Cilostazol

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 a phosphodiesterase III inhibitor (PDE III inhibitor) indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance ( 1 )

DOSAGE AND ADMINISTRATION The recommended dosage of cilostazol tablets is 100 mg twice daily taken at least half an hour before or two hours after breakfast and dinner ( 2.1 ) Reduce the dose to 50 mg twice daily when coadministered 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 tablets 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 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced. If symptoms are unimproved after 3 months, discontinue cilostazol tablets. 2.2 Dose Reduction with CYP3A4 and CYP2C19 Inhibitors Reduce dose to 50 mg twice daily when coadministered 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 )] .

WARNINGS AND PRECAUTIONS Risks of tachycardia, palpitation, tachyarrhythmia or hypotension. Risks of exacerbations of angina pectoris or myocardial infarction in patients with a history of ischemic heart disease ( 5.2 ) Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped interventricular septum ( 5.1 ) Risks of thrombocytopenia or leukopenia progressing to agranulocytosis-monitor platelets and white blood cell counts ( 5.3 ) Avoid use in patients with hemostatic disorders or active pathologic bleeding ( 5.4 ) 5.1 Tachycardia Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction. 5.2 Left Ventricular Outflow Tract Obstruction Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped interventricular septum. Monitor patients for the development of a new systolic murmur or cardiac symptoms after starting cilostazol. 5.3 Hematologic Adverse Reactions Cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued have been reported. Agranulocytosis is reversible on discontinuation of cilostazol. Monitor platelets and white blood cell counts periodically. 5.4 Hemostatic Disorders or Active Pathologic Bleeding Cilostazol inhibits platelet aggregation in a reversible manner. Cilostazol has not been studied in patients with hemostatic disorders or active pathologic bleeding. Avoid use of cilostazol tablets in these patients.

CONTRAINDICATIONS 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 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 tablets (e.g., anaphylaxis, angioedema) Heart failure of any severity ( 4 ) Hypersensitivity to cilostazol or any components of cilostazol tablets ( 4 )

