Bestazol 50/Bestazol 100

Bestazol 50: Each tablet contains cilostazol 50 mg.
Bestazol 100: Each tablet contains cilostazol 100 mg.
Tablet for oral use.

Pharmacology: Pharmacodynamics: Mechanism of Action: Cilostazol and several of its metabolites are PDE 3 inhibitors, inhibiting PDE activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively. It reversibly inhibits platelet aggregation induced by various stimuli, including thrombin, adenosine diphosphate (ADP), collagen, arachidonic acid, epinephrine and shear stress.
Cardiovascular Effect: Cilostazol affects both vascular beds and cardiovascular function. It produces nonhomogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.
In animal studies, cilostazol increased heart rate, myocardial contractile force, coronary blood flow, ventricular automaticity, left ventricular contractility and atrioventricular conduction. In humans, dose-proportional heart rate increased were observed at therapeutic doses. Non-dose-related increases in ventricular premature beats and transient ventricular tachycardia were observed in high numbers of cilostazol-treated patients than in those treated with placebo.
Pharmacokinetics: Absorption: Cilostazol is absorbed after oral administration. A high-fat meal increases absorption, with an approximately 90% increase in maximum plasma concentration (C_max) and a 25% increase in the area under the plasma concentration-time curve (AUC). Absolute bioavailability is not known.
Distribution: Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-cilostazol is 97.4% and for 4'-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin and omeprazole was not clinically significant.
Metabolism: Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4 and, to a lesser extent, 2C19. Two metabolites are active, with 1 metabolite (3,4-dehydro-cilostazol) appearing to account for at least 50% of the pharmacologic (PDE 3 inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional.
Excretion: Cilostazol metabolites largely excreted in urine. Cilostazol and its active metabolites have apparent elimination half-lives of about 11 to 13 hours. They accumulate about 2-fold with chronic administration and reach steady-state blood levels within a few days. Following oral administration of radio-labeled cilostazol 100 mg, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4 to 7 times as active as cilostazol) and 4% was 4'-trans-hydroxy-cilostazol (one-fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in the feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in the urine as 4'-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
Special Populations: Age and Gender: The total and unbound oral clearances, adjusted for body weight of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50 to 80 year old age range.
Smokers: Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.
Hepatic Impairment: The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects. Patients with moderate or severe hepatic impairment have not been studied.
Renal Function Impairment: The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in healthy subjects. Severe renal function impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, based on plasma concentrations and relative to PDE 3 inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%).

Chronic arterial occlusion: Cilostazol is indicated for treatment of ischemic symptoms, including ulceration, pain, and coldness of the extrimeties, in chronic arterial occlusion.
Secondary prevention of cerebral infarction: Cilostazol is used for prevention of recurrence of cerebral infarction (excluding cardiogenic cerebral embolism).

The usual adult dose of cilostazol is 100 mg twice daily taken at least 30 minutes before or 2 hours after breakfast and dinner.
A reduced dose of 50 mg twice daily should be considered during coadministration of such inhibitors CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.
Duration of therapy: 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.
Mode of Administration: Tablets for oral administration.

Overdose: 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, including the following: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias.
The oral median lethal dose of cilostazol is greater than 5 g/kg in mice and rats and greater than 2 g/kg in dogs.
Treatment: Carefully observe the patient and provide supportive treatment. Since cilostazol is highly protein bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis.

Cilostazol is contraindicated in the following patients: Congestive heart failure of any severity.
Hemostatic disorders or active pathologic bleeding such as bleeding peptic ulcer and intracranial bleeding.
Known or suspected hypersensitivity to any of its components.
Woman who are pregnant or may possibility become pregnant.

This drug may increase heart rate, PVCs and nonsustained ventricular tachycardia.
Do not take this drug if symptoms of congestive heart failure (e.g., shortness of breath, swelling of the legs) are present.
Cardiovascular risk may observe during long-term use of this drug.
Use in patient with a history of hypersensitivity to any ingredient of the drug is contraindicated.
Breast-feeding is not recommended because of possible unwanted effects in nursing infants.
This drug 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 with high blood pressure, blood pressure should be sufficiently controlled during cilostazol treatment.

