ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:oPatients with Heart Failure [see Boxed Warning]oTachycardia [see Warnings and Precautions (5.1)]oHematologic Adverse Reactions [see Warnings and Precautions (5.2)]oHemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions (5.3)] oPatients with Heart Failure [see Boxed Warning]. oTachycardia [see Warnings and Precautions (5.1)]. oHematologic Adverse Reactions [see Warnings and Precautions (5.2)]. oHemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions (5.3)] Most common adverse reactions greater than or equal to 2% and at least twice that for placebo in patients on 100 mg twice daily are headache, diarrhea, abnormal stools, and palpitation (6.1)To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical 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 (n=1301) or placebo (n=973), with median treatment duration of 127 days for patients on cilostazol 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 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 (all doses) versus 0.1% for placebo.The most common adverse reactions, occurring in at least 2% of patients treated with cilostazol 50 or 100 mg twice daily, are shown in Table 1.Table 1: Most Common Adverse Reactions in Patients on Cilostazol 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 ReactionsPlacebo(N=973)Cilostazol 50 mgtwice daily(N=303)Cilostazol 100 mgtwice daily(N=998)Headache14%27%34%Diarrhea7%12%19%Abnormal Stools4%12%15%Palpitation1%5%10%Dizziness6%9%10%Pharyngitis7%7%10%Infection8%14%10%Peripheral Edema4%9%7%Rhinitis5%12%7%Dyspepsia4%6%6%Abdominal Pain3%4%5%Tachycardia1%4%4%Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with cilostazol50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at frequency in the 100mg twice daily group greater than in the placebo group are listed below.Body as whole: fever, generalized edema, malaiseCardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardiaDigestive: anorexia, melenaHematologic and Lymphatic: anemiaMetabolic and Nutritional: increased creatinine, hyperuricemiaNervous: insomniaRespiratory: epistaxisSkin and Appendages: urticariaSpecial Senses: conjunctivitis, retinal hemorrhage, tinnitusUrogenital: urinary frequency. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of cilostazol. Because these reactions are reported voluntarily from population of an unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and lymphatic system disorders:Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendencyCardiac disorders:Torsade de pointes and QTc prolongation in patients with cardiac disorders (e.g. complete atrioventricular block, heartfailure; and bradyarrythmia), angina pectoris.Gastrointestinal disorders:Gastrointestinal hemorrhage, vomiting, flatulence, nauseaGeneral disorders and administration site conditions:Pain, chest pain, hot flushesHepatobiliary disorders:Hepatic dysfunction/abnormal liver function tests, jaundiceImmune system disorders:Anaphylaxis, angioedema, and hypersensitivityInvestigations:Blood glucose increased, blood uric acid increased, increase in BUN (blood urea increased), blood pressure increaseNervous system disorders:Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematomaRenal and urinary disorders:HematuriaRespiratory, thoracic and mediastinal disorders:Pulmonary hemorrhage, interstitial pneumoniaSkin and subcutaneous tissue disorders:Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitismedicamentosa), rashVascular disorders:Subacute stent thrombosis, hypertension.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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 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 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 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 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.

BOXED WARNING SECTION.

