Fluorouracil

Trade Names:Adrucil- Injection, solution 50 mg/mL

Trade Names:Carac- Cream 0.5%

Trade Names:Efudex- Cream 5%- Solution 5%

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

Trade Names: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

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

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

Superficial basal cell carcinoma.

Unlabeled Uses

Condylomata acuminata (topical).

Contraindications

Hypersensitivity to any component of the product.

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

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

Dosage and Administration

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

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.

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.

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.

Topical

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.

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.

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.

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

Store at 68° to 77°F.

Store at 68° to 77°F.

Store at 59° to 86°F.

Store at 59° to 86°F. Avoid freezing.

Drug Interactions

The following drug interactions pertain to the injection doseform.

May increase serum concentrations of fluorouracil and potentially increase toxicity.

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

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

Fluorouracil-induced leukopenia may be prolonged.

Anticoagulant effect of warfarin may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Angina, myocardial ischemia, thrombophlebitis.

CNS

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

Headache (3%).

Emotional upset, insomnia, irritability.

Dermatologic

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.

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

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.

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

EENT

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

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

Conjunctival reaction, corneal reaction, lacrimation, nasal irritation.

GI

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

Medicinal taste, stomatitis.

Hematologic-Lymphatic

Agranulocytosis, anemia, leukopenia, pancytopenia, thrombocytopenia.

Eosinophilia, thrombocytopenia, toxic granulation.

Hypersensitivity

Anaphylaxis, generalized allergic reactions.

Miscellaneous

Herpes simplex.

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

Precautions

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.

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