Aducyl pills 50mg, 60pcs

Composition

Tablets – 1 tab. :

• Active ingredient: 50 mg of cilostazol;
• Excipients: corn starch, microcrystalline cellulose 101, calcium carmellose, hypromellose, magnesium stearate.

Pharmacological action

Antiplatelet agent.

Pharmacokinetics

Absorption rate

In patients with occlusive diseases of the peripheral arteries, with regular intake of cilostazol at a dose of 100 mg 2 times a day, the equilibrium concentration of the drug in the blood is reached after 4 days.

The maximum concentration (Cmax) of cilostazol and its major metabolites increases less than proportionally 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.

Distribution and metabolism

Cilostazol is 95-98% bound to blood proteins, mainly albumin. Cilostazol is mainly metabolized in the liver by the CYP3A4 isoenzyme, to a lesser extent by the CYP2C19 isoenzyme, and to an even lesser extent by the CYP1A2 isoenzyme. Cyostazole is not an inducer of hepatic microsomal peroxidation enzymes.

The plasma concentrations of dehydrocylostazole and 4′ – trans-hydroxycylostazole (estimated based on AUC) are approximately 41% and approximately 12% of the unchanged cilostazole concentration, respectively. Dehydrocylostazole and 4’-trans-hydroxycylostazole bind to blood proteins by 97.4% and 66%, respectively.

Elimination

Cilostazol is mainly excreted by the kidneys (74%), the remaining drug is excreted through the intestines. In the urine, unchanged cilostazol is practically not detected. Less than 2% of the drug dose is excreted by the kidneys in the form of dehydrocylostazole. Approximately 30% of the dose is excreted by the kidneys in the form of 4 ‘ – trans-hydroxycylostazole.

The remaining drug is excreted in the form of various metabolites, each of which is no more than 5% of the dose taken.

The elimination half-life of cilostazol is 10.5 hours. The two main metabolites, dehydrocylostazole and 4’ – trans-hydroxycylostazole, have similar elimination half-lives.

Special patient groups

In studies involving healthy volunteers aged 50-80 years, it was found that age and gender do not significantly affect the pharmacokinetics of cilostazol.

Kidney failure

It was found that in patients with severe renal insufficiency, the free fraction of cilostazol is 27% higher, and the Cmax and AUC values of unchanged cilostazol are 29% and 39% lower, respectively, than in individuals with normal renal function.

The Cmax and AUC values of dehydrocylostazole in patients with severe renal insufficiency are 41% and 47% lower, respectively, than in patients with normal renal function.

The Cmax and AUC values of 4′-trans-hydroxycylostazole (the main metabolite excreted by the kidneys)are also shown in patients with severe renal insufficiency, they increase by 173% and 209%, respectively, compared with patients without impaired renal function. Cilostazol is contraindicated in patients with severe renal insufficiency (creatinine clearance < 25 ml/min).

Liver failure

In patients with moderate hepatic insufficiency, plasma Cmax and AUC increased by 25 and 10%, respectively, compared with healthy people. In patients with moderate renal insufficiency, peak plasma concentrations and AUC were increased by 50 and 16%, respectively, compared with healthy subjects.

There are no data on the use of cilostazol in patients with moderate to severe hepatic insufficiency. Since cilostazol is largely metabolized by hepatic enzymes of microsomal oxidation, its use is contraindicated in patients with moderate or severe hepatic insufficiency.

Pharmacodynamics

The main mechanism of pharmacological action of cilostazol is inhibition of phosphodiesterase type 3 (PTE-3) and, consequently, an increase in the intracellular content of cyclic adenosine monophosphate (cAMP) in various organs and tissues.

In experimental and small clinical studies, it has been established that cilostazol has a vasodilating effect. Cilostazol inhibits the proliferation of human and rat smooth muscle cells in vitro.

In experimental and clinical studies in vivo and ex vivo, cilostazol was found to increase the content of cAMP in platelets and cause a reversible antiplatelet effect. In addition, cilostazol blocks the release of platelet-derived growth factor and platelet-derived factor 4 (PF-4) by human platelets.

