cilostazol 100 MG Oral Tablet

Generic Name: CILOSTAZOL
Brand Name: Cilostazol
  • Substance Name(s):
  • CILOSTAZOL

DRUG INTERACTIONS

7 • Strong 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 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)].

OVERDOSAGE

10 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 5 g per kg in mice and rats and greater than 2 g per kg in dogs.

DESCRIPTION

11 Cilostazol is a 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 a crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH. Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch (corn), methylcellulose, carboxymethylcellulose calcium and magnesium stearate. Chemical Structure

CLINICAL STUDIES

14 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 mg 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 2 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 change from baseline, was 28% to 100%. The corresponding changes in the placebo group were –10% to 41%. The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg twice daily or 50 mg twice daily reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated. A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4 %) on cilostazol and 6.8% (95% CI of 1.9 to 11.5 %) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis. Figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How supplied Cilostazol tablets for oral administration are available as: 50 mg: White to off-white, round, debossed with “E” over “123” on one side and plain on the other and supplied as: NDC 0185-0123-60 bottles of 60 NDC 0185-0123-05 bottles of 500 100 mg: White to off-white, round, debossed with “E” over “223” on one side and plain on the other and supplied as: NDC 0185-0223-60 bottles of 60 NDC 0185-0223-05 bottles of 500 16.2 Storage and handling Store cilostazol tablets at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects (n = 2,274) in clinical studies of cilostazol, 56 percent were 65 years old and over, while 16 percent were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be excluded. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.

DOSAGE FORMS AND STRENGTHS

3 Cilostazol tablets are available as 50 mg and 100 mg round, white to off-white debossed tablets. •Tablets: 50 mg and 100 mg (3)

MECHANISM OF ACTION

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 mg and 100 mg twice daily, respectively.

INDICATIONS AND USAGE

1 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)

PEDIATRIC USE

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

PREGNANCY

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 a body surface area basis. There are no adequate and well-controlled studies in pregnant women. In a 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 5 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 a systemic exposure basis). In a 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 a systemic exposure basis).

NUSRING MOTHERS

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.

BOXED WARNING

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS Cilostazol is 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. WARNING: CONTRAINDICATED IN HEART FAILUREPATIENTS See full prescribing information for complete boxed warning. Cilostazol is 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)

WARNING AND CAUTIONS

5 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 (5.1) •Risks of thrombocytopenia or leukopenia progressing to agranulocytosis–monitor platelets and white blood cell counts (5.2) •Avoid 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 5 bpm 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 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 a reversible manner. Cilostazol has not been studied in patients with hemostatic disorders or active pathologic bleeding. Avoid use of cilostazol in these patients.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Advise the patient: •to take cilostazol tablets at least one-half hour before or two hours after food. •to discuss with their doctor before taking any CYP3A4 or CYP2C19 inhibitors (e.g., omeprazole). •that the beneficial effects of cilostazol tablets on the symptoms of intermittent claudication may not be immediate. Although the patient may experience benefit in 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be required before a beneficial effect is experienced. Discontinue cilostazol tablets if symptoms do not improve after 3 months.

DOSAGE AND ADMINISTRATION

2 •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 Dosage 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)].