Pletaal

Cilostazol.

Each tablet of PLETAAL Tablets 50 contains 50 mg of cilostazol. Each tablet of PLETAAL Tablets 100 contains 100 mg of cilostazol. (See Table 1.)


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Non-proprietary name: Cilostazol (JAN).
Chemical name: 6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butyloxy]-3,4-dihydroquinolin-2(1H)-one.
Molecular formula: C₂₀H₂₇N₅O₂.
Molecular weight: 369.46
Melting point: 158-162°C.
Cilostazol occurs as white to pale yellowish white crystals or crystalline powder. It is slightly soluble in methanol, in ethanol (99.5) and in acetonitrile, and practically insoluble in water.

Pharmacology: Antiplatelet Action: In vitro studies: Cilostazol inhibited platelet aggregation induced by ADP, collagen, arachidonic acid, adrenaline and thrombin in humans. The drug also inhibited shear stress-induced platelet aggregation.
Cilostazol inhibited ADP- and adrenaline-induced primary aggregation and exhibited a dispersing effect on human platelet aggregates induced by various aggregating agents.
Cilostazol inhibited thromboxane A₂ (TXA₂) production in activated human platelets.
Cilostazol inhibited the procoagulant activity of human platelets.
In vivo studies: Cilostazol inhibited ADP- and collagen-induced platelet aggregation when orally administered to beagle dogs and pigs.
The inhibitory effect of cilostazol on ADP-induced platelet aggregation was unchanged during repeated oral administration in rats.
Cilostazol prevented platelet aggregation induced by ADP, collagen, arachidonic acid, and adrenaline when orally administered to patients with chronic arterial occlusion or cerebral infarction.
The onset of cilostazol's platelet aggregation inhibitory effect was prompt in humans, and the effect persisted during repeated administration.
Following discontinuation of cilostazol administration, as the plasma concentration of the drug declined, platelet aggregability returned to baseline levels with no rebound phenomenon (no increase of platelet aggregation).
Antithrombotic Action: Cilostazol reduced mortality due to pulmonary embolism induced experimentally in mice by intravenous administration of ADP or collagen.
Cilostazol suppressed the progression of peripheral thrombotic circulatory insufficiency in the hind limbs induced by the intra-arterial injection of sodium laurate solution into the femoral artery of dogs.
Cilostazol inhibited thrombotic occlusion of prosthetic artificial grafts placed in the femoral artery of dogs.
Cilostazol inhibited electrical stimulation-induced thrombus formation in the carotid artery of pigs.
Cilostazol reduced the size of cerebral infarction induced by injection of arachidonic acid into the internal carotid artery of rabbits.
Cilostazol reduced the incidence of ischemic attacks in patients with transient ischemic attacks.
Vasodilating Action: Cilostazol inhibited KCl- and prostaglandin F2α-induced contraction of the isolated femoral, middle cerebral, and basilar arteries in dogs.
Cilostazol increased blood flow in the femoral, vertebral, common carotid, and internal carotid arteries in anesthetized dogs.
Cilostazol increased blood flow in the cerebral cortex in anesthesized dogs and cats.
Cilostazol increased blood flow in the cerebral cortex and hypothalamus in conscious rats.
Results of a plethysmographic study showed that cilostazol increased blood flow in the occluded ankle and calf region in patients with chronic arterial occlusion, and results of a thermographic plethysmographic study demonstrated that the drug induced an increase in skin temperature of the extremities and increased cutaneous blood flow in patients with chronic arterial occlusion.
Cilostazol increased cerebral blood flow in patients with ischemic cerebrovascular diseases, as determined by the xenon-inhalation method.
Effects on Vascular Smooth Muscle Cells: Cilostazol suppressed the proliferation of vascular smooth muscle cells in cultured human vascular smooth muscle.
Cilostazol suppressed intimal thickening of rat carotid arteries induced by intimal balloon injury.
Effects on Vascular Endothelial Cells: Cilostazol augmented NO production by cultured human endothelial cells.
Cilostazol suppressed injuries of cultured human endothelial cells.
Cilostazol suppressed the depletion of lactate dehydrogenase from cultured human endothelial cells stimulated with homocysteine or lipopolysaccharide.
Mechanism of Action: Experiments in rabbits showed that cilostazol suppressed serotonin release from platelets without affecting serotonin and adenosine uptake by platelets. The drug inhibited platelet aggregation induced by thromboxane A₂ (TXA₂).
Cilostazol exerts its antiplatelet and vasodilating actions by selectively inhibiting PDE3 (cGMP-inhibited PDE) in platelets and vascular smooth muscle.
Cilostazol's antiaggregation effect in human platelets was augmented in the presence of vascular endothelial cells²⁵ or prostaglandin E₁.
Cilostazol's antiaggregation effect in canine platelets was augmented in the presence of prostaglandin I₂ or adenosine.
Pharmacokinetics: Plasma Concentration: Following single oral administration of Cilostazol 100 mg to fasted normal healthy individuals, the plasma cilostazol concentration promptly rose to a maximum level of 763.9 ng/mL in 3 hours. The plasma half life of the drug estimated using a two-compartment model was 2.2 hours in the α-phase and 18.0 hours in the β-phase. Two metabolites were found to be active: OPC-13015 (dehydrated metabolite) and OPC-13213 (hydroxylated metabolite).
Administration of a single oral dose of cilostazol 50 mg in a fed state was associated with a 2.3-fold increase in C_max and a 1.4-fold increase in AUC_inf compared with administration in fasted state.
When PLETAAL SR capsule was administered orally to healthy adult male subjects at multiple dose of 200 mg as cilostazol in fasting condition for 5 days, the following pharmacokinetic parameters were obtained at steady state. (See Table 2.)


