Instructions for use Plestazol tablets 50 mg blister No. 60
Composition
active ingredient: cilostazol;
1 tablet contains cilostazol 50 mg or 100 mg;
Excipients: corn starch, hypromellose, microcrystalline cellulose, magnesium stearate, carmellose calcium.
Dosage form
Pills.
Main physicochemical properties:
50 mg tablets: flat-cylindrical tablets with a bevel, white or almost white in color;
100 mg tablets: flat-cylindrical tablets with a bevel and a score, white or almost white in color.
Pharmacotherapeutic group
Antithrombotic agents. Antiplatelet agents.
ATX code B01A C23.
Pharmacological properties
Pharmacodynamics.
Cilostazol is an inhibitor of platelet aggregation. The drug improves exercise capacity, as assessed by absolute distance with intermittent claudication (or maximum walking distance (MWD)) and initial distance with intermittent claudication (or pain-free walking distance (PFWD)) in a treadmill test. Studies at various loads showed a significant absolute improvement of 42 meters in maximum walking distance (MWD) compared with placebo. This corresponds to a relative improvement of 100% over placebo. This effect was somewhat lower in patients with diabetes.
Cilostazol has a vasodilatory effect, which was confirmed by measuring lower limb blood flow using strain gauge plethysmography. Cilostazol also inhibits smooth muscle cell proliferation and inhibits the platelet-derived growth factor and PF-4 release response in human platelets.
Studies have shown that cilostazol causes reversible inhibition of platelet aggregation. Inhibition is effective against a number of aggregators (including arachidonic acid, collagen, ADP and adrenaline), inhibition lasts up to 12 hours in patients, and after stopping cilostazol, aggregation recovery occurred within 48-96 hours, without a rebound effect (hyperaggregation). The effect of cilostazol on lipids circulating in blood plasma has also been established. Taking the drug reduces triglyceride levels and increases HDL cholesterol levels. Long-term use of the drug did not cause an increase in mortality among patients compared with placebo.
Pharmacokinetics.
With regular administration of cilostazol at a dose of 100 mg twice daily in patients with peripheral vascular disease, steady state is achieved within 4 days. Cmax of cilostazol and its primary metabolites increases less proportionally with increasing dose. However, AUC of cilostazol and its metabolites increases approximately proportionally with dosage. The apparent half-life of cilostazol is 10.5 hours. There are two main metabolites - dehydrocilostazol and 4'-trans-hydroxycilostazol, which have similar half-lives. The dehydrometabolite has 4-7 times higher antithrombotic activity than the parent substance, and the 4'-trans-hydroxymetabolite has 1/5 the activity of cilostazol. Plasma concentrations (derived from AUC) of the dehydro- and 4'-trans-hydroxy metabolites are approximately 41% and 12% of the cilostazol concentration, respectively.
Cilostazol is eliminated primarily by metabolism and subsequent urinary excretion of its metabolites. The primary cytochrome P450 isoenzymes involved in its metabolism are CYP3A4, to a lesser extent CYP2C19 and to a lesser extent CYP1A2. The major route of elimination is via the urine (74%), with residual amounts excreted in the feces. Minor amounts of unchanged cilostazol are excreted in the urine, and less than 2% of the dose is excreted as dehydrocilostazol. Approximately 30% of the initial dose is excreted in the urine as the 4'-trans-hydroxymetabolite. The remainder is excreted as the sum of metabolites, none of which accounts for more than 5% of the total.
Cilostazol is 95-98% protein bound, primarily to albumin. The dehydrometabolite and 4'-trans-hydroxymetabolite are 97.4% and 66% protein bound, respectively.
There is no evidence of the ability of cilostazol to induce liver microsomal enzymes. The pharmacokinetics of cilostazol and its metabolites did not depend significantly on age or gender in patients 50-80 years of age.
In subjects with severe renal impairment, the free fraction of cilostazol was 27% higher and Cmax and AUC were 29% and 39% lower, respectively, than in subjects with normal renal function. Cmax and AUC of the dehydrometabolite were 41% and 47% lower, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Cmax and AUC of 4'-trans-hydroxycilostazol were 173% and 209% higher in subjects with severe renal impairment. No data are available in subjects with moderate and severe hepatic impairment.
Indication
To increase the maximum pain-free walking distance in patients with intermittent claudication who do not have pain at rest and signs of peripheral tissue necrosis (peripheral arterial disease, Fontaine stage II).
Use as second-line therapy for patients in whom lifestyle changes (including smoking cessation and supervised exercise programs) and other appropriate interventions have not resulted in significant improvement in the symptoms of intermittent claudication.