Additional potentially beneficial effects of cilostazol found in experimental and clinical studies were a decrease in serum triglyceride concentrations and an increase in the concentration of cholesterol in high-density lipoproteins (HDL).

In a clinical study, taking cilostazol 100 mg twice daily for 12 weeks compared to placebo reduced the blood triglyceride content by an average of 0.33 mmol / l (by 15%) and increased the blood HDL cholesterol content by an average of 0.10 mmol/l (by 10%).

Cilostazol has a positive inotropic effect. In experimental studies, cilostazol exerted a species-specific damaging effect on the cardiovascular system.

The efficacy of cilostazol in patients with intermittent claudication was confirmed in 9 placebo-controlled clinical trials.

It was found that therapy with cilostazol at a dose of 100 mg 2 times a day for 24 weeks approximately doubles the maximum walking distance (from 60.4 m to 129.1 m; the average absolute increase in the maximum walking distance is 42 meters) and the distance traveled before the onset of pain (from 47.3 m to 93.6 m).

The effectiveness of the drug in patients with diabetes mellitus was lower than in those without impaired carbohydrate metabolism. In a prospective double-blind clinical trial, cilostazol was found not to increase mortality in patients with intermittent claudication.

Indications

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 no signs of peripheral tissue necrosis (chronic ischemia of the lower extremities of the second degree according to the Fontaine classification).

Cilostazol is intended for use as a second-line therapy in patients with intermittent claudication in whom lifestyle changes (including smoking cessation and [specialist-supervised] physical rehabilitation programs) and other appropriate interventions have not been sufficient to reduce the symptoms of intermittent claudication.

Use during pregnancy and lactation

Pregnancy

There are no data on the use of cilostazol in pregnant women.

Experimental animal studies have shown that cilostazol has reproductive toxicity.

The use of cilostazol during pregnancy is contraindicated.

Breast-feeding period

In experimental studies on animals, it was found that cilostazol penetrates into breast milk. It is not known whether cilostazol is excreted in human breast milk. Due to possible adverse effects on the newborn, the use of cilostazol during breastfeeding is contraindicated.

Fertility

In experimental studies, it was found that cilostazol did not adversely affect the fertility of laboratory animals.

Contraindications

• Hypersensitivity to cilostazol or any other component of the drug;
• Severe renal insufficiency (creatinine clearance ≤25 ml / min);
• Moderate or severe liver failure;
• Chronic heart failure;
• Predisposition to bleeding (for example, acute gastric or duodenal ulcer, recent (within the last 6 months) hemorrhagic stroke, proliferative diabetic retinopathy, poorly controlled arterial hypertension);
• Ventricular tachycardia, ventricular fibrillation or polytopic ventricular extrasystole in the anamnesis (regardless of the presence or absence of adequate antiarrhythmic therapy);
• Extended QT interval on the ECG;
• A history of severe tachyarrhythmia.
• Unstable angina or myocardial infarction in the last 6 months;
• Invasive intervention on the coronary arteries during the last 6 months;
• Concomitant use of two or more antiplatelet or anticoagulant medications (for example, acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban);
• Concomitant use of potent CYP3A4 or CYP2C19 inhibitors (e. g., cimetidine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole, and HIV-1 protease inhibitors);
• Pregnancy;
• Breast-feeding period;
• Age below 18 years (safety and efficacy have not been studied).

With caution:

• Mild hepatic insufficiency;
• Chronic ischemic heart disease (in particular, stable angina pectoris);
• Atrial or ventricular extrasystole, fibrillation and atrial flutter;
• Diabetes mellitus;
• Simultaneous use of medications that reduce blood pressure;
• Simultaneous use of medications that reduce blood clotting;
• Concomitant use of CYP3A4 or CYP2C19 substrates (e. g. cisapride, midazolam, nifedipine, verapamil);
• Advanced age.

