Description
Release form
Tablets
Pharmacological action of
Pharmacodynamics of
The main mechanism of pharmacological action of cilostazol is the inhibition of type 3 phosphodiesterase and, therefore, an increase in the intracellular content of cyclic adenosine monophosphate (cAMP) in various organs and tissues.
In experimental and small clinical trials, cilostazol has a vasodilating effect. Cilostazol dilates mainly the femoral arteries, to a lesser extent – the vertebral, carotid and superior mesenteric arteries. The renal arteries are not sensitive to the effects of cilostazol. Cilostazol inhibits the proliferation of smooth muscle cells in humans and rats in vitro.
In experimental and clinical studies in vivo and ex vivo, it was found that cilostazol increases the content of cAMP in platelets and causes a reversible antiplatelet effect. Cilostazol reversibly inhibits platelet aggregation caused by various stimuli such as thrombin, adenosine diphosphate, collagen, arachidonic acid, adrenaline and mechanical stress (hemodynamic shock). In addition, cilostazol blocks the release of human platelet platelet growth factor and platelet factor 4 (PF-4).
Additional potentially beneficial effects of cilostazol found in experimental and clinical studies include lowering serum triglycerides and increasing cholesterol in high-density lipoprotein (HDL). In a clinical study, the administration of cilostazol at a dose of 100 mg 2 times a day for 12 weeks compared with placebo reduced the level of triglycerides in the blood by an average of 0.33 mmol / L (by 15%) and increased the level of HDL cholesterol in the blood by an average of 0.10 mmol / L (10%).
Cilostazol has a positive inotropic effect. In experimental studies, cilostazol had a species-specific damaging effect on the cardiovascular system (found in dogs, but not detected in rats and monkeys). Cilostazol does not increase the duration of the QT interval in dogs and monkeys.
The efficacy of cilostazol in patients with intermittent claudication was confirmed in 9 placebo-controlled clinical trials. Established that cilostazol therapy at a dose of 100 mg 2 times a day for 24 weeks approximately doubles the maximum traveled distance (from 60.4 m to 129.1 m, the average absolute increase in the maximum traveled distance is 42 meters) and the distance traveled before the onset of pain ( from 47.3 m to 93.6 m). The effectiveness of cilostazol in patients with diabetes was lower than in individuals without impaired carbohydrate metabolism. In a prospective double-blind clinical study, it was found that cilostazol does not increase mortality in patients with intermittent claudication.
Pharmacokinetics
Cilostazol is readily absorbed by ingestion. Compared with taking the drug on an empty stomach, the maximum concentration (Cmax) is 16% higher after taking the drug 30 minutes after eating and 93% when taking 2 hours after eating.
The maximum concentration (Cmax) of cilostazol and its main metabolites increases less than in proportion to the dose increase. In this case, the area under the concentration-time curve (AUC) of cilostazol and its main metabolites increases approximately in proportion to the dose increase.
In patients with peripheral arterial occlusion diseases, when taken regularly at a dose of 100 mg 2 times a day, the equilibrium concentration of cilostazol in the blood is reached after 4 days.
Cilostazol has two pharmacologically active metabolites (dehydrocylostazole and 4′-trans-hydroxycylostazole). Dehydrocylostazole is 4-7 times superior to cilostazole in its ability to inhibit platelet aggregation. 4`-trans-hydroxycylostazole, which has five times less pronounced ability to inhibit platelet aggregation compared with unchanged cilostazol. The plasma concentration (measured by AUC) of dehydrocylostazole and 4`-trans-hydroxycylostazole is respectively ~ 41% and ~ 12% of the concentration of cilostazol.
The relationship of cilostazol with plasma proteins (mainly with albumin) is 95-98%. Dehydrocylostazole and 4`-trans-hydroxycylostazole bind to plasma proteins by 97.4% and 66% respectively
Cilostazol is actively metabolized mainly by the action of the isoenzyme CYP3A4, to a lesser extent by the isoenzyme CYP2C19, and to an even lesser extent by the isoenzyme CYP1A2. Cilostazol is not an inducer of hepatic microsomal peroxidation enzymes.