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS Cilostazol tablets are contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with the pharmacologic effect have caused decreased survival compared to placebo patients with class III-IV heart failure.. WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS See full prescribing information for complete boxed warning.Cilostazol tablets are contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with the pharmacologic effect have caused decreased survival compared to placebo patients with class III-IV heart failure. (4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.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 times in females, the exposure in humans at the MRHD.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cilostazol and several of its metabolites inhibit phosphodiesterase III activity and suppress cAMP degradation with resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.Cilostazol reversibly inhibits platelet aggregation induced by variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress.Cardiovascular effectsCilostazol affects both vascular beds and cardiovascular function. It produces heterogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.In dogs or cynomolgus monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in dose-proportional manner by mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg twice daily, respectively.. 12.2 Pharmacodynamics Cilostazols 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 range of doses from 50 mg every day to 100 mg three times day. Cilostazol significantly inhibited platelet aggregation in dose-dependent manner. The effects were observed as early as hours post-dose and lasted up to 12 hours following 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. 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 reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL cholesterol of 4.0 mg/dL 10%).Drug InteractionsAspirinShort-term (less than or equal to days) co-administration 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 days) co-administration 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 co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term co-administration in the general population are unknown.In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered 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.WarfarinCilostazol did not inhibit the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after 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. high fat meal increases absorption, with an approximately 90% increase in Cmax and 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to lesser extend, 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 few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD). Figure 1shows the mean +- SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg twice daily.Figure 1: Mean +- SEM Plasma Concentration-time Profile at Steady State after Multiple Dosing of Cilostazol 100 mg Twice DailyDistributionCilostazol is 95% to 98% protein bound, predominantly to albumin. The mean percent 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.MetabolismCilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazols metabolism are CYP3A4 and, to 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 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 the 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 PopulationsAge and GenderThe 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.SmokersPopulation pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.Hepatic ImpairmentThe 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 ImpairmentThe 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 InteractionsCilostazol does not appear to inhibit CYP3A4.WarfarinCilostazol did not inhibit the metabolism of R- and S-warfarin after single 25 mg dose of warfarin.ClopidogrelMultiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.Strong Inhibitors of CYP3A4A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax 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 similar effect [see Dosage and Administration (2.2), Drug Interactions (7.1)].Moderate Inhibitors of CYP3A4Erythromycin and other macrolide antibiotics: Erythromycin is moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg every 8h with 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% [see Dosage and Administration (2.2)].DiltiazemDiltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40% [see Dosage and Administration (2.2)].Grapefruit JuiceGrapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.Inhibitors of CYP2C19Omeprazole: Co-administration 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 omeprazoles potent inhibition of CYP2C19 [see Dosage and Administration (2.2)].QuinidineConcomitant administration of quinidine with single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.LovastatinThe concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUC by 15%. There is also decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and ss-hydroxylovastatin AUC approximately 70% and is not expected to be clinically significant.. figure-1.jpg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks duration involving 2,274 patients using dosages of 50 mg twice daily (n=303), 100 mg twice daily (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 cilostazol 50 or 100 mg twice daily 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 cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.Figure depicts the percent 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 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 therapeutic intervention on walking ability. In 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 of 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 lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with 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 75% increase in the risk of mortality on cilostazol, which was the priori study hypothesis. Figure 2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Cilostazol is contraindicated in patients with:oHeart failure of any severity: Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure.Hypersensitivity to cilostazol or any components of cilostazol (e.g., anaphylaxis, angioedema).. oHeart failure of any severity: Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure.. oHeart failure of any severity (4)oHypersensitivity to cilostazol or any components of cilostazol (4). oHeart failure of any severity (4). oHypersensitivity to cilostazol or any components of cilostazol (4).

DESCRIPTION SECTION.