Side effects

In clinical trials, the most common adverse reactions were headache (30%), diarrhea (15%), and stool disorders (15%). These adverse reactions were usually mild to moderate in intensity, and sometimes their severity decreased with a decrease in the dose of the drug.

Other side effects reported in clinical trials and post-marketing use of cilostazol preparations are listed below.

Adverse reactions were classified by frequency as follows: Very frequent: ≥1/10, Frequent: ≥1/100 to

Adverse reactions observed with post-marketing use of cilostazol preparations are classified as side effects with an unknown frequency (the frequency cannot be determined based on available data).

Cilostazol has an increased risk of causing bleeding and this risk may increase when used simultaneously with other drugs with a similar effect.

The risk of intraocular bleeding may be higher in patients with diabetes mellitus.

An increase in the frequency of diarrhea and palpitations was observed in patients over 70 years of age.

Interaction

Platelet aggregation inhibitors

Cilostazol is a PDE-3 inhibitor with antithrombotic activity. Its use in healthy individuals at a dose of 150 mg for 5 days did not lead to prolonged bleeding time.

Acetylsalicylic Acid

Short-term (>4 days) concomitant use of cilostazol and acetylsalicylic acid resulted in a 23-25% increase in blocking of ADP-induced platelet aggregation in ex vivo compared to acetylsalicylic acid monotherapy.

There was no apparent trend of increased hemorrhagic side effects in patients treated with cilostazol and aspirin compared to patients treated with placebo and an equivalent dose of acetylsalicylic acid.

Clopidogrel and other antiplatelet drugs

In a study in healthy volunteers, concomitant use of cilostazol with clopidogrel had no effect on platelet count, prothrombin time (PV), and activated partial thromboplastin time (APTT).

When clopidogrel was used both as monotherapy and in combination with cilostazol, the bleeding time increased in healthy volunteers. Cilostazol use did not lead to an additional significant prolongation of the bleeding time.

However, caution is recommended when cilostazol is co-administered with any drug that inhibits platelet aggregation. It is recommended to monitor the bleeding time regularly.

Cilostazol is contraindicated in patients receiving two or more antiplatelet and/or anticoagulant medications at the same time.

Oral anticoagulants

In a clinical study, a single dose of cilostazol did not inhibit the metabolism of warfarin and did not affect blood clotting parameters (PV, APTT, bleeding time). However, caution is recommended when cilostazol is co-administered with any anticoagulant drug.

Cilostazol is contraindicated in patients receiving two or more antiplatelet and/or anticoagulant medications at the same time.

Inhibitors of cytochrome P-450 isoenzymes

In the liver, cilostazol is mainly metabolized by cytochrome P-450 enzymes, mainly CYP3A4 and CYP2C19 and, to a lesser extent, CYP1A2. It is believed that dehydrocylostazol, which is 4-7 times superior to cilostazol in its ability to inhibit platelet aggregation, is formed mainly with the participation of CYP3A4.4 ‘ – trans-hydroxycylostazol, which has a five-fold less pronounced ability to inhibit platelet aggregation, is formed mainly under the influence of CYP2C19.

Accordingly, drugs that inhibit CYP3A4 (for example, certain macrolides [erythromycin, clarithromycin], azole antifungal drugs [ketoconazole, itraconazole], protease inhibitors) and CYP2C19 (for example, proton pump inhibitors [omeprazole, esomeprazole]) increase the overall pharmacological activity of cilostazol and may contribute to the enhancement of its undesirable effects.

Accordingly, patients receiving potent CYP3A4 or CYP2C19 inhibitors should be prescribed cilostazol 50 mg twice daily.

When cilostazol is co-administered with erythromycin (a potent CYP3A4 inhibitor), the AUC values of cilostazol, dehydrocylostazol, and 4 – trans-hydroxycylostazol increase by 72%,6%, and 119%, respectively. Based on changes in AUC parameters, it was found that the total pharmacological activity of cilostazol when used simultaneously with erythromycin increases by 34%.