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Following single oral administration of cilostazol to healthy adult male subjects, two metabolites were found to be active: OPC-13015 (dehydrated metabolite) and OPC-13213 (hydroxylated metabolite).
Metabolizing Enzymes: Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly CYP3A4, and to a lesser extent, CYP2D6 and CYP2C19 (in vitro).
Protein Binding: Cilostazol: Greater than 95% (equilibrium dialysis in vitro, 0.1-6 μg/mL).
Active metabolite OPC-13015H 97.4% (ultrafiltration in vitro, 1 μg/mL).
Active metabolite OPC-13213: 53.7% (ultrafiltration in vitro, 1 μg/mL).
Pharmacokinetics in Patients with Renal Impairment (Outside Japan): Repeated oral administration of cilostazol at a daily dose of 100 mg for 8 days in patients with severe renal impairment showed decreases (C_max by 29% and AUC by 39%) in plasma concentrations of cilostazol and marked increases (C_max by 173% and AUC by 209%) in plasma concentrations of the active metabolite OPC-13213 compared with administration in normal healthy individuals. However, the concentrations of cilostazol and OPC-13213 in patients with mild to moderate renal impairment were similar to those in normal healthy individuals.
Pharmacokinetics in Patients with Hepatic Impairment (Outside Japan): Plasma concentrations of cilostazol following single oral administration of cilostazol 100 mg in patients with mild to moderate hepatic impairment were similar (C_max decreased by 7%, AUC increased by 8%) to those in normal healthy individuals.
Drug Interactions (Outside Japan): Cilostazol 100 mg did not inhibit either the metabolism or pharmacological effects of R- and S-warfarin when administered in combination with a single dose of warfarin 25 mg.
Coadministration of a single dose of cilostazol 100 mg and erythromycin 500 mg tid after 7-day treatment with erythromycin 500 mg tid increased cilostazol C_max by 47% and AUC by 87% compared with administration of cilostazol alone.
Coadministration of a single dose of ketoconazole 400 mg with a single dose of cilostazol 100 mg increased cilostazol C_max by 94% and AUC by 129% compared with administration of cilostazol alone. (The oral formulation of the azole antimycotic ketoconazole has not yet been approved in Japan.)
Coadministration of diltiazem hydrochloride 180 mg with a single dose of cilostazol 100 mg increased cilostazole C_max by 34% and AUC by 44% compared with administration of cilostazol alone.
Administration of a single dose of cilostazol 100 mg with 240 mL of grapefruit juice increased cilostazol C_max by 46% and AUC by 14% compared with administration of cilostazol without grapefruit juice.
Coadministration of cilostazol 100 mg and omeprazole 40 mg qd after 7-day treatment with omeprazole 40 mg qd increased cilostazol C_max by 18% and AUC by 26% compared with administration of cilostazol alone.