11 DESCRIPTION Cilostazol is an quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1. The structural formula is:Cilostazol USP occurs as white to off-white crystals or as crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 HCl, and 0.1 NaOH.Cilostazol Tablets USP are available for oral administration containing 50 mg or and 100 mg cilostazol USP. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.Each tablet meets the requirements of Test for Dissolution in the USP monograph for Cilostazol Tablets USP.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oThe recommended dosage of cilostazol is 100 mg twice daily taken at least half an hour before or two hours after breakfast and dinner (2.1)oReduce the dose to 50 mg twice daily when co-administered with CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and diltiazem, or CYP2C19 inhibitors such as ticlopidine, fluconazole, and omeprazole (2.2). oThe recommended dosage of cilostazol is 100 mg twice daily taken at least half an hour before or two hours after breakfast and dinner (2.1). oReduce the dose to 50 mg twice daily when co-administered with CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and diltiazem, or CYP2C19 inhibitors such as ticlopidine, fluconazole, and omeprazole (2.2). 2.1 Recommended Dosage The recommended dosage of cilostazol is 100 mg twice daily taken at least half an hour before or two hours after breakfast and dinner.Patients may respond as early as to weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before beneficial effect is experienced. If symptoms are unimproved after months, discontinue cilostazol.. 2.2 Dose Reduction with CYP3A4 and CYP2C19 Inhibitors Reduce dose to 50 mg twice daily when co-administered with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, and diltiazem) or inhibitors of CYP2C19 (e.g., ticlopidine, fluconazole, and omeprazole) [see Drug Interactions (7.1)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Cilostazol Tablets USP are available as 50 mg and 100 mg round, white tablets. The 50 mg tablet is flat faced beveled edge tablet, debossed with product identification 54 521 on one side and plain on the other side. The 100 mg tablet is biconvex tablet, debossed with product identification 54 757 on one side and plain on the other side.. oTablets: 50 mg and 100 mg (3). oTablets: 50 mg and 100 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oStrong and moderate CYP3A4 and CYP2C19 inhibitors: Increase exposure to cilostazol. Reduce cilostazol dose (2.2, 7.1). oStrong and moderate CYP3A4 and CYP2C19 inhibitors: Increase exposure to cilostazol. Reduce cilostazol dose (2.2, 7.1). 7.1 Inhibitors of CYP3A4 or CYP2C19 Inhibitors of CYP3A4Co-administration of strong (e.g., ketoconazole) and moderate (e.g., erythromycin, diltiazem and grapefruit juice) CYP3A4 inhibitors can increase exposure to cilostazol. Reduce cilostazol dose to 50 mg twice daily when co-administered with strong or moderate inhibitors of CYP3A4 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].Inhibitors of CYP2C19Co-administration with CYP2C19 inhibitors (e.g., omeprazole) increases systemic exposure of cilostazol active metabolites. Reduce cilostazol dose to 50 mg twice daily when co-administered with strong or moderate inhibitors of CYP2C19 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use Of the total number of subjects (n=2274) 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 ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Product: 68151-3844NDC: 68151-3844-2 TABLET in PACKAGE.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Cilostazol tablets are indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance.. Cilostazol tablets are phosphodiesterase III inhibitor (PDE III inhibitor) indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information)Advise the patient:oto take cilostazol at least one-half hour before or two hours after food.oto discuss with their doctor before taking any CYP3A4 or CYP2C19 inhibitors (e.g., omeprazole).that the beneficial effects of cilostazol on the symptoms of intermittent claudication may not be immediate. Although the patient may experience benefit in to weeks after initiation of therapy, treatment for up to 12 weeks may be required before beneficial effect is experienced. Discontinue cilostazol if symptoms do not improve after months.Distr. by: West-Ward Pharmaceuticals Corp.Eatontown, NJ 0772410003054/08 Revised April 2016. oto take cilostazol at least one-half hour before or two hours after food.. oto discuss with their doctor before taking any CYP3A4 or CYP2C19 inhibitors (e.g., omeprazole).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Cilostazol and several of its metabolites inhibit phosphodiesterase III activity and suppress cAMP degradation with resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.Cilostazol reversibly inhibits platelet aggregation induced by variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress.Cardiovascular effectsCilostazol affects both vascular beds and cardiovascular function. It produces heterogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.In dogs or cynomolgus monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in dose-proportional manner by mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg twice daily, respectively.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.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 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 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 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 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 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE 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 patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis. The oral LD50 of cilostazol is greater than g/kg in mice and rats and greater than g/kg in dogs.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Cilstazol. Label Image.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of cilostazol in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Cilostazols 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 range of doses from 50 mg every day to 100 mg three times day. Cilostazol significantly inhibited platelet aggregation in dose-dependent manner. The effects were observed as early as hours post-dose and lasted up to 12 hours following 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. 