ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol tablets (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 only adverse event resulting in discontinuation of therapy in >= 3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with cilostazol 50 mg b.i.d., 100 mg b.i.d. or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol (all doses) versus 0.1% for placebo.The most commonly reported adverse events, occurring in >= 2% of patients treated with cilostazol 50 or 100 mg b.i.d., are shown in the table below.Other events seen with an incidence of >= 2%, but occurring in the placebo group at least as frequently as in the 100 mg b.i.d. group were: asthenia, hypertension, vomiting, leg cramps, hyperesthesia, paresthesia, dyspnea, rash, hematuria, urinary tract infection, flu syndrome, angina pectoris, arthritis, and bronchitis.Most Commonly Reported AEs (Incidence >=2%) in Patients on Cilostazol 50 mg b.i.d. or 100 mgb.i.d. and Occurring at Rate in the 100 mg b.i.d.Group Higher Than in Patients on Placebo Adverse Events (AEs)by Body System Cilostazol 50 mg b.i.d.(N=303)% Cilostazol 100 mg b.i.d.(N=998)% Placebo(N=973)% BODY AS WHOLE Abdominal pain 5 Back pain 7 Headache 27 34 14 Infection 14 10 CARDIOVASCULAR Palpitation 10 Tachycardia 4 DIGESTIVE Abnormal stools 12 15 Diarrhea 12 19 Dyspepsia 6 Flatulence 3 Nausea 7 METABOLIC NUTRITIONAL Peripheral edema 7 MUSCULO-SKELETAL Myalgia 3 NERVOUS Dizziness 10 Vertigo 1 RESPIRATORY Cough increased 4 Pharyngitis 10 Rhinitis 12 5Less frequent adverse events (< 2%) that were experienced by patients exposed to cilostazol 50 mg b.i.d. or 100 mg b.i.d. in the eight controlled clinical trials and that occurred at frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are listed below.Body As Whole: Chills, face edema, fever, generalized edema, malaise, neck rigidity, pelvic pain, retroperitoneal hemorrhage. Cardiovascular: Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, heart arrest, hemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia. Digestive: Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum hemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, stomach ulcer, tongue edema. Endocrine: Diabetes mellitus. Hemic and Lymphatic: Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura. Metabolic and Nutritional:: Increased creatinine, gout, hyperlipemia, hyperuricemia. Musculoskeletal: Arthralgia, bone pain, bursitis. Nervous: Anxiety, insomnia, neuralgia. Respiratory: Asthma, epistaxis, hemoptysis, pneumonia, sinusitis. Skin and Appendages: Dry skin, furunculosis, skin hypertrophy, urticaria.Special Senses: Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye hemorrhage, retinal hemorrhage, tinnitus. Urogenital: Albuminuria, cystitis, urinary frequency, vaginal hemorrhage, vaginitis. Post Marketing Experience. The following adverse events have been reported spontaneously from worldwide post-marketing experience since launch of cilostazol in the US.Blood and lymphatic system disorders:agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendencyCardiac disorders:Torsades de pointes, QTc prolongation (Torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrythmia, when treated with cilostazol. Cilostazol was used off label due to its positive chronotropic action.) Gastrointestinal disorders:gastrointestinal hemorrhageGeneral disorders and administration site conditions:pain, chest pain, hot flushesHepatobiliary disorders:hepatic dysfunction/abnormal liver function tests, jaundiceInjury, poisoning and procedural complications:extradural hematoma and subdural hematomaInvestigations :blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea increased), blood pressure increaseNervous system disorders:intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accidentRespiratory, thoracic and mediastinal disorders:pulmonary hemorrhage, interstitial pneumoniaSkin and subcutaneous tissue disorders:hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)Vascular disorders:subacute thrombosis (These cases of subacute thrombosis occurred in patients treated with aspirin and off label use of cilostazol for prevention of thrombotic complication after coronary stenting.). Blood and lymphatic system disorders:agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendency. agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendency. Cardiac disorders:Torsades de pointes, QTc prolongation (Torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrythmia, when treated with cilostazol. Cilostazol was used off label due to its positive chronotropic action.) Torsades de pointes, QTc prolongation (Torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrythmia, when treated with cilostazol. Cilostazol was used off label due to its positive chronotropic action.) Gastrointestinal disorders:gastrointestinal hemorrhage. gastrointestinal hemorrhage. General disorders and administration site conditions:pain, chest pain, hot flushes. pain, chest pain, hot flushes. Hepatobiliary disorders:hepatic dysfunction/abnormal liver function tests, jaundice. hepatic dysfunction/abnormal liver function tests, jaundice. Injury, poisoning and procedural complications:extradural hematoma and subdural hematoma. extradural hematoma and subdural hematoma. Investigations :blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea increased), blood pressure increase. blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea increased), blood pressure increase. Nervous system disorders:intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident. intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident. Respiratory, thoracic and mediastinal disorders:pulmonary hemorrhage, interstitial pneumonia. pulmonary hemorrhage, interstitial pneumonia. Skin and subcutaneous tissue disorders:hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa). hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa). Vascular disorders:subacute thrombosis (These cases of subacute thrombosis occurred in patients treated with aspirin and off label use of cilostazol for prevention of thrombotic complication after coronary stenting.). subacute thrombosis (These cases of subacute thrombosis occurred in patients treated with aspirin and off label use of cilostazol for prevention of thrombotic complication after coronary stenting.).

