Aducil, tablets 100 mg 60 pcs

Antiplatelet agent.

Pharmacokinetics

Absorption

In patients with peripheral arterial occlusive disease, with regular administration of cilostazol at a dose of 100 mg twice daily, the equilibrium concentration of the drug in blood is reached after 4 days.

The maximum concentration (Cmax) of cilostazolum and its major metabolites increases less than proportionally with increasing dose. At the same time, the value of the area under the curve “concentration-time” (AUC) of cilostazol and its main metabolites increases approximately in proportion to increasing the dose.

Distribution and metabolism

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

Cylostasol is excreted from the body mainly by the kidneys (74%), the remaining drug is excreted through the intestine. In the urine unchanged cilostazolol is practically not determined. Less than 2% of the administered dose is excreted by the kidneys in the form of dehydrocylostazole. Approximately 30% of the administered dose is excreted by the kidneys in the form of 4′-trans-hydroxycylostazole.

The remaining drug is excreted as a variety of metabolites, each of which is no more than 5% of the dose taken.

The elimination half-life of cilostazolol is 10, 5 hours. The two main metabolites, dehydrocylostazole and 4′-trans-hydroxycylostazole, have similar half-lives.

Particular patient groups

In studies involving healthy volunteers aged 50-80 years it was found that age and gender had no significant effect on the pharmacokinetics of cilostazol.

Renal impairment

Patients with severe renal impairment were found to have a 27% higher free fraction of cilostazol, and Cmax and AUC values of unchanged cilostazol were 29% and 39% lower respectively than those with normal renal function.

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

The Cmax and AUC of 4′-trans-hydroxycylostazol (the main renal excreted metabolite) are increased by 173% and 209% respectively in patients with severe renal impairment compared to patients without renal impairment. The use of cilostazolum is contraindicated in patients with severe renal impairment (creatinine clearance ≤25 ml/min).

Hepatic impairment

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

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

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

In experimental and small clinical studies it was found that cilostazol has a vasodilatory effect. Cilostazol inhibits proliferation of human and rat smooth muscle cells under in vitro conditions.

In experimental and clinical studies under in vivo and ex vivo conditions it was found that cilostazol increases the content of cAMP in platelets and causes a reversible anti-aggregant effect. In addition, cilostazol blocks the release of platelet growth factor and platelet factor 4 (PF-4) by human platelets.

Additional potentially beneficial effects of cilostazol found in experimental and clinical studies were decreased serum triglyceride concentrations and increased high-density lipoprotein (HDL) cholesterol concentrations.

In a clinical study, taking cilostazol at a dose of 100 mg twice daily for 12 weeks compared to placebo reduced blood triglycerides by an average of 0.33 mmol/L (15%) and increased HDL cholesterol 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.

The efficacy of cilostazolum in patients with intermittent claudication has been confirmed in 9 placebo-controlled clinical trials.

The therapy with cilostazolum at a dose of 100 mg twice daily for 24 weeks was found to approximately double maximal walking distance (from 60.4 m to 129.1 m; the average absolute increase in maximal walking distance is 42 m) and the distance walked before pain appeared (from 47.3 m to 93.6 m).

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

Indications

Cilostazol is used to increase maximal and pain-free distance in patients with intermittent claudication who have no resting pain and no signs of peripheral tissue necrosis (grade II chronic lower extremity ischemia according to the Fontaine classification).

Cilostazol is indicated for use as second-line therapy in patients with intermittent claudication for whom lifestyle changes (including smoking cessation and [supervised] physical rehabilitation programs) and other appropriate interventions have been insufficient to reduce the symptoms of intermittent claudication.

Active ingredient

Composition

Tablets – 1 tablet:

How to take, the dosage

The recommended dose of cilostazolum is 100 mg twice daily. Cilostazolol should be taken 30 minutes before meals. When taking cilostazolum with meals, an increase in plasma Cmax is noted, which may be associated with an increase in the number of adverse events. Therapy with cilostazolol should be started under the supervision of a physician experienced in the treatment of intermittent claudication.

The physician should reassess the patient after 3 months of treatment. If cilostazol therapy is not working adequately or there is no reduction in symptoms of claudication, cilostazol should be discontinued and other treatment options should be considered.

Patients on cilostazolol treatment should continue to follow lifestyle recommendations (smoking cessation, exercise) and medication therapy (taking hypolipidemic and antiplatelet medications) to reduce the risk of cardiovascular complications.

Cilostazol is not a substitute for this treatment.

If less than 6 hours have passed since the next dose was missed, the missed dose must be taken immediately, and then the next doses must be taken at the usual time.

