Cilostazol Tablets
50 mg and 100 mg
Rx only

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.

DESCRIPTION
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 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.

The ability of cilostazol 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 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 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, respectively, at study end for each of the eight studies.

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 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 a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 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 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. No reliable estimate of its effect on survival is available (see PRECAUTIONS).

Cilostazol tablets are indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

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 a reversible manner.

Cilostazol tablets are contraindicated in patients with known or suspected hypersensitivity to any of its components.

Cilostazol is contraindicated in patients with congestive heart failure. In patients without congestive heart failure, the long-term effects of PDE III inhibitors (including cilostazol) are unknown. Patients in the 3-6 month placebo-controlled trials of cilostazol were relatively stable (no recent myocardial infarction or strokes, no rest pain or other signs of rapidly progressing disease) and only 19 patients died (0.7% in the placebo group and 0.8% in the group on cilostazol). The calculated relative risk of death of 1.2 has a wide 95% confidence limit (0.5-3.1). There are no data as to longer-term risk or risk in patients with more severe underlying heart disease.

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 (n=1301) or placebo (n=973), with a 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.

Less 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 a frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are uled below.

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.

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. A 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 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.

HOW SUPPLIED
Cilostazol 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 60's
NDC 64720-158-10   in bottles of 100's
NDC 64720-158-50   in bottles of 500's
NDC 64720-158-11   in bottles of 1000's

For the 100 mg strength
They are supplied as follows:

NDC 64720-159-06   in bottles of 60's
NDC 64720-159-10   in bottles of 100's
NDC 64720-159-50   in bottles of 500's
NDC 64720-159-11   in bottles of 1000's

Cilostazol Tablets 50 mg and 100 mg

Patient Information about cilostazol (sil-OS-tah-zol)

Please read this leaflet before you start taking cilostazol and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.