Treatment of ischemic symptoms, including ulceration, pain and coldness of the extremities, in chronic arterial occlusion.
Prevention of recurrence of cerebral infarction (excluding cardiogenic cerebral embolism).

The usual adult dose of PLETAAL Tablets is 100 mg of Cilostazol, twice daily by the oral route. The dosage may be adjusted according to the age of the patients and the severity of symptoms.

Patients with hemorrhage (e.g., hemophilia, increased capillary fragility, intracranial hemorrhage in the urinary tract, hemoptysis, and hemorrhage in the vitreous body) (Bleeding tendency may be increased).
Patients with congestive heart failure (Condition may be worsened). (See Important Precautions under Precautions.)
Patients with a history of hypersensitivity to any ingredient of the drug.
Women who are pregnant or may possibly become pregnant (see Use in Pregnancy & Lactation).

Patients should be closely monitored for any anginal symptoms (e.g., chest pain), since treatment with cilostazol may increase pulse rate, which could induce angina pectoris. [A significant increase in PRP (pressure rate product) was observed during long-term administration of cilostazol in a clinical trial to evaluate the drug's efficacy in the prevention of recurrence of cerebral infarction. Also, angina pectoris was observed in some of the patients treated with cilostazol.] (See Careful Administration and Important Precautions under Precautions and Clinically significant adverse reactions: Congestive heart failure, myocardial infarction, angina pectoris, and ventricular tachycardia under Adverse Reactions.)

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 C_max 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.