Based on these data, it is recommended to use cilostazol at a dose of 50 mg twice a day simultaneously with erythromycin or similar medications (for example, clarithromycin).

When cilostazol is co-administered with ketoconazole (a potent CYP3A4 inhibitor), the cilostazol AUC increases by 117%, the dehydrocylostazol AUC decreases by 15%, and the 4′-trans-hydroxycylostazol AUC increases by 87%.

Based on changes in the AUC values, it was found that the total pharmacological activity of cilostazol when co-administered with ketoconazole increases by 35%. Based on these data, it is recommended to use cilostazol at a dose of 50 mg twice a day when taken simultaneously with kenoconazole or similar medications (for example, itraconazole).

When cilostazol is co-administered with diltiazem (a weak CYP3A4 inhibitor), the AUC values of cilostazol, dehydrocylostazol, and 4′-trans-hydroxycylostazol increase by 44%,4%, and 43%, respectively.

Based on changes in AUC values, it was found that the total pharmacological activity of cilostazol when used simultaneously with diltiazem increases by 19%. No dose adjustment of cilostazol is required for concomitant use with diltiazem.

A single dose of 100 mg of cilostazol concomitantly with 240 ml of grapefruit juice (an intestinal CYP3A4 inhibitor) did not significantly change the pharmacokinetic parameters of cilostazol. No dose adjustment of cilostazol is required.

However, taking more grapefruit juice may have an effect on the pharmacokinetics of cilostazol.

When cilostazol is co-administered with omeprazole (a potent CYP2C19 inhibitor), the AUC values of cilostazol and dehydrocylostazol increase by 22% and 68%, respectively, while the AUC of 4′-trans-hydroxycylostazol decreases by 36%.

Based on changes in AUC parameters, it was found that the total pharmacological activity of cilostazol when used simultaneously with omeprazole increases by 47%. It is recommended to reduce the dose of cilostazol to 50 mg 2 times a day when used simultaneously with omeprazole.

Substrates of cytochrome P-450 isoenzymes

Cilostazol increases the AUC of lovastatin (a CYP3A4 substrate) and its beta-hydroxyl metabolite by 70%. Caution is recommended when using cilostozol concomitantly with CYP3A4 substrates that have a narrow therapeutic range (such as cisapride, halofantrine, pimozide, ergot alkaloids).

Caution is also recommended when using cilostozol concomitantly with HMG-CoA reductase inhibitors (statins) that metabolize CYP3A4 (simvastatin, atorvastatin and lovastatin).

Inducers of cytochrome P-450 isoenzymes

The effect of drugs that increase the activity of CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin, St. John’s wort) on the pharmacokinetics of cilastazole has not been studied. With simultaneous use, it is theoretically possible to reduce the antiplatelet effect of cilostazol, so it is necessary to regularly monitor the bleeding time.

In clinical studies, smoking (a factor that increases the activity of CYP1A2) reduces the concentration of cilostazol in blood plasma by 18%.

Other medicinal products

Caution should be exercised when combining cilostazol with antihypertensive drugs, as well as any other drugs that potentially reduce blood pressure (including nitrates and phosphodiesterase-5 inhibitors), since an additive hypotensive effect with the development of reflex tachycardia is possible.

An increase in heart rate and peripheral edema was observed with the simultaneous use of cilostazol and other vasodilating agents, such as dihydropyridine calcium channel blockers.

How to take, course of use and dosage

The recommended dose of cilostazol is 100 mg twice daily. Cilostazol should be taken 30 minutes before meals. When taking cilostazol during meals, an increase in Cmax in blood plasma is noted, which may be associated with an increase in the number of adverse events. Cilostazol therapy should be initiated under the supervision of a physician experienced in the treatment of intermittent claudication.

The doctor should re-evaluate the patient’s condition after 3 months of treatment. If cilostazol therapy does not have an adequate effect or there is no reduction in the severity of symptoms of intermittent claudication, cilostazol should be discontinued and other treatment options should be considered.

