Cilostazol

CILOSTAZOL- cilostazol tablet
West-Ward Pharmaceuticals Corp.

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS

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 the pharmacologic effect have caused decreased survival compared to placebo patients with class III-IV heart failure.

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of cilostazol 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.

2.2 Dose Reduction with CYP3A4 and CYP2C19 Inhibitors

Reduce dose to 50 mg twice daily when co-administered 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) ]

3 DOSAGE FORMS AND STRENGTHS

Cilostazol Tablets USP are available as 50 mg and 100 mg round, white tablets. The 50 mg tablet is a flat faced beveled edge tablet, debossed with product identification “54 521” on one side and plain on the other side. The 100 mg tablet is a standard biconvex tablet, debossed with product identification “54 757” on one side and plain on the other side.

4 CONTRAINDICATIONS

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.

Hypersensitivity to cilostazol or any components of cilostazol (e.g., anaphylaxis, angioedema).

5 WARNINGS AND PRECAUTIONS

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 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.

6 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) ]
Hematologic Adverse Reactions [see Warnings and Precautions (5.2) ]
Hemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions (5.3) ]

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 (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 most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with cilostazol 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 (all doses) versus 0.1% for placebo.

The most common adverse reactions, occurring in at least 2% of patients treated with cilostazol 50 or 100 mg twice daily, are shown in Table 1.

Table 1: Most Common Adverse Reactions in Patients on Cilostazol 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 50 mg

twice daily

(N=303)

Cilostazol 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

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