DRUG INTERACTIONS Strong and moderate CYP3A4 and CYP2C19 inhibitors: Increase exposure to cilostazol. Reduce cilostazol tablets dose ( 2.2 , 7.1 ) 7.1 Inhibitors of CYP3A4 or CYP2C19 Inhibitors of CYP3A4 Coadministration 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 coadministered with strong or moderate inhibitors of CYP3A4 [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]. Inhibitors of CYP2C19 Coadministration with CYP2C19 inhibitors (e.g., omeprazole) increases systemic exposure of cilostazol active metabolites. Reduce cilostazol dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of CYP2C19 [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Patients with Heart Failure [see Boxed Warning] Tachycardia [see Warnings and Precautions ( 5.1 )] Left Ventricular Outflow Tract Obstruction [see Warnings and Precautions ( 5.2 )] Hematologic Adverse Reactions [see Warnings and Precautions ( 5.3 )] Hemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions ( 5.4 )] 5.2 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 Apotex Inc. at 1-800-706-5575 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 a 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 tablets (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol tablets and 134 days for patients on placebo. The most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with cilostazol tablets was headache [50 mg twice daily (1.3%), 100 mg twice daily (3.5%) and placebo (0.3%)]. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol tablets (all doses) versus 0.1% for placebo. The most common adverse reactions, occurring in at least 2% of patients treated with cilostazol tablets 50 or 100 mg twice daily, are shown in Table 1. Table 1: Most Common Adverse Reactions in Patients on cilostazol tablets 50 or 100 mg Twice Daily (Incidence at least 2% and Occurring More Frequently (≥ 2%) in the 100 mg Twice Daily Group than on Placebo) Adverse Reactions Placebo (N=973) Cilostazol tablets 50 mg twice daily (N=303) Cilostazol tablets 100 mg twice daily (N=998) Headache 14% 27% 34% Diarrhea 7% 12% 19% Abnormal stools 4% 12% 15% Palpitation 1% 5% 10% Dizziness 6% 9% 10% Pharyngitis 7% 7% 10% Infection 8% 14% 10% Peripheral edema 4% 9% 7% Rhinitis 5% 12% 7% Dyspepsia 4% 6% 6% Abdominal pain 3% 4% 5% Tachycardia 1% 4% 4% Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with cilostazol 50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at a frequency in the 100 mg twice daily group greater than in the placebo group are listed below. Body as a whole: fever, generalized edema, malaise Cardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia Digestive: anorexia, melena Hematologic and Lymphatic: anemia Metabolic and Nutritional: increased creatinine, hyperuricemia Nervous: insomnia Respiratory: epistaxis Skin and Appendages: urticaria Special Senses: conjunctivitis, retinal hemorrhage, tinnitus Urogenital: urinary frequency 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of cilostazol tablets. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendency Cardiac disorders: Torsade de pointes and QTc prolongation in patients with cardiac disorders (e.g. complete atrioventricular block, heart failure; and bradyarrythmia), angina pectoris. Gastrointestinal disorders: Gastrointestinal hemorrhage, vomiting, flatulence, nausea General disorders and administration site conditions: Pain, chest pain, hot flushes Hepatobiliary disorders: Hepatic dysfunction/abnormal liver function tests, jaundice Immune system disorders: Anaphylaxis, angioedema, and hypersensitivity Investigations: Blood glucose increased, blood uric acid increased, increase in BUN (blood urea increased), blood pressure increase Nervous system disorders: Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematoma Renal and urinary disorders: Hematuria Respiratory, thoracic and mediastinal disorders: Pulmonary hemorrhage, interstitial pneumonia Skin and subcutaneous tissue disorders: Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa), rash Vascular disorders: Subacute stent thrombosis, hypertension. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cilostazol and several of its metabolites inhibit phosphodiesterase III activity and suppress cAMP degradation with a 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 a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Cardiovascular effects: Cilostazol 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 a 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 a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg twice daily, respectively. 12.2 Pharmacodynamics Cilostazol’s effects on platelet aggregation were evaluated in both healthy subjects and in patients with stable symptoms of cerebral thrombosis, cerebral embolism, transient ischemic attack, or cerebral arteriosclerosis over a range of doses from 50 mg every day to 100 mg three times a day. Cilostazol significantly inhibited platelet aggregation in a dose-dependent manner. The effects were observed as early as 3 hours post-dose and lasted up to 12 hours following a single dose. Following chronic administration and withdrawal of cilostazol, the effects on platelet aggregation began to subside 48 hours after withdrawal and returned to baseline by 96 hours with no rebound effect. A cilostazol dosage of 100 mg twice daily consistently inhibited platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate (ADP). Bleeding time was not affected by cilostazol administration. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg twice daily produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (≅ 10%). Drug Interactions Aspirin Short-term (less than or equal to 4 days) coadministration of aspirin with cilostazol increased the inhibition of ADP- induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (less than or equal to 4 days) coadministration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short- term coadministration of aspirin with cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in frequency of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin. Warfarin Cilostazol did not inhibit the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S- warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacodynamics of both drugs is unknown. 12.3 Pharmacokinetics Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C max and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy subjects and patients with intermittent claudication due to peripheral arterial disease (PAD). Figure 1 shows the mean plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg twice daily. Figure 1: Mean Plasma Concentration-time Profile at Steady State after Multiple Dosing of cilostazol 100 mg Twice Daily Distribution Cilostazol is 95 to 98% protein bound, predominantly to albumin. The binding for 3,4-dehydro-cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in healthy volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant. Metabolism Cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol’s metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown. Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4 to 7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (20% as active as cilostazol). Elimination The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro- cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes. Special Populations Age and Gender The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age (50 to 80 years) or gender. Smokers Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%. Hepatic Impairment The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects. Patients with moderate or severe hepatic impairment have not been studied. Renal Impairment The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in healthy subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95 to 98%). Drug Interac