Drug Interactions between aminophylline and zileuton

ADJUST DOSE: Coadministration with zileuton may significantly increase the plasma concentrations of theophylline. The proposed mechanism is zileuton inhibition of theophylline metabolism via CYP450 1A2. In 16 healthy adult male volunteers, administration of theophylline 200 mg four times daily in combination with zileuton 800 mg twice daily for 5 days resulted in an approximately 73% increase in mean steady-state theophylline peak serum concentration (Cmax) and 92% increase in systemic exposure (AUC) compared to administration with placebo. In addition, the apparent plasma clearance of theophylline decreased by nearly 50%, the time to peak concentration (Tmax) delayed by 0.5 hours, and the half-life prolonged by 1.5 hours (24%) during coadministration with zileuton. Fourteen subjects reported 44 mild or moderately severe adverse events possibly or probably related to coadministration of zileuton, including three who withdrew from the study prematurely, compared to eight subjects who reported 8 such events during placebo coadministration.

MANAGEMENT: Caution is advised if theophylline is prescribed in combination with zileuton, particularly in the elderly and patients with chronic obstructive pulmonary disease, congestive heart failure or cirrhosis, as these patients generally have lower theophylline clearance rates and may be particularly vulnerable to theophylline toxicity. When zileuton is initiated in patients receiving theophylline, the theophylline dosage should be reduced by approximately one-half and theophylline levels closely monitored. Similarly, when initiating therapy with theophylline in patients receiving zileuton, the maintenance dosage and/or dosing interval of theophylline should be adjusted accordingly and guided by serum theophylline levels. Patients should be advised to notify their physician if they experience signs and symptoms suggestive of theophylline toxicity such as nausea, vomiting, diarrhea, headache, tremor, irritability, insomnia, seizures, palpitation, or arrhythmia.