Cilostazol is excreted mainly in the urine (74%), the remaining drug is excreted in the feces. In urine, unchanged cilostazol is practically not determined. Less than 2% of the dose taken is excreted in the urine in the form of dehydrocylostazole. Approximately 30% of the dose taken is excreted in the urine in the form of 4′-trans-hydroxycylostazole. The remaining drug is excreted in the form of a variety of metabolites, each of which is no more than 5% of the dose taken.
The observed elimination half-life of cilostazol is 10.5 hours. The two main metabolites (dehydrocylostazole and 4′-trans-hydroxycylostazole) have similar observed half-lives.
Special patient groups
Renal failure
It was found that in patients with severe renal failure, the free fraction of cilostazol is 27% higher, and the Cmax and AUC of unchanged cilostazol are respectively 29% and 39% lower than in individuals with normal renal function. Cmax and AUC dehydrocylostazole in patients with severe renal failure are respectively 41% and 47% lower than in patients with normal renal function. At the same time, Cmax and AUC of 4′-trans-hydroxycylostazole (the main metabolite excreted in the urine) in patients with severe renal failure increase by 173% and 209%, respectively, compared with patients without impaired renal function. The use of cilostazol is contraindicated in patients with severe renal failure (creatinine clearance 25 ml / min).
Hepatic insufficiency
In patients with moderate liver failure, peak plasma concentrations and AUC increased by 25 and 10%, respectively, compared with healthy people. In patients with moderate renal failure, peak plasma concentrations and AUC increased by 50 and 16%, accordingly, compared with healthy people. Data on the use of cilostazol in patients with moderate and severe hepatic insufficiency are absent. Since cilostazol is largely metabolized by hepatic microsomal oxidation enzymes, use is contraindicated in patients with moderate or severe hepatic insufficiency.
Age and gender
In studies involving healthy volunteers aged 50-80 years, it was found that age and gender do not significantly affect the pharmacokinetics of cilostazol.
Indications
Symptomatic treatment of intermittent claudication.
Cilostazol is used to increase the maximum distance and distance traveled without pain in patients with intermittent claudication who have no pain at rest and have no signs of peripheral tissue necrosis (chronic ischemia of the lower extremities of the II degree according to Fontaine’s classification).
Cilostazol is intended for use as second-line therapy in patients with intermittent claudication in whom lifestyle changes (including smoking cessation and [specialist-led] physical rehabilitation programs) and other appropriate interventions have been found to be insufficient to reduce the symptoms of intermittent claudication.
Special instructions
Before starting treatment with cilostazol, other treatments, such as surgical revascularization or conservative therapy, should be considered.
Due to the mechanism of pharmacological action, cilostazol can cause tachycardia, palpitations, tachyarrhythmias and / or arterial hypotension. When taking cilostazol, the heart rate may increase by 5-7 beats per minute, which can provoke an attack of angina pectoris in patients at risk (for example, patients with stable angina pectoris).
Patients who are at increased risk of developing severe cardiovascular complications due to an increase in heart rate (for example, patients with stable coronary artery disease) need careful monitoring during treatment with cilostazol. The use of cilostazol is contraindicated in patients with unstable angina or myocardial infarction / invasive intervention on the coronary arteries over the past 6 months, as well as in patients with a history of severe tachyarrhythmia.
Caution should be exercised when administering cilostazol to patients with atrial or ventricular extrasystoles, as well as to patients with atrial fibrillation or atrial flutter.
You should warn the patient about the need to report any case of bleeding or the appearance of a ² Ñbruise ² Ñ (subcutaneous hematoma) with a slight bruise. If hemorrhage develops in the retina, cilostazol must be discontinued.
Since cilostazol is an inhibitor of platelet aggregation, there is an increased risk of bleeding during surgery (including small invasive procedures, such as tooth extraction). With the planned surgical interventions (if an antiplatelet effect is undesirable), cilostazole should be discontinued 5 days before surgery.
Rare or very rare cases of hematologic disorders have been reported, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, or aplatic anemia. In most cases, these disorders occurred after cilostazol was discontinued. However, in several cases, pancytopenia and aplastic anemia have been fatal.
The patient should be warned of the need to immediately inform the doctor of any symptoms that may be early manifestations of hematological complications, such as high fever (pyrexia) and tonsillitis. An extensive blood test should be performed if an infection is suspected or if clinical symptoms of hematological complications appear. It is necessary to immediately stop taking cilostazol in case of clinical symptoms or laboratory signs of hematological complications.
