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Careful Administration (Cilostazol should be administered with caution in the following patients.): Patients on anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin, ticlopidine hydrochloride, or clopidogrel sulfate), thrombolytic drugs (e.g., urokinase or alteplase), or prostaglandin E1 or its derivatives (e.g., alprostadil or limaprost alfadex) (see Interactions).
Patients during menstruation (There is a risk of menorrhagia).
Patients with bleeding tendency or predisposition to bleeding (If bleeding occurs, bleeding tendency may be increased.).
Patients with coronary artery stenosis (Increased pulse rate possibly resulting from treatment with cilostazol could induce angina pectoris.). (See Warnings, Important Precautions as follows, Clinically significant adverse reactions: Congestive heart failure, myocardial infarction, angina pectoris, and ventricular tachycardia under Adverse Reactions.)
Patients with diabetes mellitus or abnormal glucose tolerance (Hemorrhagic adverse events may occur.).
Patients with severe hepatic impairment (Blood concentration of cilostazol may be increased.). (See Pharmacology: PHARMACOKINETICS under Actions).
Patients with renal impairment (Renal function may be aggravated. Blood concentrations of the metabolites of cilostazol may be increased). (See Clinically significant adverse reactions: Acute renal failure under Adverse Reactions and Pharmacology: PHARMACOKINETICS under Actions).
Patients with hypertension with consistently high blood pressure (e.g., malignant hypertension) (See Other Precautions as follows).
Patients with ventricular transposition, atrial transposition, atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, multifocal ventricular ectopics and prolongation of the QTc interval.
Important Precautions: Cilostazol should not be administered to patients with cerebral infarction until their condition has stabilized.
When cilostazol is administered to patients with cerebral infarction, administration should be performed with caution for possible interaction with other drugs, such as antiplatelet drugs. In cerebral infarction patients with high blood pressure, blood pressure should be sufficiently controlled during cilostazol treatment. (See Careful Administration as previously mentioned and Interactions).
If an excessive increase in pulse rate is observed in patients with coronary artery stenosis during treatment with cilostazol, the dosage should be reduced or the drug discontinued and appropriate measures should be taken, since the increased pulse rate could induce angina pectoris. (See WARNINGS, Careful administration as previously mentioned, Clinically significant adverse reactions: Congestive heart failure, Myocardial infarction, angina pectoris, and ventricular tachycardia under Adverse Reactions.)
Taking cilostazol with meal has been shown to increase the plasma concentrations of cilostazol, which may be associated with an increased incidence of adverse reactions. So, it's recommended to 3 hours interval between administration and meal. Especially, patients with high fat diet have to be careful, since a high fat meal following single-dosing of this drug 200 mg increase absorption, with an approximately 100% increase in Cmax and a 40% increase in AUC versus fasting.
Cilostazol is a drug with PDE3 inhibitory activity. Long-term comparative studies of cardiotonic agents with PDE3 inhibitory activity (milrinone1) and (vesnarinone2) in patients with congestive heart failure (NYHA class III to IV) conducted outside Japan demonstrated lower survival rates in patients receiving such cardiotonic agents compared with patients receiving placebo. In addition, prognosis following long-term treatment with PDE3 inhibitors, including cilostazol, has not yet been determined in patients without congestive heart failure.
In a clinical study to evaluate cilostazol's efficacy in the prevention of recurrent of cerebral infarction, diabetes mellitus occurred or was worsened in more patients in this drug group (11/520 patients) than in the placebo (1/523 patients).
The effects of cilostazol on cerebral infarction have not been studied in patients with asymptomatic cerebral infarction.
Other Precautions: Endocardial thickening and coronary arterial lesions were observed at high doses in 13- and 52-week oral repeated dose toxicity studies of cilostazol in beagle dogs. The non-toxic doses were 30 and 12 mg/kg/day, respectively. These cardiac changes were not observed in either rats or monkeys. In 1-week intravenous repeated-dose cardiotoxicity studies, changes in the left ventricular endocardium, right atrial epicardium, and coronary arteries were observed in dogs and mild hemorrhagic changes in the left ventricular endocardium were observed in monkeys. Cardiac changes have also been reported in studies of other PDE inhibitors and vasodilators, and dogs are considered to be highly sensitive in showing such changes.
The mean survival time of stroke-prone spontaneously hypertensive rats (SHR-SP) given 0.3% cilostazol in the diet was shorter than that of control animals (40.2 weeks versus 43.5 weeks).
In a clinical study to evaluate Cilostazol's efficacy in the prevention of recurrence of cerebral infarction, diabetes mellitus occurred or was worsened in more patients in the Cilostazol group (11/520 patients) than in the placebo group (1/523 patients).
Coadministration of a single dose of lovastatin 80 mg with a single dose of cilostazol 100 mg increased the lovastatin AUC by 64% compared with administration of lovastatin alone.
Use in Pregnancy & Lactation: Cilostazol should not be used in women who are pregnant or who may possibly become pregnant. (Rat teratogenicity and peri- and post-natal studies of the drug showed an increased number of abnormal fetuses, low birth weight, and an increased number of stillborns.
Nursing should be suspended during use of the drug by nursing women. (Rat studies showed that cilostazol was distributed to breast milk in nursing rats).
Use in Children: The safe use of cilostazol in low birth weight infants, newborns, suckling infants, infants, and children has not been established. (Clinical experience in these populations is insufficient.).
Use in the Elderly: Elderly patients may be physiologically more sensitive to cilostazol than younger patients. It may be necessary to use a reduced dosage when prescribing cilostazol for elderly patients.
