indication

For the reduction of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest).

pharmacology

Cilostazol is a quinolinone derivative indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs.

mechanism of action

Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.

toxicity

Information on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD₅₀ of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.

biotransformation

Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol.

absorption

Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C_max and a 25% increase in AUC. Absolute bioavailability is not known.

half life

11-13 hours.

route of elimination

Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-trans-hydroxy-cilostazol.

drug interactions

Diltiazem: Diltiazem, a moderate CYP3A4 inhibitor, may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cilostazol if diltiazem is initiated, discontinued or dose changed.

Erythromycin: Erythromycin increases the effect of cilostazol

Fluconazole: Fluconazole may decrease the effect of cilostazol.

Fluoxetine: Fluoxetine, a moderate CYP2C19 inhibitor, may decrease the metabolism of cilostazol. Monitor for changes in the therapeutic and adverse effects of cilostazol if fluoxetine is initiated, discontinued or dose changed.

Fluvoxamine: Fluvoxamine increases the effect of cilostazol

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Itraconazole: Itraconazole may increase the effect of cilostazol.

Josamycin: Erythromycin increases the effect of cilostazol

Ketoconazole: Ketoconazole may increase the effect of cilostazol.

Nefazodone: Nefazodone increases the effect of cilostazol

Omeprazole: Omeprazole increases the effect of cilostazol

Sertraline: Sertraline increases the effect of cilostazol

Telithromycin: Telithromycin may reduce clearance of Cilostazol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Cilostazol if Telithromycin is initiated, discontinued or dose changed.

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of Cilostazol. Consider alternate therapy or monitor for adverse/toxic effects of Cilostazol if Ticlopidine is initiated, discontinued or dose changed.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Cilostazol. Monitor for increased bleeding during concomitant thearpy.

Voriconazole: Voriconzole may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for increased therapeutic/adverse effects of cilostazol and consider reducing the dose during concomitant therapy.