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 reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL cholesterol of 4.0 mg/dL 10%).Drug InteractionsAspirinShort-term (less than or equal to days) co-administration 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 days) co-administration 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 co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term co-administration in the general population are unknown.In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered 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.WarfarinCilostazol did not inhibit the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after single 25 mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacodynamics of both drugs is unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Cilostazol is absorbed after oral administration. high fat meal increases absorption, with an approximately 90% increase in Cmax and 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to lesser extend, 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 few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD). Figure 1shows the mean +- SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg twice daily.Figure 1: Mean +- SEM Plasma Concentration-time Profile at Steady State after Multiple Dosing of Cilostazol 100 mg Twice DailyDistributionCilostazol is 95% to 98% protein bound, predominantly to albumin. The mean percent 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.MetabolismCilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazols metabolism are CYP3A4 and, to 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 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 the 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 PopulationsAge and GenderThe 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.SmokersPopulation pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.Hepatic ImpairmentThe 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 ImpairmentThe 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 InteractionsCilostazol does not appear to inhibit CYP3A4.WarfarinCilostazol did not inhibit the metabolism of R- and S-warfarin after single 25 mg dose of warfarin.ClopidogrelMultiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.Strong Inhibitors of CYP3A4A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax 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 similar effect [see Dosage and Administration (2.2), Drug Interactions (7.1)].Moderate Inhibitors of CYP3A4Erythromycin and other macrolide antibiotics: Erythromycin is moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg every 8h with 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% [see Dosage and Administration (2.2)].DiltiazemDiltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40% [see Dosage and Administration (2.2)].Grapefruit JuiceGrapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.Inhibitors of CYP2C19Omeprazole: Co-administration 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 omeprazoles potent inhibition of CYP2C19 [see Dosage and Administration (2.2)].QuinidineConcomitant administration of quinidine with single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.LovastatinThe concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUC by 15%. There is also decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and ss-hydroxylovastatin AUC approximately 70% and is not expected to be clinically significant.. figure-1.jpg.

PREGNANCY SECTION.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C.Cilostazol has been shown to be teratogenic in rats at doses that are greater than 5-times the human MRHD on body surface area basis. There are no adequate and well-controlled studies in pregnant women.In rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on systemic exposure basis). In rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In non-pregnant 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-dehydrocilostazol 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 systemic exposure basis).

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage The recommended dosage of cilostazol is 100 mg twice daily taken at least half an hour before or two hours after breakfast and dinner.Patients may respond as early as to weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before beneficial effect is experienced. If symptoms are unimproved after months, discontinue cilostazol.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C.Cilostazol has been shown to be teratogenic in rats at doses that are greater than 5-times the human MRHD on body surface area basis. There are no adequate and well-controlled studies in pregnant women.In rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on systemic exposure basis). In rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In non-pregnant 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-dehydrocilostazol 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 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 The safety and effectiveness of cilostazol in pediatric patients have not been established.. 8.5 Geriatric Use Of the total number of subjects (n=2274) 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 ruled out. 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oRisks of tachycardia, palpitation, tachyarrhythmia or hypotension. Risks of exacerbations of angina pectoris or myocardial infarction in patients with history of ischemic heart disease (5.1) oRisks of thrombocytopenia or leukopenia progressing to agranulocytosis monitor platelets and white blood cell counts (5.2)oAvoid use in patients with hemostatic disorders or active pathologic bleeding (5.3). oRisks of tachycardia, palpitation, tachyarrhythmia or hypotension. Risks of exacerbations of angina pectoris or myocardial infarction in patients with history of ischemic heart disease (5.1) oRisks of thrombocytopenia or leukopenia progressing to agranulocytosis monitor platelets and white blood cell counts (5.2). oAvoid use in patients with hemostatic disorders or active pathologic bleeding (5.3). 5.1 Tachycardia Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately to bpm. Patients with history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction.. 5.2 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.. 5.3 Hemostatic Disorders or Active Pathologic Bleeding Cilostazol inhibits platelet aggregation in reversible manner. Cilostazol has not been studied in patients with hemostatic disorders or active pathologic bleeding. Avoid use of cilostazol in these patients.