BOXED WARNING SECTION.

CONTRAINDICATION. 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 congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. The mechanism of the effects of Cilostazol Tablets, USP on the symptoms of intermittent claudication is not fully understood. Cilostazol Tablets, USP and several of its metabolities are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degration with resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.Cilostazol Tablets, USP inhibits platelet aggregation induced by variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking Cilostazol Tablets, USP. After 12 weeks, as compared to placebo, Cilostazol Tablets, USP 100 mg b.i.d. produced reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL 10%).. Cardiovascular Effects. Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous 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 cynomolgous 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 b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated; the increases were not dose-related.. Pharmacokinetics. Cilostazol Tablets, USP 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 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 Tablets, USP. 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).The mean +- SEM plasma concentration-time profile at steady state after multiple dosing of Cilostazol Tablets, USP 100 mg b.i.d. is shown below:Plasma Concentration Time profile. Graph. Distribution. Plasma Protein and Erythrocyte Binding: Cilostazol 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 normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.. Metabolism and Excretion:. Cilostazol is elminated predominately 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 (one fifth as active as cilostazol). 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 4trans-hydroxy-cilostazol. The remainder was excreted asother metabolites, non of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES:. The ability of Cilostazol Tablets, USP 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 Cilostazol Tablets, USP 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 Cilostazol Tablets, USP 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.Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical TrialsAcross the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Cilostazol Tablets, USP 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 therapeutic intervention on walking ability. In pooled analysis of the six trials, patients treated with either Cilostazol Tablets, USP 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 of calcium channel blockers. Cilostazol Tablets, USP 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. 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 the 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 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 the priori study hypothesis.. Graph 2.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. 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 congestive heart failure. Cilostazol Tablets, USP are contraindicated in patients with congestive heart failure of any severity.Cilostazol Tablets, USP are contraindicated in patients with haemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding. Cilostazol Tablets, USP inhibit platelet aggregation in reversible manner.Cilostazol Tablets, USP are contraindicated in patients with known or suspected hypersensitivity to any of its components.

DESCRIPTION SECTION.

DESCRIPTION. Cilostazol is 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 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 for oral administration are available as 50 mg or 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, corn starch, hypromellose, magnesium stearate and microcrystalline cellulose.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The recommended dosage of cilostazol is 100 mg b.i.d. taken at least half an hour before or two hours after breakfast and dinner. dose of 50 mg b.i.d. should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.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.. Discontinuation of Therapy. The available data suggest that the dosage of cilostazol can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).

DRUG INTERACTIONS SECTION.

