Tolak (fluorouracil)

At equivalent concentrations, the solutions are considered more effective than the creams.

Fluorouracil cream or solution is applied topically with a nonmetallic applicator, clean fingertips, or gloved fingers in an amount sufficient to cover the lesions. If the fingers are used to apply the drug, the hands should be washed immediately afterward.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Fluorouracil & Fluorouracil Prodrugs/Brivudine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Brivudine is an irreversible inhibitor of dihydropyrimidine dehydrogenase, which catalyzes the rate-limiting step in the catabolism of fluorouracil.(1-5) Brivudine may decrease the clearance and increase the toxicity of fluorouracil.

CLINICAL EFFECTS: Concurrent use of brivudine with fluorouracil or fluorouracil prodrugs (e.g., capecitabine, tegafur) may result in elevated levels of fluorouracil and serious toxicity, including melenic diarrhea, mucositis, hand-foot syndrome, pancytopenia, and death.(1-5)

PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3)

PATIENT MANAGEMENT: The use of fluorouracil or fluorouracil prodrugs is contraindicated during and for 4 weeks after therapy with brivudine. Treatment with brivudine can be started 24 hours after the last dose of fluorouracil or fluorouracil prodrug. If brivudine is coadministered with fluorouracil or fluorouracil prodrugs, immediate hospitalization is recommended and effective measures should be taken to reduce the toxicity of capecitabine, including prevention of systemic infections and dehydration.(1)

DISCUSSION: Brivudine inhibition of dihydropyrimidine dehydrogenase has been reported to cause a 5- to 15-fold increase in 5-fluorouracil (5-FU) concentrations.(2) In June 2012, the Spanish Agency of Medicines and Health Products (AEMPS) reported that 29 cases of concomitant use of a fluoropyrimidine and brivudine had occurred in Europe, with 23 of the cases resulting in death.(6) In September 2017, the AEMPS issued an update that an additional 7 fatalities had occurred since 2012 as a result of this drug combination.(7) In a case report, an 80-year-old woman with metastatic colon cancer on capecitabine was given brivudine for herpes zoster. She took two doses of brivudine prior to stopping therapy due to rash and mucositis. Nevertheless, two weeks later, she was hospitalized with skin lesions that progressed to Stevens-Johnson Syndrome, leukopenia, and thrombocytopenia. She developed septic shock and ultimately died.(2) Another two case reports describe similar patients with metastatic colon cancer who received combinations of brivudine with 5-FU. One patient had overlapping therapy for one day, and the other received 5-FU four days after stopping brivudine. Both developed mucositis, pancytopenia, and respiratory failure and died.(3,4) A 66-year-old woman with metastatic breast cancer took brivudine on the last 4 days of a chemotherapy cycle that included capecitabine. She was hospitalized for over 3 weeks with hand-foot syndrome, severe mucositis requiring parenteral nutrition, pancytopenia requiring filgrastim, platelet transfusion, and blood transfusion, and sepsis. She recovered from symptoms of hand-food syndrome and mucositis after about 6 weeks.(5)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

There is no enhanced messaging for this drug.

• Dihydropyrimidine dehydrogenase deficiency
• Lactation
• Pregnancy

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

More Frequent

• Dermatitis due to topical drug
• Pruritus of skin
• Skin rash

Rare or Very Rare

• Eosinophilia
• Leukocytosis
• Thrombocytopenic disorder

More Frequent

• Dry skin
• Erythema
• Paresthesia
• Skin photosensitivity
• Stinging of skin

Less Frequent

• Headache disorder
• Ocular irritation
• Pain
• Skin irritation
• Skin swelling

Rare or Very Rare

• Acquired ichthyosis
• Alopecia
• Basal cell carcinoma of skin
• Conjunctivitis
• Dyschromia
• Dysgeusia
• Eye tearing
• Skin scaling
• Skin thickening
• Skin ulcer
• Squamous cell carcinoma of skin
• Telangiectasia

No enhanced messaging available.

No enhanced messaging available.

Safe use of fluorouracil topical solution or cream during pregnancy has not been established.

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No enhanced messaging available.