Congestive heart failure: Cilostazol is contraindicated in patients with congestive heart failure. In patients without congestive heart failure, the long-term effects of PDE 3 inhibitors (including cilostazol) are unknown. Patients in the 3 to 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 cilostazol group). There are no data as to longer-term risk or risk in patients with more severe underlying heart disease.
Hematologic effects: Rare cases of thrombocytopenia or leukopenia progressing to agranulocytosis have been reported when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.
Use with clopidogrel: There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there is an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution should be advised for checking bleeding times during coadministration.
Concomitant therapy with other platelet aggregation inhibitors: Use with caution in patients receiving other platelet aggregation inhibitors.
Use with other CYP3A4 or CYP2C19 inhibitors: Use with caution in patients receiving CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin and diltiazem) or CYP2C19 inhibitors (e.g., omeprazole). If concurrent use is warrented, consider dosage adjustment of cilostazol. (see Dosage & Administration).
Prior to elective surgical procedures: Withhold for at least 4-6 half-lives prior to elective surgical procedures.
Cardiovascular toxicity: Repeated oral administration of cilostazol to dog (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg bid.
Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma cilostazol levels were less than those seen in humans given the MRHD and those seen in dogs given doses associated with cardiovascular lesions.
Hepatic impairment: Patients with moderate or severe hepatic impairment have not been studied in clinical trials. Special caution is advised when cilostazol is used in such patients.
Renal impairment: Patients on dialysis have not been studied but it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%). Special caution should be advised when cilostazol is used in patients with severe renal impairment: creatinine clearance <25 ml/min.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No evidence of carcinogenic potential was exhibited in animal studies with doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice administered for up to 104 weeks. Based on systemic exposure, the maximum doses in mice and rats were less than human exposure at the maximum recommended human dose (MRHD).
Although a significant increase in chromosomal aberrations was associated with cilostazol in the in vivo Chinese Hamster Ovary Cell assay, negative results were reported in the following assays: bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration.
Cilostazol had no effect on the fertility of reproductive performance of male and female rats at doses of up to 1000 mg/kg/day. In comparison to systemic exposure (AUC) to unbound cilostazol in humans, this dose was less than 1.5 times the MHRD in male rats and approximately 5 times the MRHD in female rats.
Use in Children: The safety and efficacy of cilostazol in children have not been established.
Use in the Elderly: No substantial differences in safety and efficacy relative to younger adults but increased sensitivity cannot be ruled out.

Use in Pregnancy: FDA pregnancy category C.
Reproduction studies have been conducted with cilostazol in rats and rabbits. In pregnant rats, 1000 mg/kg/day dose resulted in decreased fetal weights and an increased incidence of congenital malformations in the cardiovascular, renal and skeletal systems. Increased incidences of ventricular septal defects and retarded ossification were also observed at 150 mg/kg/day. This same dose administered to rats in late pregnancy was associated with stillbirths and decreased birth weight. In pregnant rabbits, a dose of 150 mg/kg/day was associated with an increased incidence of retarded ossification of the sternum.
No reports describing the use of cilostazol during human pregnancy have been located. The drug is teratogenic and toxic in two animal species, but the complete lack of human data prevents any assessment of the risk that cilostazol presents to a human fetus.
Use in Lactation: No reports describing the use of cilostazol during human lactation have been located. The drug is excreted into the milk of lactating rats. This is consistent with the relatively low molecular weight (about 369) of the drug and excretion into breast milk should be expected. The effect on a nursing infant from exposure to cilostazol in milk is unknown. Because of the potential for severe adverse effects, breastfeeding while receiving cilostazol is not recommended.

The only adverse reaction resulting in discontinuation of therapy in greater than or equal to 3% of patients treated with cilostazol 50 or 100 mg twice daily was headache, which occurred with an incidence of 1.3%, 3.5% and 0.3% in patients treated with cilostazol 50 mg twice daily, 100 mg twice daily, or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for cilostazol (all dose) versus 0.1% for placebo. (See table.)

