Drug Interaction Report

GENERALLY AVOID: Coadministration with a nitroimidazole may increase the toxicity of 5-fluorouracil (5-FU). The interaction has been observed with both metronidazole and misonidazole. The proposed mechanism involves reduced clearance of 5-FU in the presence of nitroimidazoles. In a study of 27 patients with metastatic colorectal cancer who received metronidazole (750 mg/m2 IV) an hour before 5-FU (600 mg/m2 IV) on five consecutive days per week every 4 weeks, an unusually high incidence of fluorouracil toxicity was observed, including granulocytopenia (74%), anemia (41%), stomatitis and oral ulceration (34%), nausea and vomiting (48%), and thrombocytopenia (19%). In another study, 15 patients receiving 5-FU (1 gm/m2) with misonidazole 2 gm/m2 or 3 gm/m2 for advanced colorectal cancer had an increased incidence (44% and 56%, respectively) and severity of nausea and vomiting compared to administration of 5-fluorouracil alone (27%) in a prior course. The incidence of leukopenia was also higher with the combination than 5-FU alone (18% versus 13%), although the difference was not statistically significant. Despite an increase in toxicity, in vitro studies performed by the first group of investigators failed to detect any additive or synergistic antineoplastic effect secondary to the interaction.

MANAGEMENT: Given the potential for increased toxicity, 5-fluorouracil and its prodrugs, capecitabine and tegafur, should probably not be used with nitroimidazoles unless benefits are anticipated to outweigh the risks.

GENERALLY AVOID: Use of alcohol or products containing alcohol during nitroimidazole therapy may result in a disulfiram-like reaction in some patients. There have been a few case reports involving metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have questioned the disulfiram-like properties of metronidazole. One study found neither elevations in blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects who received placebo.

MANAGEMENT: Because clear evidence is lacking concerning the safety of ethanol use during nitroimidazole therapy, patients should be apprised of the potential for interaction and instructed to avoid alcoholic beverages and products containing alcohol or propylene glycol while using oral, intravenous, or vaginal preparations of a nitroimidazole. Alcoholic beverages should not be consumed for up to 3 days after completion of systemic nitroimidazole therapy.