aped interventricular septum. monitor patients for the development of a new systolic murmur or cardiac symptoms after starting cilostazol. 5.3 hematologic adverse reactions cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued have been reported. agranulocytosis is reversible on discontinuation of cilostazol. monitor platelets and white blood cell counts periodically. 5.4 hemostatic disorders or active pathologic bleeding cilostazol inhibits platelet aggregation in a reversible manner. cilostazol has not been studied in patients with hemostatic disorders or active pathologic bleeding. avoid use of cilostazol tablets in these patients.

em) or inhibitors of cyp2c19 (e.g., ticlopidine, fluconazole, and omeprazole) [see drug interactions ( 7.1 )] .

trials of another drug and may not reflect the rates observed in practice. adverse reactions were assessed in eight placebo-controlled clinical trials involving patients exposed to either 50 or 100 mg twice daily cilostazol tablets (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol tablets and 134 days for patients on placebo. the most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with cilostazol tablets was headache [50 mg twice daily (1.3%), 100 mg twice daily (3.5%) and placebo (0.3%)]. other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol tablets (all doses) versus 0.1% for placebo. the most common adverse reactions, occurring in at least 2% of patients treated with cilostazol tablets 50 or 100 mg twice daily, are shown in table 1. table 1: most common adverse reactions in patients on cilostazol tablets 50 or 100 mg twice daily (incidence at least 2% and occurring more frequently (≥ 2%) in the 100 mg twice daily group than on placebo) adverse reactions placebo (n=973) cilostazol tablets 50 mg twice daily (n=303) cilostazol tablets 100 mg twice daily (n=998) headache 14% 27% 34% diarrhea 7% 12% 19% abnormal stools 4% 12% 15% palpitation 1% 5% 10% dizziness 6% 9% 10% pharyngitis 7% 7% 10% infection 8% 14% 10% peripheral edema 4% 9% 7% rhinitis 5% 12% 7% dyspepsia 4% 6% 6% abdominal pain 3% 4% 5% tachycardia 1% 4% 4% less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with cilostazol 50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at a frequency in the 100 mg twice daily group greater than in the placebo group are listed below. body as a whole: fever, generalized edema, malaise cardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia digestive: anorexia, melena hematologic and lymphatic: anemia metabolic and nutritional: increased creatinine, hyperuricemia nervous: insomnia respiratory: epistaxis skin and appendages: urticaria special senses: conjunctivitis, retinal hemorrhage, tinnitus urogenital: urinary frequency 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of cilostazol tablets. because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. blood and lymphatic system disorders: aplastic anemia, granulocytopenia, pancytopenia, bleeding tendency cardiac disorders: torsade de pointes and qtc prolongation in patients with cardiac disorders (e.g. complete atrioventricular block, heart failure; and bradyarrythmia), angina pectoris. gastrointestinal disorders: gastrointestinal hemorrhage, vomiting, flatulence, nausea general disorders and administration site conditions: pain, chest pain, hot flushes hepatobiliary disorders: hepatic dysfunction/abnormal liver function tests, jaundice immune system disorders: anaphylaxis, angioedema, and hypersensitivity investigations: blood glucose increased, blood uric acid increased, increase in bun (blood urea increased), blood pressure increase nervous system disorders: intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematoma renal and urinary disorders: hematuria respiratory, thoracic and mediastinal disorders: pulmonary hemorrhage, interstitial pneumonia skin and subcutaneous tissue disorders: hemorrhage subcutaneous, pruritus, skin eruptions including stevens-johnson syndrome, skin drug eruption (dermatitis medicamentosa), rash vascular disorders: subacute stent thrombosis, hypertension.

f ossification of the sternum was seen at doses as low as 150 mg/kg/day. in nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the mrhd, and exposure to 3,4-dehydro- cilostazol was barely detectable. when cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the mrhd on a systemic exposure basis). 8.3 nursing mothers transfer of cilostazol into milk has been reported in rats. because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cilostazol, discontinue nursing or discontinue cilostazol. 8.4 pediatric use safety and effectiveness of cilostazol in pediatric patients have not been established. 8.5 geriatric use of the total number of subjects (n = 2,274) in clinical studies of cilostazol, 56 percent were 65 years old and over, while 16 percent were 75 years old and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be excluded. pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites. 8.6 hepatic impairment no dose adjustment is required in patients with mild hepatic impairment. patients with moderate or severe hepatic impairment have not been studied in clinical trials and dosing recommendations cannot be provided [see clinical pharmacology ( 12.3 )]. 8.7 renal impairment no dose adjustment is required in patients with 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 to 98%) [see clinical pharmacology ( 12.3 )].

