In a drug-interaction study in 16 healthy volunteers, co-administration of multiple doses of zileuton (800 mg
every 12 hours) and theophylline (200 mg every 6 hours) for 5 days resulted in a significant decrease
(approximately 50%) in steady-state clearance of theophylline, an approximate doubling of theophylline A.C. and an
increase in theophylline Cmax (by 73%). The elimination half-life of theophylline
was increased by 24%. Also, during co-administration, theophylline-related adverse events were observed more
frequently than after theophylline alone. Upon initiation of ZYFLO in patients receiving theophylline, the
theophylline dosage should be reduced by approximately one-half and plasma theophylline concentrations monitored.
Similarly, when initiating therapy with theophylline in a patient receiving ZYFLO, the maintenance dose and/or dosing
interval of theophylline should be adjusted accordingly and guided by serum theophylline determinations .
Concomitant administration of multiple doses of ZYFLO (600 mg every 6 hours) and warfarin (fixed daily dose
obtained by titration in each subject) to 30 healthy male volunteers resulted in a 15% decrease in R-warfarin
clearance and an increase in AUC of 22%. The pharmacokinetics of S-warfarin were not affected. These pharmacokinetic
changes were accompanied by a clinically significant increase in prothrombin times. Monitoring of prothrombin time,
or other suitable coagulation tests, with the appropriate dose titration of warfarin is recommended in patients
receiving concomitant ZYFLO and warfarin therapy .
Co-administration of ZYFLO and propranolol results in a significant increase in propranolol concentrations.
Administration of a single 80-mg dose of propranolol in 16 healthy male volunteers who received ZYFLO 600 mg
every 6 hours for 5 days resulted in a 42% decrease in propranolol clearance. This resulted in an increase in
propranolol Cmax, AUC, and elimination half-life by 52%, 104%, and 25%,
respectively. There was an increase in ß-blockade and decrease in heart rate associated with the
co-administration of these drugs. Patients on ZYFLO and propranolol should be closely monitored and the dose of
propranolol reduced as necessary. No formal drug-drug interaction studies between ZYFLO and other beta-adrenergic
blocking agents (i.e., ß-blockers) have been conducted. It is reasonable to employ appropriate clinical
monitoring when these drugs are co-administered with ZYFLO.
In a drug interaction study in 16 healthy volunteers, co-administration of multiple doses of terfenadine
(60 mg every 12 hours) and ZYFLO (600 mg every 6 hours) for 7 days resulted in a decrease in clearance of
terfenadine by 22% leading to a statistically significant increase in mean AUC and Cmax of terfenadine of approximately 35%. This increase in terfenadine plasma concentration in the
presence of ZYFLO was not associated with a significant prolongation of the QTc interval. Although there was no
cardiac effect in this small number of healthy volunteers, given the high inter-individual pharmacokinetic
variability of terfenadine, co-administration of ZYFLO and terfenadine is not recommended.
Drug-drug interaction studies conducted in healthy volunteers between ZYFLO and prednisone and ethinyl estradiol
(oral contraceptive), drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme, have shown no significant
interaction. However, no formal drug-drug interaction studies between ZYFLO and dihydropyridine, calcium channel
blockers, cyclosporine, cisapride, and astemizole, also metabolized by CYP3A4, have been conducted. It is reasonable
to employ appropriate clinical monitoring when these drugs are co-administered with ZYFLO.
Drug-drug interaction studies in healthy volunteers have been conducted with ZYFLO and digoxin, phenytoin,
sulfasalazine, and naproxen. There was no significant interaction between ZYFLO and any of these drugs.