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

The use of cilostazolum in special patient groups

Elderly age

There is no need to adjust the dose of cilostazolum in elderly patients.

Children

The safety and effectiveness of cilostazolum in children under 18 years of age have not been studied.

Renal failure

In patients with a creatinine clearance of >25 ml/min, no change in dose is required. Cilostazolol is contraindicated in patients with creatinine clearance ≤25 ml/min.

Hepatic failure

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

Concomitant use of potent CYP3A4 inhibitors win CYP2C19

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

Interaction

Platelet aggregation inhibitors

Cilostazol is an FDE-3 inhibitor with antithrombotic activity. Its use in healthy subjects at a dose of 150 mg for 5 days did not result in prolongation of bleeding time.

Acetylsalicylic acid

Short-term (for ≥4 days) concomitant use of cilostazol and acetylsalicylic acid leads to an increase of 23-25% blocking of ADP-induced platelet aggregation in ex vivo compared with acetylsalicylic acid monotherapy.

There was no apparent trend for increased hemorrhagic adverse events in patients receiving cilostazol and aspirin compared to patients receiving placebo and equivalent dose of acetylsalicylic acid.

Clopidogrel and other antiaggregant drugs

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

The use of clopidogrel both as monotherapy and in combination with cilostazol increased bleeding time in healthy volunteers. Administration of cilostazol did not result in an additional significant prolongation of bleeding time.

Special Instructions

Before initiating cilostazolol 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, cilostazolum may cause tachycardia, palpitations, tachyarrhythmias and/or arterial hypotension. When taking cilostazolol the heart rate may increase by 5-7 beats per minute.

In patients in the risk group (e.g., in patients with stable angina pectoris) the increased heart rate may provoke an attack of angina pectoris. These patients should be monitored closely.

Patients with atrial or ventricular extrasystoles, as well as patients with atrial fibrillation or atrial flutter should be cautioned when prescribing cilostazol.

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

Because cilostazolol is an inhibitor of platelet aggregation, there is an increased risk of bleeding during surgical interventions (including small invasive procedures such as tooth extraction). For planned surgical interventions (if antiaggregant effect is undesirable), cilostazol should be discontinued 5 days before surgery.

Rare or very rare cases of hematologic disorders have been reported, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, or aplastic anemia. In most cases, these abnormalities went away after discontinuation of cilostazol. However, in a few cases pancytopenia and aplastic anemia were fatal.

The patient should be warned to immediately inform the physician of any symptoms that may be early manifestations of hematologic complications, such as high fever (pyrexia) and sore throat. A complete blood count should be done if infection is suspected or if clinical symptoms of hematologic complications appear.

Cylostazol should be discontinued immediately if clinical symptoms or laboratory signs of hematologic complications appear.

Caution should be exercised when concomitant use of cilostazolum with drugs that lower blood pressure (possibility of additive hypotensive effect with development of reflex tachycardia) and those that reduce blood clotting or inhibit platelet aggregation.

Impact on the ability to drive vehicles and mechanisms

Cilostazol may cause dizziness. Caution is recommended when driving or operating machinery during treatment.

Contraindications

With caution:

Side effects

In clinical trials, the most common adverse reactions were headache (30%), diarrhea (15%), and stool disturbances (15%). These adverse reactions were generally mild to moderate in intensity, and sometimes decreased in severity when the drug dose was reduced.

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

The adverse reactions by frequency of occurrence have been classified as follows: Very frequent: ≥1/10, Frequent: ≥1/100 to

The adverse reactions observed with postmarketing use of cilostazol preparations are classified as adverse effects of unknown frequency (frequency cannot be determined from available data).

Cilostazol has an increased risk of causing bleeding and this risk may be increased when used concomitantly with other drugs with similar effects.

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

An increased incidence of diarrhea and palpitations has been noted in patients over 70 years of age.

Overdose

There is limited information on acute overdose in humans. The expected symptoms are severe headache, diarrhea, tachycardia, and possibly cardiac arrhythmias.

The stomach should be cleared by inducing vomiting or gastric lavage should be performed according to generally accepted recommendations.

Patient monitoring and supportive treatment is necessary.

Pregnancy use

Pregnancy

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

In experimental studies on animals it was found that cilostazolum has reproductive toxicity.

The use of cilostazolum during pregnancy is contraindicated.

Breastfeeding period

In experimental animal studies it was found that cilostazol penetrates into breast milk. It is not known whether cilostazol penetrates into human breast milk. Because of possible adverse effects on the newborn, the use of cilostazolum during breastfeeding is contraindicated.

Fertility

In experimental studies it was found that cilostazolum had no adverse effect on the fertility of laboratory animals.

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