Cilostazol: Package Insert and Label Information

CILOSTAZOL- cilostazol tablet
Slate Run Pharmaceuticals, LLC

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 this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure [see Contraindications (4)].

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 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)]

3 DOSAGE FORMS AND STRENGTHS

Cilostazol Tablets USP are available as 50 mg and 100 mg round, white debossed tablets.

4 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)

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 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 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)]
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)]

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 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 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 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. 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.

7 DRUG INTERACTIONS

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)].

8 USE IN SPECIFIC POPULATIONS

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).

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.

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