Click on icon to see table/diagram/image

Other adverse reactions: Other adverse reaction seen with an incidence of greater than or equal to 2%, but occurring in the placebo group at least as frequently as in the 100 mg twice daily group, were as follows: Cardiovascular: Angina pectoris, hypertension.
Central Nervous System: Hypesthesia, paresthesia.
Dermatologic: Rash.
Gastrointestinal: Vomiting.
Genitourinary: Hematuria, urinary tract infection.
Respiratory: Bronchitis, dyspnea.
Miscellaneous: Arthritis, asthenia, flu syndrome, leg cramps.
Less frequent adverse reactions (less than 2%) that were experienced by patients exposed to cilostazol 50 or 100 mg twice daily in the 8 controlled clinical trials and that occurred at a greater frequency in the 100 mg twice-daily group than in the placebo group, regardless of suspected drug relationship, were as follows: Cardiovascular: Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, heart arrest, hemorrhage, hypotension, myocardial infarction, myocardial ischemia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia.
Central Nervous System: Anxiety, insomnia, malaise, neuralgia.
Dermatologic: Dry skin, furunculosis, skin hypertrophy, urticaria.
Endocrine: Diabetes mellitus.
Gastrointestinal: Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, gastritis, gastroenteritis, gum hemorrhage, hematemesis, increased gamma-glutamyltransferase, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, stomach ulcer, tongue edema.
Genitourinary: Albuminuria, cystitis, urinary frequency, vaginal hemorrhage, vaginitis.
Hematologic/Lymphatic: Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura.
Metabolic/Nutritional: Gout, hyperlipemia, hyperuricemia, increased creatinine.
Musculoskeletal: Arthralgia, bone pain, bursitis, neck rigidity.
Respiratory: Asthma, epistaxis, hemoptysis, pneumonia, sinusitis.
Special senses: Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye hemorrhage, retinal hemorrhage, tinnitus.
Miscellaneous: Chills, face edema, fever, generalized edema, pelvic pain, retroperitoneal hemorrhage.
Postmarketing experience: The following events have been reported spontaneously from worldwide postmarketing experience since launch of cilostazol in the United States.
Hematologic/Lymphatic: Agranulocytosis, granulocytopenia, thrombocytopenia, leucopenia, bleeding tendency.
Cardiovascular: Torsades de pointes, QTc prolongation (Torsades de pointes and QTc prolongation occurred in patients with cardiac disorders e.g., complete atrioventricular block, cardiac failure and bradyarrythmia, when treated with cilostazol), subacute thrombosis (occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting).
Gastrointestinal: Gastrointestinal hemorrhage.
General disorders and administration site conditions: Pain, chest pain, hot flushes.
Hepatobilliary disorders: Hepatic dysfunction/abnormal liver function tests, jaundice.
Injury, poisoning and procedural complications: Extradural hematoma and subdural hematoma.
Investigations: Blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, blood urea increased.
Central Nervous System: Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident.
Respiratory: Pulmonary hemorrhage, interstitial pneumonia.
Skin: Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens Johnson syndrome, skin drug eruption (dermatitis medicamentosa).

Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19.
Aspirin: Coadministration of aspirin with cilostazol increased the inhibition of platelet aggregation compared to either product alone. Coadministration had no clinically significant impact on PT, aPTT or bleeding time.
HMG-CoA reductase inhibitors (i.e., simvastatin, lovastatin): Cilostazol may inhibit the metabolism (CYP3A4) of certain HMG-CoA reductase inhibitors. Plasma concentrations of certain HMG-CoA reductase inhibitors may be elevated by cilostazol, increasing the therapeutic and adverse reactions.
Lovastatin: The coadministration of lovastatin with cilostazol decreased cilostazol C_{ss, max} and AUC by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration increases lovastatin AUC by approximately 70%.
Warfarin: The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25 mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
Clopidogrel: Additive effects on bleeding times not determined.
Caution is advised and bleeding times should be monitored during such concomitant therapy.
Drugs that inhibit or are substrates for CYP3A4: Potential pharmacokinetic interaction (increased plasma cilostazol concentrations, decreased clearance) with other inhibitors of CYP3A4 isoenzyme, including certain azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, miconazole), certain macrolide antibiotics (e.g., erythromycin or clarithromycin but not azithromycin), certain selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, nefazodone, sertraline), certain antiretroviral agents (e.g., indinavir), metronidazole, diltiazem and danazol.
Erythromycin or other macrolide antibiotics: Certain macrolide antibiotics may inhibit the metabolism (CYP3A4) of cilostazol. Erythromycin decreases the metabolism of cilostazol through inhibition of the CYP3A4 isoenzyme; similar effects are expected from other macrolide antibiotics. Cilostazol plasma concentrations may be elevated, increasing the therapeutic and adverse effects.
It may be necessary to decrease the dose of cilostazol during coadministration of certain macrolide antibiotics. Consider a dosage of cilostazol 50 mg twice daily in patients receiving one of these macrolide antibiotics.
Diltiazem: Cilostazol plasma concentrations are increased by diltiazem. Diltiazem 180 mg decreased the clearance of cilostazol by approximately 30% and increased the C_max and AUC approximately 30% and 40%, respectively.
Quinidine: Concomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.
Omeprazole: Omeprazole may inhibit the metabolism (CYP2C19) of cilostazol. Cilostazol plasma concentrations may be elevated, increasing the therapeutic and adverse effects.
It may be necessary to decrease the dose of cilostazol during coadministration of omeprazole. Consider a dosage of cilostazol 50 mg twice daily in patients receiving omeprazole.
Ginkgo biloba: Ginkgo biloba does not appear to affect the antiplatelet activity of cilostazol. However, bleeding time may be prolonged by additive or synergistic effect.
Food: Grapefruit juice increased the C_max of cilostazol by approximately 50%, but had no effect on AUC. A high-fat meal increases absorption with an approximately 90% increase in C_max and a 25% increase in the AUC.
Smoking, tobacco: Systemic cilostazol exposure is decreased by approximately 20% in association with tobacco smoking.

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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