Drug Interactions. Since Cilostazol Tablets, USP is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when Cilostazol Tablets, USP is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4 (see CLINICAL PHARMACOLOGY, Pharmacokinetic andPharmacodynamic Drug-Drug Interactions). Cilostazol Tablets, USP does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, drug with metabolism very sensitive to CYP3A4 inhibition.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Cilostazol Tablets, USP 100mg are white,round compressed tablets debossed cor over 159 on one side and other side is plain.They are supplied as follows: Bottles of 30 NDC 54868-5411-1 Bottles of 60 NDC 54868-5411-0 STORAGE. Store at 20 to 25C (68 to 77F) excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Dispense in tight container as defined in the USP/NF.Keep this and all drugs out of the reach of children.Rev. October 2009MF 334-04Manufactured and Distributed by:Corepharma LLCMiddlesex, NJ 08846Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Cilostazol Tablets, USP are indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Please refer to the patient package insert.Patients should be advised:to read the patient package insert for Cilostazol Tablets USPcarefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.to take cilostazol at least one-half hour before or two hours after food.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.. to read the patient package insert for Cilostazol Tablets USPcarefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.. to take cilostazol at least one-half hour before or two hours after food.. 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.

OVERDOSAGE SECTION.

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 >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL. Cilostazol Tablets, USP 100mg Cilostazol 100 MG.

PRECAUTIONS SECTION.

PRECAUTIONS. Hematologic Adverse Reactions. Rare cases have been reported of thrombocytopenia or leucopenia progressing to agranulocytosis 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, platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration.. Information for Patients. Please refer to the patient package insert.Patients should be advised:to read the patient package insert for Cilostazol Tablets USPcarefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.to take cilostazol at least one-half hour before or two hours after food.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.. to read the patient package insert for Cilostazol Tablets USPcarefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.. to take cilostazol at least one-half hour before or two hours after food.. 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.. Hepatic Impairment. Patients with moderate or severe hepatic impairment have not been studied in clinical trials.Special caution is advised when Cilostazol Tablets, USP 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 to 98%).Special caution is advised when Cilostazol Tablets, USP is used in patients with severe renal impairment; estimated creatinine clearence, <25 ml/min.. Drug Interactions. Since Cilostazol Tablets, USP is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when Cilostazol Tablets, USP is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4 (see CLINICAL PHARMACOLOGY, Pharmacokinetic andPharmacodynamic Drug-Drug Interactions). Cilostazol Tablets, USP does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, drug with metabolism very sensitive to CYP3A4 inhibition.. Use with other antiplatelet agents. Cilostazol Tablets, USP inhibits platelet aggregation but in reversible manner. Cuation is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping Cilostazole Tablets, USP. Cuation is advised in patients receiving both Cilostazol Tablets, USP and any other antiplatelet agent, or in patients with thrombocytopenia.. Cardiovascular Toxicity. 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 haemorrhage, hemosiderin deposition and fibrosis inthe left ventricle, haemorrhage in the right atrial wall, haemorrhage 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) tounbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. 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 lesionswere also not seen in rats following 52 weeks of administration of cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposure (AUCs) tounbound cilostazol were about 0.5 and times (male and female rates, 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.. 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.. Pregnancy. Pregnancy Category C: 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 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 systemic exposure basis). There are no adequate and well-controlled studies in pregnant women.. Nursing Mothers. Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, decision should be made to discontinue nursing or to discontinue cilostazol. Pediatric Use. The safety and effectiveness of cilostazol in pediatric patients have not been established.. 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.

SPL UNCLASSIFIED SECTION.

Pharmacokinetics. Cilostazol Tablets, USP 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 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 Tablets, USP. 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).The mean +- SEM plasma concentration-time profile at steady state after multiple dosing of Cilostazol Tablets, USP 100 mg b.i.d. is shown below:Plasma Concentration Time profile. Graph.

STORAGE AND HANDLING SECTION.

STORAGE. Store at 20 to 25C (68 to 77F) excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Dispense in tight container as defined in the USP/NF.Keep this and all drugs out of the reach of children.Rev. October 2009MF 334-04Manufactured and Distributed by:Corepharma LLCMiddlesex, NJ 08846Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146.