise patient to notify health care provider if any of the following occurs: diarrhea with 4 to 6 stools per day or diarrhea at night; fever, chills, or other signs of infection; persistent vomiting; redness, swelling, and pain of the hands or feet; sores in the mouth.
• Advise patient that hair loss and skin reactions (dermatitis) occur frequently during treatment but that these effects are reversible once therapy has been discontinued.

• Topical Solution and Cream
• Teach patient or caregiver proper technique for applying solution or cream.
• Instruct patient, unless advised differently by health care provider, to apply twice daily until ulceration of application site occurs and then to discontinue use of solution or cream.
• Advise patient or caregiver that response to therapy is slow and may take several weeks, with complete healing taking up to 1 to 2 mo to occur following discontinuation of therapy.
• Advise patient or caregiver that most common adverse reactions are application-site reactions (eg, burning, irritation, swelling) and to inform health care provider if reaction occurs and is intolerable.
• Advise patient or caregiver that treated areas may be unsightly during therapy and for several weeks following therapy and that area may be covered with a gauze wrap for cosmetic reasons. Caution patient not to cover area with an occlusive wrap.
• Caution patient to avoid prolonged or unnecessary exposure to UV light (eg, sunlight, tanning booths) while under treatment with fluorouracil to prevent increasing intensity of skin reaction to medication.
• Instruct patient to avoid contact with eyes, nose, mouth, and mucous membranes or inflamed skin.
• Instruct patient to wash hands immediately after applying topical medication.

Copyright © 2009 Wolters Kluwer Health.