Patients receiving cilostazol treatment should continue to follow recommendations for lifestyle changes (smoking cessation, exercise) and drug therapy (taking lipid-lowering and antiplatelet medications) aimed at reducing the risk of cardiovascular complications.

Cilostazol is not a substitute for this treatment.

Skipping the next dose

If less than 6 hours have passed since you missed the next dose, then you should immediately take the missed dose of the drug, and then take the next dose at the usual time.

If more than 6 hours have passed since the next dose was missed, then the patient should take the next dose at the usual time (do not take a double dose).

Use of cilostazol in special patient groups

Advanced age

No dose adjustment of cilostazol a is required in elderly patients.

Children

The safety and efficacy of cilostazol in children under 18 years of age have not been studied.

Kidney failure

In patients with creatinine clearance >25 ml/min, no dose adjustment is required. Cilostazol is contraindicated in patients with creatinine clearance < 25 ml/min.

Liver failure

In patients with mild hepatic insufficiency, no dose adjustment is required. There are no data on the use of cilostazol in patients with moderate to severe hepatic insufficiency. Since cilostazol is largely metabolized by microsomal liver oxidation enzymes, the use of the drug is contraindicated in patients with moderate to severe hepatic insufficiency.

Concomitant use of potent CYP3A4 win and CYP2C19 inhibitors

In patients receiving drugs that have a strong blocking effect on CYP3A4 (for example, certain macrolides), or drugs that have a strong blocking effect on CYP2C19 (for example, omeprazole), the dose of cilostazol should be reduced to 50 mg twice daily.

Overdose

Information about acute overdose in humans is limited. Expected symptoms include severe headache, diarrhea, tachycardia, and possibly cardiac arrhythmias.

It is necessary to clear the stomach, causing vomiting, or perform gastric lavage in accordance with generally accepted recommendations.

Patients should be monitored and given supportive treatment.

Special instructions

Before starting cilostazol therapy, the possibility of prescribing other treatment options, such as surgical revascularization or conservative therapy, should be evaluated.

Due to the mechanism of pharmacological action, cilostazol may cause tachycardia, palpitations, tachyarrhythmia and / or hypotension. When taking cilostazol, the heart rate may increase by 5-7 beats per minute.

In patients at risk (for example, patients with stable angina), an increased heart rate can trigger an angina attack. It is necessary to carefully monitor the condition of such patients.

Caution should be exercised when prescribing cilostazol to patients with atrial or ventricular extrasystole, as well as patients with atrial fibrillation or atrial flutter.

Patients should be warned to report any case of bleeding or the appearance of a “bruise” (subcutaneous hematoma) with a small bruise. If a retinal hemorrhage develops, cilostazol should be discontinued.

Since cilostazol is an inhibitor of platelet aggregation, there is an increased risk of bleeding during surgical procedures (including minor invasive procedures such as tooth extraction). For planned surgical interventions (if the antiplatelet effect is undesirable), cilostazol should be discontinued 5 days before the operation.

Rare or very rare cases of hematological disorders have been reported, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, or aplastic anemia. In most cases, these disorders resolved after discontinuation of cilostazol. However, pancytopenia and aplastic anemia have been fatal in several cases.

The patient should be warned to immediately inform the doctor about any symptoms that may be early signs of hematological complications, such as high fever (pyrexia) and sore throat. A detailed blood test should be performed if an infection is suspected or if there are clinical symptoms of hematological complications.

You should immediately stop taking cilostazol in case of clinical symptoms or laboratory signs of hematological complications.

Caution should be exercised when using cilostazol concomitantly with medications that reduce blood pressure (the possibility of an additive hypotensive effect with the development of reflex tachycardia), as well as reduce blood clotting or inhibit platelet aggregation.

Effects on the ability to drive vehicles and mechanisms

Cilostazol may cause dizziness. It is recommended to use caution when driving vehicles or working with mechanisms during treatment.

Active ingredient

Cilostazol

Conditions of release from pharmacies

By prescription

Dosage form

Tablets