ontractility was increased at doses required to inhibit platelet aggregation. a-v conduction was accelerated. in humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg twice daily, respectively. 12.2 pharmacodynamics cilostazol’s effects on platelet aggregation were evaluated in both healthy subjects and in patients with stable symptoms of cerebral thrombosis, cerebral embolism, transient ischemic attack, or cerebral arteriosclerosis over a range of doses from 50 mg every day to 100 mg three times a day. cilostazol significantly inhibited platelet aggregation in a dose-dependent manner. the effects were observed as early as 3 hours post-dose and lasted up to 12 hours following a single dose. following chronic administration and withdrawal of cilostazol, the effects on platelet aggregation began to subside 48 hours after withdrawal and returned to baseline by 96 hours with no rebound effect. a cilostazol dosage of 100 mg twice daily consistently inhibited platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate (adp). bleeding time was not affected by cilostazol administration. effects on circulating plasma lipids have been examined in patients taking cilostazol. after 12 weeks, as compared to placebo, cilostazol 100 mg twice daily produced a reduction in triglycerides of 29.3 mg/dl (15%) and an increase in hdl-cholesterol of 4.0 mg/dl (≅ 10%). drug interactions aspirin short-term (less than or equal to 4 days) coadministration of aspirin with cilostazol increased the inhibition of adp- induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. short-term (less than or equal to 4 days) coadministration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. however, short- term coadministration of aspirin with cilostazol had no clinically significant impact on pt, aptt, or bleeding time compared to aspirin alone. effects of long-term coadministration in the general population are unknown. in eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201 patients. the most frequent doses and mean durations of aspirin therapy were 75 to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). there was no apparent increase in frequency of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin. warfarin cilostazol did not inhibit the pharmacologic effects (pt, aptt, bleeding time, or platelet aggregation) of r- and s- warfarin after a single 25-mg dose of warfarin. the effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacodynamics of both drugs is unknown. 12.3 pharmacokinetics 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. 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. pharmacokinetics are approximately dose proportional. cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. the pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy subjects and patients with intermittent claudication due to peripheral arterial disease (pad). figure 1 shows the mean plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg twice daily. figure 1: mean plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg twice daily distribution cilostazol is 95 to 98% protein bound, predominantly to albumin. the binding for 3,4-dehydro-cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. mild hepatic impairment did not affect protein binding. the free fraction of cilostazol was 27% higher in subjects with renal impairment than in healthy volunteers. the displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant. metabolism cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. based on in vitro studies, the primary isoenzymes involved in cilostazol’s metabolism are cyp3a4 and, to a lesser extent, cyp2c19. the enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown. following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4 to 7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (20% as active as cilostazol). elimination 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. the remainder was excreted as other metabolites, none of which exceeded 5%. there was no evidence of induction of hepatic microenzymes. special populations age and gender the total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age (50 to 80 years) or gender. smokers population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%. hepatic impairment the pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects. patients with moderate or severe hepatic impairment have not been studied. renal impairment the total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in healthy subjects. severe renal impairment increases metabolite levels and alters protein binding of the parent. the expected pharmacologic activity, however, based on plasma concentrations and relative pde iii inhibiting potency of parent drug and metabolites, appeared little changed. 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 to 98%). drug interactions cilostazol does not appear to inhibit cyp3a4. warfarin cilostazol did not inhibit the metabolism of r- and s-warfarin after a single 25-mg dose of warfarin. clopidogrel multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol. strong inhibitors of cyp3a4 a priming dose of ketoconazole 400 mg (a strong inhibitor of cyp3a4), was given one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg. this regimen increased cilostazol c max by 94% and auc by 117%. other strong inhibitors of cyp3a4, such as itraconazole, voriconazole, clarithromycin, ritonavir, saquinavir, and nefazodone would be expected to have a similar effect [see dosage and administration ( 2.2 ), drug interactions ( 7.1 )]. moderate inhibitors of cyp3a4 erythromycin and other macrolide antibiotics: erythromycin is a moderately strong inhibitor of cyp3a4. coadministration of erythromycin 500 mg every 8h with a single dose of cilostazol 100 mg increased cilostazol c max by 47% and auc by 73%. inhibition of cilostazol metabolism by erythromycin increased the auc of 4´-trans-hydroxy- cilostazol by 141% [see dosage and administration ( 2.2 )]. diltiazem: diltiazem 180 mg decreased the clearance of cilostazol by ~30%. cilostazol c max increased ~30% and auc increased ~40% [see dosage and administration ( 2.2 )]. grapefruit juice: grapefruit juice increased the c max 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 ( 2.2 )]. 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 c ss, max and aucτ by 15%. there is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. coadministration of cilostazol with lovastatin increases lovastatin and ß-hydroxylovastatin auc approximately 70% and is not expected to be clinically significant.

imal species. cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. at this dose, systemic exposures (aucs) to unbound cilostazol were less than 1.5 times in males, and about 5 times in females, the exposure in humans at the mrhd. 13.2 animal toxicology and/or pharmacology repeated oral administration of cilostazol to dogs (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 twice daily. similar lesions have been reported in dogs following the administration of other positive inotropic agents (including pde iii inhibitors) and/or vasodilating agents. no cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of cilostazol at doses up to 1500 mg/kg/day. at this dose, systemic exposures (aucs) to unbound cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the mrhd. cardiovascular lesions were also not seen in rats following 52 weeks of administration of cilostazol at doses up to 150 mg/kg/day. at this dose, systemic exposures (aucs) to unbound cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the mrhd. in female rats, cilostazol aucs were similar at 150 and 1500 mg/kg/day. 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.

ercent mean improvement in maximal walking distance, at study end for each of the eight studies. figure 2: percent mean improvement in maximal walking distance at study end for the eight randomized, double-blind, placebo-controlled clinical trials across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg twice daily, expressed as the 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 cilostazol 100 mg twice daily or 50 mg twice daily 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. cilostazol 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.