Caution should be exercised when cilostazol is used concomitantly with drugs that lower blood pressure (the possibility of an additive effect with the development of arterial hypotension and reflex tachycardia) and also reduce blood coagulation or inhibit platelet aggregation.
Effect on ability to drive vehicles,
mechanisms Cilostazole may cause dizziness. Caution is advised when driving or operating machinery during the treatment period.
Composition
Active ingredient: cilostazol 50.0 mg / 100.0 mg. Excipients: pre-gelatinized potato starch 81.8 mg / 84.0 mg, microcrystalline cellulose 26.0 mg / 35.0 mg carmellose calcium 1.5 mg / 2.2 mg magnesium stearate 1.7 mg / 2.3 mg hypromellose 19.0 mg / 26.5 mg.
Dosage and Administration
Inside.
The recommended dosage of cilostazol is 100 mg twice daily.
Cilostazol should be taken 30 minutes before a meal. When taking cilostazol with food, an increase in the maximum concentration (Cmax) in the blood plasma is noted, which may be associated with an increase in the frequency of adverse events.
If you skip taking the drug, you must take the next tablet at the usual time. Do not take a double dose of cilostazol.
Cilostazole therapy should be started under the supervision of a physician with experience in treating intermittent claudication.
The doctor should reassess the patient’s condition after 3 months of treatment. If cilostazol therapy does not have an adequate effect or there is no decrease in the severity of symptoms of intermittent claudication, cilostazol should be discontinued and other treatment methods considered.
Patients receiving treatment with cilostazol should continue to follow lifestyle recommendations (smoking cessation, exercise) and drug therapy (taking lipid-lowering and antiplatelet drugs) to reduce the risk of cardiovascular complications. Cilostazol is not a substitute for this treatment.
Use in special patient groups
Elderly
There are no special requirements for changing the dosage of cilostazol in elderly patients.
Renal failure
In patients with creatinine clearance> 25 ml / min, a dosage change is not required. Cilostazol is contraindicated in patients with creatinine clearance <25 ml / min. Hepatic n sufficiency In patients with mild hepatic insufficiency, a dosage change is not required. There is no experience with the use of cilostazol in patients with moderate to severe hepatic impairment. Since cilostazol is largely metabolized by enzymes of microsomal oxidation of the liver, the use of the drug is contraindicated in patients with moderate and severe liver failure. Simultaneous administration of potent inhibitors of CYP3A4 or CYP2C19 In patients receiving drugs that have a potent inhibitory effect on CYP3A4 (e.g., some macrolides) or drugs that have a potent inhibitory effect on CYP2C19 (e.g., omeprazole), the dose of cilostazol should be reduced to 50 mg twice a day. Side effects of The most commonly reported side effects in clinical trials were headache (> 30%), diarrhea and stool disorders (> 15% each). These side effects were mild to moderate in intensity.
