Moderate Inhibitors of CYP3A4

1. Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).
2. Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40% (see DOSAGE AND ADMINISTRATION).
3. Grapefruit Juice: Grapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.

INHIBITORS OF CYP2C19

Omeprazole: Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole's potent inhibition of CYP2C19 (see DOSAGE AND ADMINISTRATION).

Quinidine

Concomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.

Lovastatin

The concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUCτ by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin increases lovastatin and β-hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.

Clinical Studies

The ability of Pletal to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.

Compared to patients treated with placebo, patients treated with Pletal 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of Pletal on walking distance was seen as early as the first on-therapy observation point of two or four weeks.

The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Pletal 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.

The corresponding changes in the placebo group were –10% to 41%.

The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either Pletal 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers. Pletal has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.

A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4 %) on cilostazol and 6.8% (95% CI of 1.9 to 11.5 %) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.

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