Drug Interactions between cilostazol and esomeprazole / naproxen

MONITOR: Systemically and topically administered nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of bleeding in patients treated with anticoagulants and other drugs that affect hemostasis such as platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The pharmacologic effects of NSAIDs that contribute to this interaction include prolongation of prothrombin time and inhibition of platelet adhesion and aggregation.

MANAGEMENT: Caution is advised if NSAIDs are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

GENERALLY AVOID: Theoretically, proton pump inhibitors may decrease the gastrointestinal absorption of enteric-coated naproxen, which requires an acidic environment for dissolution. The proposed mechanism is an increase in gastric pH (i.e. decreased gastric acidity) induced by proton pump inhibitors. In patients treated with proton pump inhibitors, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered.

MANAGEMENT: Concomitant use of these drugs is generally not recommended.

MONITOR: 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-hydroxycilostazol (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-dehydrocilostazol (the most active metabolite of cilostazol) was increased by 69%.

MANAGEMENT: Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 and/or 2C19 inhibitor is added to or withdrawn from cilostazol therapy, and the 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.