Drug Interactions between Duzallo and fluorouracil

MONITOR CLOSELY: Coadministration with folate therapy may potentiate the pharmacologic effects of 5-fluorouracil (5-FU). The exact mechanism of interaction is unknown. Although enhancement of 5-FU cytotoxicity may be used to advantage in some cancer patients, increased toxicity should also be considered. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. In a clinical study consisting of 148 patients with advanced untreated colorectal cancer, weekly administration of 5-FU (600 mg/m2) in combination with leucovorin (500 mg/m2) was associated with a higher response rate than 5-FU alone (23% versus 8%). However, the combination was also more toxic than 5-FU alone, as evidenced by a higher incidence of grade 3 to 4 diarrhea (19.5% versus 8.5%) and conjunctivitis (26.5% versus 5.6%), as well as one recorded toxic death versus none. No differences in median survival and time to progression were observed between the two groups. Similar results were observed in another study with capecitabine, a prodrug of 5-FU. The interaction has also been reported with folic acid. A published case report describes two patients who were hospitalized for presumed 5-FU toxicity (anorexia, severe mouth ulceration, bloody diarrhea, vaginal bleeding) during concomitant treatment with a multivitamin containing folic acid (0.5 mg in one and 5 mg in the other). Both patients tolerated subsequent courses of 5-FU at the previous dosage following discontinuation of the multivitamin. Another published report describes a breast cancer patient who died during treatment with capecitabine (2500 mg/m2 daily for 14 days every 3 weeks) while taking folic acid 15 mg/day. The patient developed diarrhea, vomiting, and hand-foot syndrome eight days after starting capecitabine therapy. Her condition improved briefly following discontinuation of capecitabine and then folic acid, but she subsequently developed necrotic colitis and died from septic shock and vascular collapse.

MANAGEMENT: Caution is advised if 5-FU or any of its prodrugs (e.g., capecitabine, tegafur) are prescribed in combination with leucovorin. A lower dosage of 5-FU or the prodrug may be required. Therapy with leucovorin and fluorouracil should not be initiated or continued in patients with symptoms of gastrointestinal toxicity until such symptoms have resolved. Closely monitor patients with diarrhea until it resolves. Monitor for other potential toxicities of 5-FU such as neutropenia, thrombocytopenia, stomatitis, cutaneous reactions, and neuropathy. Patients should be instructed to avoid taking folic acid supplementation or multivitamin preparations containing folic acid without first speaking with their physician.

ADJUST DOSING INTERVAL: The tolerability of allopurinol may be improved by giving it after a meal. Additionally, when the dose is greater than 300 mg, dividing the total daily dose into smaller doses administered more often may be appropriate to help minimize gastrointestinal irritation.

MONITOR: Concomitant use of allopurinol with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: To improve tolerability, some manufacturers suggest administering allopurinol after a meal. Additionally, if the daily dose is greater than 300 mg, administering allopurinol in divided doses may help reduce gastrointestinal intolerance. Patients should also be counseled to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.