Bestazol 50/Bestazol 100 Special Precautions

Congestive heart failure: Cilostazol is contraindicated in patients with congestive heart failure. In patients without congestive heart failure, the long-term effects of PDE 3 inhibitors (including cilostazol) are unknown. Patients in the 3 to 6 month placebo-controlled trials of cilostazol were relatively stable (no recent myocardial infarction or strokes, no rest pain or other signs of rapidly progressing disease) and only 19 patients died (0.7% in the placebo group and 0.8% in the cilostazol group). There are no data as to longer-term risk or risk in patients with more severe underlying heart disease.
Hematologic effects: Rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis have been reported when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.
Use with clopidogrel: There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there is an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution should be advised for checking bleeding times during coadministration.
Concomitant therapy with other platelet aggregation inhibitors: Use with caution in patients receiving other platelet aggregation inhibitors.
Use with other CYP3A4 or CYP2C19 inhibitors: Use with caution in patients receiving CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin and diltiazem) or CYP2C19 inhibitors (e.g., omeprazole). If concurrent use is warrented, consider dosage adjustment of cilostazol. (see Dosage & Administration).
Prior to elective surgical procedures: Withhold for at least 4-6 half-lives prior to elective surgical procedures.
Cardiovascular toxicity: Repeated oral administration of cilostazol to dog (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg bid.
Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD and those seen in dogs given doses associated with cardiovascular lesions.
Hepatic impairment: Patients with moderate or severe hepatic impairment have not been studied in clinical trials. Special caution is advised when cilostazol is used in such patients.
Renal impairment: Patients on dialysis have not been studied but it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%). Special caution should be advised when cilostazol is used in patients with severe renal impairment: creatinine clearance <25 ml/min.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No evidence of carcinogenic potential was exhibited in animal studies with doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice administered for up to 104 weeks. Based on systemic exposure, the maximum doses in mice and rats were less than human exposure at the maximum recommended human dose (MRHD).
Although a significant increase in chromosomal aberrations was associated with cilostazol in the in vivo Chinese Hamster Ovary Cell assay, negative results were reported in the following assays: bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration.
Cilostazol had no effect on the fertility of reproductive performance of male and female rats at doses of up to 1000 mg/kg/day. In comparison to systemic exposure (AUC) to unbound cilostazol in humans, this dose was less than 1.5 times the MHRD in male rats and approximately 5 times the MRHD in female rats.
Use in Children: The safety and efficacy of cilostazol in children have not been established.
Use in the Elderly: No substantial differences in safety and efficacy relative to younger adults but increased sensitivity cannot be ruled out.