Drug Interactions between voriconazole and Yosprala

ADJUST DOSE: Coadministration with voriconazole may significantly increase the plasma concentrations of omeprazole and other proton pump inhibitors (PPIs). The proposed mechanism is voriconazole inhibition of PPI metabolism via CYP450 2C19 and 3A4. In healthy volunteers, administration of omeprazole 40 mg once daily with voriconazole 200 mg twice daily for 7 days increased steady-state omeprazole peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 2- and 4-fold, respectively, compared to omeprazole administered alone. Since all PPIs are metabolized by CYP450 2C19 and 3A4, a similar interaction with voriconazole should be expected.

MONITOR: Omeprazole and possibly other PPIs may also increase the plasma concentrations of voriconazole. The proposed mechanism is PPI inhibition of voriconazole metabolism via CYP450 2C19 and 3A4. In 18 healthy volunteers, administration of voriconazole 200 mg twice daily with omeprazole 40 mg once daily for 10 days increased the steady-state Cmax and AUC of voriconazole by an average of 15% and 41%, respectively, compared to administration with placebo. These changes are not generally considered clinically significant. However, an observational study of 52 voriconazole patients who received therapeutic drug monitoring reported that 5 out of 16 patients with voriconazole trough levels above 5.5 mg/L after one week of therapy experienced serious neurological adverse events (compared to none of the patients with lower trough levels), and 7 of the 16 were on concomitant omeprazole. Additionally, a suspected interaction between omeprazole and voriconazole was cited as a possible cause, or at least a contributing factor, in the development of torsade de pointes and cardiac arrest in the case of a young girl with congenital long QT syndrome.

MANAGEMENT: According to the manufacturers, dosage adjustment of omeprazole is not normally required when used with dual inhibitors of CYP450 2C19 and 3A4 such as voriconazole. However, it may be necessary in patients receiving higher dosages, such as those with Zollinger-Ellison syndrome. Voriconazole product labeling suggests reducing the omeprazole dosage by one-half upon initiation of voriconazole therapy in patients who are receiving omeprazole dosages of 40 mg/day or higher. Dosage adjustment recommendations for other PPIs are not available. Patients receiving PPIs with voriconazole should be monitored for potentially increased adverse reactions to both the PPI and voriconazole.

Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.