Adverse reactions by frequency of occurrence were classified as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1 / 1,000 and <1/100), rarely (? 1 / 10,000 and <1/1000), very rarely (<1 / 10,000), the frequency is unknown (cannot be determined based on available data). Disorders of the blood and lymphatic system Often: ecchymosis. Infrequently: anemia. Rarely: increased bleeding time, thrombocytosis. Frequency unknown: bleeding tendency, thrombocytopenia, granulocytopia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia. Immune system disorders Infrequently: allergic reaction. Metabolic and nutritional disorders Often: edema (peripheral edema, facial edema), anorexia. Infrequently: hyperglycemia, diabetes mellitus. Mental disorders Infrequently: Anxiety. Disturbances from the nervous system Very often: headache Often: dizziness. Infrequently: insomnia, sleep disturbance (unusual dreams), intracranial hemorrhage. Frequency unknown: paresis, hypesthesia. Visual disturbances Often: intraocular hemorrhage. Frequency unknown: conjunctivitis. Hearing impairment and labyrinthine disorders Frequency unknown: ringing in the ears. Disorders of the heart Often: palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles. Infrequently: myocardial infarction, atrial fibrillation, chronic heart failure, supraventricular tachycardia, ventricular tachycardia, syncope. Vascular disorders Often: orthostatic hypotension. Infrequently: hot flashes, arterial hypertension, arterial hypotension. Disorders of the respiratory system, chest and mediastinal organs Often: rhinitis, pharyngitis. Infrequently: shortness of breath (dyspnea), pneumonia, cough, pulmonary hemorrhage, airway bleeding. Frequency unknown: interstitial pneumonia. Gastrointestinal disorders Very common: diarrhea, stool disorders. Often: nausea, vomiting, dyspepsia, flatulence, abdominal pain, gastrointestinal bleeding. Infrequently: gastritis. Disorders of the liver and biliary tract Frequency unknown: hepatitis, deviation of liver function from normal values, jaundice. Disorders of the skin and subcutaneous tissue Often: skin rash, itching. Infrequently: eczema, skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, subcutaneous hemorrhage. Disorders of the musculoskeletal and connective tissue Infrequently: myalgia, intramuscular hematomas. Disorders of the kidneys and urinary tract Rarely: renal failure, impaired renal function. Frequency unknown: hematuria, pollacuria. General disorders and disorders at the injection site Often: chest pain, asthenia. Infrequently: chills, malaise. Frequency unknown: pyrexia, pain. Laboratory and instrumental data Frequency unknown: increased uric acid in the blood, increased urea in the blood, increased creatinine in the blood. An increase in the incidence of palpitations and peripheral edema was noted with cilostazol in combination with other vasodilators that cause reflex tachycardia (for example, dihydropyridine blockers of slow calcium channels). Cilostazol alone increases the risk of bleeding, and this risk can be further increased while cilostazol is used with any other drug with the same potential. The risk of intraocular hemorrhage may be increased in patients with diabetes. A higher incidence of diarrhea and heart palpitations in patients older than 70 years has been established. Drug interactions Acetylsalicylic acid Short-term (within? 4 days) simultaneous use of cilostazol and acetylsalicylic acid leads to an increase of 23-25% in ADP-induced platelet aggregation under ex vivo compared with monotherapy with acetyl salicylic acid. Due to the increased risk of bleeding with simultaneous use with cilostazol, careful monitoring is necessary. Clopidogrel and other antiplatelet drugs In a study in healthy volunteers, the simultaneous use of cilostazole with clopidogrel had no effect on platelet count, prothrombin time (PV) and activated partial thromboplastin time (APTT). When using clopidogrel as in the form of monotherapy, and in combination with cilostazol, healthy volunteers increased bleeding time. Reception of cilostazol did not lead to an additional significant lengthening of bleeding time. Nevertheless, caution is advised when cilostazol is used concomitantly with any medication that inhibits platelet aggregation. It is recommended to regularly monitor the bleeding time. The use of cilostazol is contraindicated in patients receiving two or more antiplatelet and / or anticoagulant drugs at the same time. Oral anticoagulants In a clinical study, a single dose of cilostazol did not inhibit warfarin metabolism and did not affect blood coagulation (PV, APTT, bleeding time). Nonetheless, caution is advised while using cilostazol with any anticoagulant drug. The use of cilostazol is contraindicated in patients receiving two or more antiplatelet and / or anticoagulant drugs at the same time. Inhibitors of cytochrome P450 isoenzymes In the liver, cilostazol is mainly metabolized by cytochrome P450 enzymes, mainly CYP3A4 and CYP2C19 and, to a lesser extent, CYP1A2. It is believed that dehydrocylostazole, 4-7 times superior to cilostazole in its ability to inhibit platelet aggregation, is formed mainly with the participation of CYP3A4. 