Treatment of ischemic symptoms, including ulceration, pain, and coldness of the extremities, in chronic arterial occlusion: Clinical Trials in Japan: Of 1,035 patients included in safety evaluations, 90 patients (8.7%) had adverse drug reactions, including abnormal laboratory values. The most common adverse reactions were headache/dull headache (3.2%), tachycardia (1.0%), abdominal pain (0.8%), nausea/vomiting (0.8%), and dizziness (0.7%) (at time of approval of PLETAAL Tablets).
Drug-use results surveys: Of 3,335 patients included in safety evaluations, 209 patients (6.3%) had adverse drug reactions, including abnormal laboratory values. The most common adverse drug reactions were headache/dull headache (3.4%), palpitation (0.7%), dizziness (0.5%), diarrhoea (0.3%), and nausea/vomiting (0.3%) (at time of completion of reexamination for PLETAAL Tablets).
Prevention of recurrence of cerebral infarction (excluding cardiogenic cerebral embolism): Clinical trials in Japan: Of 520 patients included in safety evaluations, 137 patients (26.3%) had adverse drug reactions, including abnormal laboratory values. The most common adverse drug reactions were headache/dull headache (12.9%), palpitation (5.2%), nausea/vomiting (2.7%), dizziness (1.7%), and rash (1.3%) (at time of approval of additional indication for PLETAAL Tablets).
Long-term special surveys: Of 1,075 patients included in safety evaluation, 239 patients (22.2%) had adverse drug reactions, including abnormal laboratory values. The most common adverse drug reactions were headache/dull headache (4.6%), hepatic dysfunction (as indicated by elevated AST [GOT], ALT [GPT], A1-P, or LDH) (3.6%), palpitation (2.9%), tachycardia (2.2%), anemia (1.1%), and leukopenia (1.1%) (at time of completion of reexamination for PLETAAL Tablets).
Post-marketing clinical trials: Of 1,337 patients included in safety evaluations, 702 patients (52.5%) had adverse drug reactions, including abnormal laboratory values. The most common adverse drug reactions headache/dull headache (17.7%), palpitation (10.5%), tachycardia (9.5%), arrhythmias (including atrial fibrillation, supraventricular tachycardia, supraventricular extrasystoles, and ventricular extrasystoles) (3.7%), and abdominal pain (3.0%) (at time of completion of reexamination for PLETAAL Tablets).
The incidences listed as follows under Clinically significant adverse reactions and Other adverse reactions are based on data reported at the time of initial approval and additional indication approval for cilostazol and from drug-use results surveys, long-term special surveys, and post-marketing clinical trials.
Adverse reactions reported after market launch for which the incidence could not be calculated are also included after the drug was placed on the market.
Clinically significant adverse reactions: Congestive heart failure, myocardial infarction, angina pectoris (0.1% to less than 5% for each), and ventricular tachycardia (incidence unknown*): Congestive heart failure, myocardial infarction, angina pectoris, and ventricular tachycardia may occur. If any signs of these adverse reactions are observed, the drug should be discontinued and appropriate measures should be taken.
Hemorrhage: Intracranial hemorrhage, such as cerebral hemorrhage (0.1% to less than 5%): Intracranial hemorrhage, such as cerebral hemorrhage (Early symptoms of intracranial hemorrhage include headache, nuasea, vomiting, consciousness disturbance, and hemiplegia) may occur. If any such symptoms occur, the drug should be discontinued and appropriate measures should be taken.
Pulmonary hemorrhage (less than 0.1%), hemorrhage in the digestive tract, epistaxis, and bleeding in the ocular fundus (0.1% to less than 5% for each): Pulmonary hemorrhage, hemorrhage in the digestive tract, epistaxis, and bleeding in the ocular fundus may occur. If any such symptoms occur, the drug should be discontinued and appropriate measures should be taken.
Gastric or duodenal ulcers (0.1% to less than 5%): Gastric or duodenal ulcers with hemorrhage may occur. Patients should be closely monitored. If any signs of these adverse reactions are observed, the drug should be discontinued and appropriate measures should be taken.
Pancytopenia, agranulocytosis (both incidence unknown*), and thrombocytopenia (0.1% to less than 5%): Pancytopenia, agranulocytosis, and thrombocytopenia may occur. Patients should be closely monitored. If any signs of these adverse reactions are observed, the drug should be discontinued and appropriate measures should be taken.
Interstitial pneumonia (less than 0.1%): Interstitial pneumonia accompanied by fever, cough dyspnoea, abnormal chest X-rays, and eosinophilia may occur. If any signs of interstitial pneumonia are noted, the drug should be discontinued and appropriate measures, including adrenocorticotropic hormone administration, should be taken.
Hepatic dysfunction (0.1% to less than 5%) and jaundice (incidence unknown*): Hepatic dysfunction, as indicated by elevated AST (GOT), ALT (GPT), A1-P, or LDH, and jaundice may occur. Patients should be closely monitored. If signs of hepatic dysfunction are observed, the drug should be discontinued and appropriate measures should be taken.
Acute renal failure (less than 0.1%): Acute renal failure may occur. Patients should be closely monitored, such as by renal function testing. If signs of renal failure are observed, the drug should be discontinued and appropriate measures should be taken.
*Information concerning incidence was not obtained because adverse reactions were voluntarily reported or occurred outside Japan.
Other adverse reactions: See Table 3.


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Cilostazol is extensively metabolized by hepatic cytochrome P450 (CYP) enzymes, mainly CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C19. (See Pharmacology: PHARMACOKINETICS under Actions).
Precautions for coadministration (Cilostazol should be administered with care when coadministered with the following drugs): See Table 4.


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Store below 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC23 - cilostazol ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

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