DRUG INTERACTIONS SECTION.

Drug Interactions :Since cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when cilostazol 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 and Pharmacodynamic Drug-Drug Interactions). Cilostazol 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.

GERIATRIC USE SECTION.

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.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONSAdverse 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 PlaceboAdverse Events (AEs)by Body SystemCilostazol 50 mg b.i.d.(N=303)%Cilostazol 100 mg b.i.d.(N=998)%Placebo(N=973)%BODY AS WHOLEAbdominal pain453Back pain676Headache273414Infection14108CARDIOVASCULARPalpitation5101Tachycardia441DIGESTIVEAbnormal stools12154Diarrhea12197Dyspepsia664Flatulence232Nausea676METABOLIC NUTRITIONALPeripheral edema974MUSCULO-SKELETALMyalgia232NERVOUSDizziness9106Vertigo311RESPIRATORYCough increased343Pharyngitis7107Rhinitis1275Less 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

CLINICAL PHARMACOLOGY. Mechanism of Action:The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with resultant increase in cAMP in platelet 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. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 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 patients; the increases were not dose-related.

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

DESCRIPTION SECTION.

DESCRIPTIONCilostazol 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 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 ADMINISTRATIONThe 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).

HOW SUPPLIED SECTION.

HOW SUPPLIEDCilostazol tablets 50 mg are white, round compressed tablets debossed cor over 158 on one side and other side is plain.They are supplied as follows:NDC 64720-158-06 in bottles of 60sNDC 64720-158-10 in bottles of 100sNDC 64720-158-50 in bottles of 500sNDC 64720-158-11 in bottles of 1000sCilostazol tablets 100mg are white,round compressed tablets debossed cor over 159 on one side and other side is plain.They are supplied as follows:NDC 64720-159-06 in bottles of 60sNDC 64720-159-10 in bottles of 100sNDC 64720-159-50 in bottles of 500sNDC 64720-159-11 in bottles of 1000s. STORAGEStore 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. July 2009MF 334-03Manufactured and Distributed by:Corepharma LLCMiddlesex, NJ 08846.

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 carefully 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 carefully 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.

MECHANISM OF ACTION SECTION.

Mechanism of Action:The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with resultant increase in cAMP in platelet 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. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 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 patients; the increases were not dose-related.

PHARMACOKINETICS SECTION.

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 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 11-13 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 100 mg b.i.d. is shown below:. Graph.

PREGNANCY SECTION.

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.

SPL UNCLASSIFIED SECTION.

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 patients; the increases were not dose-related.