4`-trans-hydroxycylostazole, which has five times less pronounced ability to inhibit platelet aggregation, is formed mainly under the influence of CYP2C19. Accordingly, drugs that inhibit CYP3A4 (e.g. some macrolides [erythromycin, clarithromycin], azole antifungals [ketoconazole, itraconazole], HIV protease inhibitors) and CYP2C19 (for example, proton pump inhibitors [omeprazole, esomeprazole]) increase the overall pharmacological activity of cilostazole and may enhance its effects. Accordingly, patients receiving potent inhibitors of CYP3A4 or CYP2C19, it is recommended to prescribe cilostazol at a dose of 50 mg 2 times a day. Erythromycin While taking cilostazol with erythromycin (a potent inhibitor of CYP3A4), the AUC values of cilostazol, dehydrocylostazol and 4`-trans-hydroxycylostazol increase by 72%, 6% and 119%, respectively. Based on changes in AUC indicators, that the total pharmacological activity of cilostazol with simultaneous use with erythromycin increases by 34%. It is recommended to reduce the dose of cilostazol to 50 mg 2 times a day while using it with erythromycin and other drugs of this group (for example, clarithromycin). Ketoconazole When taking cilostazole with ketoconazole (a powerful inhibitor of CYP3A4), the AUC of cilostazol increases by 117%, the AUC of dehydrocylostazole decreases by 15%, and the AUC of 4`-trans-hydroxycylostazole increases by 87%. Based on changes in AUC indices, it was found that the overall pharmacological activity of cilostazole with simultaneous use with ketoconazole increases by 34%. It is recommended to reduce the dose of cilostazol to 50 mg 2 times a day while using it with ketoconazole and other drugs of this group (for example, with itraconazole). Diltiazem While taking cilostazol with diltiazem (a weak inhibitor of CYP3A4), the AUC values of cilostazol, dehydrocylostazol and 4`-trans-hydroxycylostazole increase by 44%, 4% and 43%, respectively. Based on changes in AUC indices, it was found that the overall pharmacological activity of cilostazol with simultaneous use with diltiazem increases by 19%. Dose adjustment of cilostazol with simultaneous use with diltiazem is not required. Grapefruit juice With a single dose of 100 mg of cilostazole simultaneously with 240 ml of grapefruit juice (an intestinal inhibitor of CYP3A4), there was no significant change in the pharmacokinetic parameters of cilostazol. Dose adjustment of cilostazol is not required. However, taking more grapefruit juice may affect the pharmacokinetics of cilostazol. Omeprazole While taking cilostazole with omeprazole (a potent inhibitor of CYP2C19), the AUC values of cilostazol and dehydrocylostazole increase by 22% and 68%, respectively, while the AUC of 4`-trans-hydroxycylostazole decreases by 36%. Based on changes in AUC indices, it was found that the overall pharmacological activity of cilostazol with simultaneous use with omeprazole increases by 47%. It is recommended to reduce the dose of cilostazol to 50 mg 2 times a day with simultaneous use with omeprazole. Cytochrome P450 isoenzyme substrates Cilostazol increases the AUC of lovastatin (CYP3A4 substrate) and its beta-hydroxyl metabolite by 70%. Caution is advised while using cilostazol with CYP3A4 substrates that have a narrow therapeutic range (such as cisapride, halofantrine, pimozide, ergot alkaloids). Caution is also recommended when using cilostazol with HMG-CoA reductase inhibitors (statins) metabolizing with CYP3A4 (simvastatin, atorvastatin and lovastatin). Inducers of cytochrome P450 isoenzymes Exposure to drugs that increase the activity of CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin, St. John’s wort preparations perforated), the pharmacokinetics of cilostazol has not been studied. With simultaneous administration, it is theoretically possible to reduce the antiplatelet effect of cilostazol, therefore, it is necessary to regularly monitor the bleeding time. In clinical studies, it was found that smoking (a factor that enhances the activity of CYP1A2) reduces the concentration of cilostazol in blood plasma by 18%. Other drugs Caution should be exercised while cilostazole is used with any drugs that lower blood pressure (including nitrates and phosphodiesterase-5 inhibitors), since an additive effect with the development of arterial hypotension and reflex tachycardia is possible. Overdose of Symptoms of Information on acute overdose of cilostazol in humans is limited. Expected overdose symptoms: severe headache, diarrhea, tachycardia, arterial hypotension, heart rhythm disturbances. Treatment Symptomatic. If an overdose occurs, careful monitoring and examination of the patient is necessary. It s necessary to empty the stomach by inducing vomiting, or perform gastric lavage in accordance with generally accepted recommendations. Due to the high degree of binding to plasma proteins, hemodialysis and peritoneal dialysis are practically ineffective. Storage conditions At a temperature not exceeding 30 ° C. Keep out of the reach of children. Expiration 3 years. tablet
