DBL Fluorouracil Drug Interactions

Cytotoxic agents: All myelosuppressive drugs (e.g., cytotoxic agents used in combination chemotherapy) can increase haematotoxicity of fluorouracil.
Folinic acid (leucovorin): Leucovorin enhances the DNA-directed toxicity of fluorouracil. This combination should be used with caution as the toxicity of fluorouracil, especially gastrointestinal (GI) and haematologic, may be increased. Careful monitoring should be observed and the dose of fluorouracil may be decreased based on current guidelines.
Allopurinol: Allopurinol may decrease the degree of bone marrow depression produced by fluorouracil. Studies of this possibility have reported conflicting results.
Various agents have been reported to biochemically modulate the antitumour efficacy or toxicity of fluorouracil. Common drugs include methotrexate, metronidazole and folinic acid (leucovorin).
Metronidazole: Metronidazole may enhance the toxicity of fluorouracil. The mechanism of interaction is presumed to be reduced clearance of fluorouracil by metronidazole. Concurrent administration should be avoided.
Levamisole: Combination therapy with 5-fluorouracil and levamisole has been associated with multifocal inflammatory leukoencephalopathy (MILE). The use of levamisole and 5-fluorouracil is no longer recommended by NH&MRC 'Clinical Practice guidelines: The prevention, early detection and management of colorectal cancer'. This combination regimen has been superseded by fluorouracil and folinic acid (see Precautions).
Cimetidine: Pre-treatment with cimetidine prior to intravenous fluorouracil increased the fluorouracil area under the concentration versus time curve (AUC) by 27%. The total body clearance was reduced by 28%. This may lead to increased plasma concentrations of fluorouracil. This effect is probably due to both inhibition of hepatic enzymes and reduction of hepatic blood flow. Caution should be taken if the patient receives fluorouracil and cimetidine concurrently.
Phenytoin: Increased phenytoin plasma concentrations have been reported during concomitant use of phenytoin with capecitabine or its metabolite fluorouracil. Formal interaction studies between phenytoin and capecitabine have not been conducted, but the mechanism of interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine. Serum levels of phenytoin sustained above the optimal range may produce encephalopathy, or confusional states (delirium psychosis), or rarely irreversible cerebellar dysfunction. Therefore, patients taking phenytoin concomitantly with capecitabine or fluorouracil should be regularly monitored for increased phenytoin plasma levels and the phenytoin dosage may need to be reduced (see Precautions).
Brivudine and sorivudine: Brivudine, sorivudine or their chemically related analogues irreversibly inhibit DPD, resulting in a significant increase in fluorouracil exposure. This may lead to increased fluoropyrimidine-related toxicities with potentially fatal outcome. Therefore, either a different antiviral therapy may be used or there should be an interval of at least 4 weeks between the administration of brivudine, sorivudine, or the analogues and the start of fluorouracil treatment (see Contraindications). In the case of accidental administration of nucleoside analogues that inhibit DPD activity to patients treated with fluorouracil, effective measures should be taken to reduce fluorouracil toxicity. Immediate hospitalisation is recommended.
Radiation therapy: Radiation therapy on the bone marrow, especially to the area of the chest and mediastinum, may potentiate the bone marrow effects of fluorouracil.
Warfarin: Elevated International Normalised Ratio (INR) levels and occasional episodes of bleeding have been reported during concomitant use of warfarin and fluorouracil or its analogues. In these cases, fluorouracil has usually been administered as one component of an antineoplastic combination regimen. Adequate anticoagulant response to warfarin and other coumarin-derivative therapy should be monitored regularly in patients taking fluorouracil.
Thiamine (vitamin B1): Fluorouracil treatment may interfere with the metabolism of thiamine (vitamin B1). Thiamine level reduction may facilitate the onset of Wernicke's encephalopathy (see Precautions and Adverse Reactions).
Live or live-attenuated vaccines: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including fluorouracil, may result in serious or fatal infections (see Precautions).
Laboratory values: Fluorouracil treatment may interfere with some laboratory tests. Increases in total serum thyroxine concentration (due to increased binding to globulin) have been reported.