Cylos Drug Interactions

Inhibitors of platelet aggregation: Cilostazol is a PDE III inhibitor with anti-platelet activity. In a clinical study in healthy subjects, Cilostazol 150mg b.i.d. for five days did not result in prolongation of bleeding time.
Aspirin: Short term (≤4 days) co-administration of aspirin with Cilostazol suggested a 23-25% increase in inhibition of ADP-induced ex vivo platelet aggregation when compared to aspirin alone. There was no additive or synergistic effect on arachidonic acid induced platelet aggregation when compared to aspirin alone.
There were no apparent trends toward a greater incidence of hemorrhagic adverse effects in patients taking Cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin. Nonetheless, patients taking Cilostazol in combination with aspirin should be monitored for bleeding events.
Clopidogrel and other antiplatelet drugs: Concomitant administration of Cilostazol 150 mg b.i.d. and clopidogrel 75 mg daily for five days did not have a notable effect on the pharmacokinetics of Cilostazol, with an increase in AUC of only 9%. However, the AUC of the dehydro metabolite, which has about 4 times the potency of cilostazol in inhibiting platelet aggregation, increased by 24%. Concomitant administration of Cilostazol and clopidogrel did not have an appreciable effect on platelet count, prothrombin time (PT) or activated partial thromboplastin time (aPTT). All healthy subjects in the study had a prolongation of bleeding time on clopidogrel alone and concomitant administration with Cilostazol did not result in a significant additional effect on bleeding time. Caution is advised when co-administering Cilostazol with any drug that inhibits platelet aggregation. Consideration should be given to monitoring the bleeding time at intervals during co-administration. Cilostazol treatment is contraindicated in patients receiving two or more additional antiplatelet/anticoagulant agents. A higher rate of hemorrhage was observed with the concomitant use of clopidogrel, aspirin and cilostazol in the CASTLE trial.
Cilostazol has not been evaluated in circumstances where clopidogrel coadministration and a high bleeding risk co-exist, such as at the time of coronary stent insertion.
Anticoagulants: In a single-dose clinical study, no inhibition of the metabolism of warfarin or an effect on the coagulation parameters (PT, aPTT, bleeding time) was observed. However, caution is advised in patients receiving both Cilostazol and any anticoagulant agent, and frequent monitoring is required to reduce the possibility of bleeding. Cilostazol treatment is contraindicated in patients receiving two or more additional antiplatelet/anticoagulant agents.
Cytochrome P-450 (CYP) enzyme inhibitors and substrates: Cilostazol is extensively metabolised by CYP enzymes, particularly CYP3A4 and CYP2C19 and to a lesser extent CYP1A2. The dehydro metabolite, which has 4-7 times the potency of cilostazol in inhibiting platelet aggregation, appears to be formed primarily via CYP3A4. The 4'-trans-hydroxy metabolite, with potency one-fifth that of cilostazol, appears to be formed primarily via CYP2C19. Therefore, drugs inhibiting CYP3A4 (e.g., some macrolides, azole antifungals, protease inhibitors) or CYP2C19 (like proton pump inhibitors, PPIs) increase the total pharmacological activity and could have the potential to enhance the undesirable effects of cilostazol. Consequently, for patients concomitantly taking strong CYP3A4 or CYP2C19 inhibitors the recommended dose is 50 mg twice daily.
Administration of cilostazol with erythromycin (an inhibitor of CYP3A4) resulted in an increase in the AUC of cilostazol by 72%, accompanied by a 6% increase in AUC of the dehydro metabolite and a 119% increase in AUC of the 4'-trans-hydroxy metabolite.
Based on AUC, the overall pharmacological activity of cilostazol increases 34% when coadministered with erythromycin. Based on these data, the recommended dose of cilostazol is 50 mg bid in the presence of erythromycin and similar agents (e.g., clarithromycin).
Co-administration of ketoconazole (an inhibitor of CYP3A4 with cilostazol resulted in a 117% increase in the AUC of cilostazol, accompanied by a 15% decrease in the AUC of the dehydro metabolite and a 87% increase in the AUC of the 4'-trans-hydroxy metabolite. Based on AUC, the overall pharmacological activity of cilostazol increases 35% when co-administered with ketoconazole. Based on these data, the recommended dose of cilostazol is 50 mg bid in the presence of ketoconazole and similar agents (e.g., itraconazole).
Administration of cilostazol with diltiazem (a weak inhibitor of CYP3A4) resulted in an increase in the AUC of cilostazol of 44%, accompanied by a 4% increase in AUC of the dehydro metabolite and a 43% increase in the AUC of the 4'-trans-hydroxy metabolite.
Based on AUC, overall pharmacological activity of cilostazol increases 19 % when co-administered with diltiazem. Based on these data, no dose adjustment is necessary.
Administration of a single dose of 100 mg cilostazol with 240 ml grapefruit juice (an inhibitor of intestinal CYP3A4) did not have a notable effect on the pharmacokinetics of cilostazol. Based on these data, no dose adjustment is necessary. A clinically relevant effect on cilostazol is still possible at higher quantities of grapefruit juice.
Administration of cilostazol with omeprazole (an inhibitor of CYP2C19) increased the AUC of cilostazol by 22%, accompanied by a 68% increase in the AUC of the dehydro metabolite and a decrease of 36% in the AUC of the 4'-trans hydroxy metabolite. Based on AUC, the overall pharmacological activity increases by 47% when co-administered with omeprazole. Based on these data, the recommended dose of cilostazol is 50 mg bid in the presence of omeprazole.
Cytochrome P-450 enzyme substrates: Cilostazol has been shown to increase the AUC of lovastatin (sensitive substrate for CYP3A4) and its β-hydroxy acid by 70%. Caution is advised when cilostazol is co-administered with CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivates). Caution is advised in case of co-administration with statins metabolised by CYP3A4, for example simvastatin, atorvastatin and lovastatin.
Cytochrome P-450 enzyme inducers: The effect of CYP3A4 and CYP2C19 inducers (such as carbamazepine, phenytoin, rifampicin and St. John's wort) on cilostazol pharmacokinetics has not been evaluated. The antiplatelet effect may theoretically be altered and should be carefully monitored when cilostazol is co-administered with CYP3A4 and CYP2C19 inducers.
In clinical trials, smoking (which induces CYP1A2) decreased cilostazol plasma concentrations by 18%.
Other potential interactions: Caution is needed when co-administering cilostazol with any other agent which has the potential to reduce blood pressure due to the possibility that there may be an additive hypotensive effect with a reflex tachycardia.