Drug Interactions between aspirin / omeprazole and cilostazol

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 and/or 2C19 may increase the plasma concentrations of cilostazol and or its pharmacologically active metabolites, which are substrates of these isoenzymes. The possibility of prolonged and/or increased pharmacologic effects of cilostazol should be considered. In pharmacokinetic studies, pretreatment with a 400 mg priming dose of ketoconazole (a potent CYP450 3A4 inhibitor) one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg resulted in a 94% increase in cilostazol peak plasma concentration (Cmax) and a 117% increase in cilostazol systemic exposure (AUC). Coadministration of the less potent inhibitor erythromycin (500 mg every 8 hours) with a single 100 mg dose of cilostazol resulted in a 47% and 73% increase in cilostazol Cmax and AUC, respectively, while AUC of 4-trans-hydroxy-cilostazol (an active metabolite with 1/5 the pharmacologic activity) increased by 141% as a result of the inhibition of cilostazol metabolism via CYP450 3A4. Coadministration with 180 mg of diltiazem, a moderate CYP450 3A4 inhibitor, decreased cilostazol clearance by 30% and increased its Cmax by 30% and AUC by 40%. In contrast, cilostazol metabolism was not significantly affected when coadministered with omeprazole, a potent CYP450 2C19 inhibitor, but the systemic exposure to 3,4-dehydro-cilostazol (the most active metabolite of cilostazol) was increased by 69%.

MANAGEMENT: A 50% dosage reduction of cilostazol (i.e., 50 mg twice a day) should be considered when used with potent or moderate CYP450 3A4 and/or 2C19 inhibitors. Close clinical and laboratory monitoring is advised whenever the inhibitor is added to or withdrawn from therapy, and the cilostazol dosage adjusted as necessary. Patients should be advised to contact their physician if they experience adverse effects of cilostazol such as dizziness, nausea, diarrhea, bleeding, or irregular heartbeat.

MONITOR: Coadministration of cilostazol with other antiplatelet agents may produce additive pharmacodynamic effects resulting in increased inhibition of platelet function. In 12 healthy male volunteers, coadministration of cilostazol (100 mg twice a day for 10 days) and aspirin (325 mg once a day for the last 5 days of cilostazol administration) resulted in a 23% to 35% increase in inhibition of adenosine diphosphate (ADP)-induced ex vivo platelet aggregation compared to aspirin plus placebo. However, there was no additive or synergistic effect on arachidonic acid-induced platelet aggregation. Cilostazol, with or without aspirin, caused no changes in PT, aPTT, or bleeding time. Drug-related adverse events were generally mild, the most frequent being headache. Another study involving 21 patients with peripheral arterial disease also found no increase in bleeding time when cilostazol (100 mg twice a day) was added to clopidogrel (75 mg once a day), aspirin (325 mg once a day), or clopidogrel and aspirin combined, each for two weeks. The investigators concluded that cilostazol may be used with other platelet inhibitors. However, effects of long-term coadministration in the general population are unknown. During clinical trials, there was no apparent increase in the incidence of hemorrhagic adverse effects in 201 patients who received cilostazol with aspirin (75 to 325 mg daily for up to 137 days) compared to those who received placebo and equivalent doses of aspirin.

MANAGEMENT: Because of theoretical concerns regarding increased inhibition of platelet aggregation, cilostazol should be used cautiously with other antiplatelet agents.

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.