Drug Interaction Report

MONITOR: Coadministration with a nitroimidazole may increase the serum concentrations of phenytoin. The interaction has been reported with metronidazole, and the proposed mechanism is inhibition of phenytoin metabolism via CYP450 2C9. In one study, metronidazole (250 mg orally three times a day for 4 days) increased the half-life of phenytoin (300 mg single intravenous dose) in healthy volunteers by 44% and reduced its clearance by 15% compared to control values. However, another study found no effect of metronidazole (400 mg orally twice a day) on the pharmacokinetics of orally administered phenytoin (300 mg single dose). No data is available for tinidazole.

MONITOR: Phenytoin may reduce the plasma concentrations of metronidazole and tinidazole by accelerating their metabolism through induction of hepatic microsomal enzymes (e.g., CYP450 3A4).

MANAGEMENT: Pharmacologic response and serum phenytoin levels should be monitored more closely whenever metronidazole is added to or withdrawn from therapy, and the phenytoin (or fosphenytoin) dosage adjusted as necessary. Patients should be advised to notify their doctor if they experience potential symptoms of phenytoin toxicity such as nausea, vomiting, nystagmus, slurred speech, lethargy, tremor, ataxia, hyperreflexia, and dysarthria. Given its structural similarities to metronidazole, the same precaution may be applicable during therapy with tinidazole, although clinical data is lacking. In addition, the potential for reduced efficacy or therapeutic failure of the nitroimidazole should be considered when administered concomitantly with phenytoin or fosphenytoin. Alternative antimicrobial agents or dosage adjustments of the nitroimidazole may be necessary if an interaction is suspected.

CONTRAINDICATED: 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. Consumption of alcoholic beverages and products containing propylene glycol is specifically contraindicated during and for at least 3 days after completion of metronidazole and benznidazole therapy according to their product labeling.