Contraindication
Known hypersensitivity to cilostazol or any component of the drug, severe renal insufficiency (creatinine clearance ≤ 25 ml/min), moderate or severe hepatic insufficiency, congestive heart failure, pregnancy, any known bleeding tendency (e.g., gastric or duodenal ulcer in the acute stage, recent hemorrhagic stroke (up to 6 months), proliferative diabetic retinopathy, poorly controlled hypertension). Contraindicated in patients with ventricular tachycardia, ventricular fibrillation, or multilocular ventricular ectopy, whether or not receiving appropriate therapy; patients with QT prolongation; severe tachyarrhythmia; unstable angina, myocardial infarction within the last 6 months, or coronary intervention within the last 6 months; Concomitant treatment with two or more additional antiplatelet agents or anticoagulants (e.g. acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban).
Interaction with other medicinal products and other types of interactions
Antithrombotic agents. Cilostazol is a phosphodiesterase III inhibitor with antiplatelet activity. Its use in healthy subjects at a dosage of 150 mg for 5 days did not lead to a prolongation of bleeding time.
Acetylsalicylic acid (ASA). Concomitant use with ASA for short periods (up to 4 days) was associated with a 23-25% increase in inhibition of ADP-induced platelet aggregation compared with ASA alone. There was no apparent trend towards an increased rate of haemorrhagic adverse events in patients receiving aspirin and cilostazol compared with patients receiving placebo and equivalent doses of ASA.
Clopidogrel and other antiplatelet agents. Concomitant administration of cilostazol and clopidogrel had no effect on platelet count, prothrombin time (PT) or activated partial thromboplastin time (APTT). All healthy subjects in the studies had prolonged bleeding times when clopidogrel was administered alone or in combination with cilostazol, without a significant overall effect on bleeding time. However, caution should be exercised when cilostazol is administered in combination with any antiplatelet agent. Periodic monitoring of bleeding time should be considered. Particular attention should be paid to patients receiving multiple antiplatelet agents.
Oral anticoagulants (e.g. warfarin). No inhibition of warfarin metabolism or effects on coagulation parameters (PCT, APTT, bleeding time) have been observed with a single dose. However, caution is recommended in patients taking cilostazol with any anticoagulant and periodic monitoring is recommended to minimize the possibility of bleeding.
Cytochrome P450 (CYP) inhibitors. Cilostazol is extensively metabolized by CYP enzymes, particularly CYP3A4 and CYP2C19, and to a lesser extent by CYP1A2. The dehydrometabolite, which has 4-7 times the antiplatelet activity of cilostazol, is likely to be formed primarily by CYP3A4. The 4'-trans-hydroxymetabolite, which has 1/5 the activity of cilostazol, is likely to be formed by CYP2C19. Thus, agents that inhibit CYP3A4 (e.g., some macrolides, azole antifungals, protease inhibitors) or CYP2C19 (e.g., proton pump inhibitors) increase the overall pharmacological activity by 32% and 42%, respectively, and may increase the side effects of cilostazol. It may be necessary to reduce the dose of cilostazol to 50 mg twice daily depending on individual efficacy and tolerability.
Taking 100 mg of cilostazol on the 7th day of erythromycin (a moderate CYP3A4 inhibitor) 500 mg 3 times a day resulted in an increase in cilostazol AUC by 74%, which was accompanied by a 24% decrease in the AUC of its dehydrometabolite, but with a significant increase in the AUC of the 4'-trans-hydroxymetabolite.
Coadministration of single doses of ketoconazole (a strong CYP3A4 inhibitor) 400 mg and cilostazol 100 mg resulted in a 117% increase in cilostazol AUC, accompanied by a 15% decrease in the AUC of the dehydrometabolite and an 87% increase in the AUC of the 4'-trans-hydroxymetabolite, resulting in a 32% increase in overall pharmacological activity compared to cilostazol monotherapy.
Coadministration of cilostazol 100 mg twice daily with diltiazem (a CYP3A4 inhibitor) 180 mg once daily resulted in a 44% increase in cilostazol AUC. Coadministration had no effect on the exposure of the dehydrometabolite but increased the AUC of the 4'-trans-hydroxymetabolite by 40%. In patients, coadministration with diltiazem resulted in a 53% increase in cilostazol AUC.
Administration of a single dose of 100 mg cilostazol with 240 ml of grapefruit juice (an inhibitor of intestinal CYP3A4) had no noticeable effect on the pharmacokinetics of cilostazol.
Cytochrome P450 enzyme substrates. Cilostazol has been shown to increase the AUC of lovastatin (a sensitive CYP3A4 substrate) and its β-hydroxyacid by up to 70%. Caution should be exercised when cilostazol is co-administered with CYP3A4 substrates with a narrow therapeutic index (e.g. cisapride, halofantrine, pimozide, ergot derivatives). Caution is required when co-administered with simvastatin.
Cytochrome P450 enzyme inducers. The effect of CYP3A4 and CYP2C19 inducers (such as carbamazepine, phenytoin, rifampicin and St. John's wort) on the pharmacokinetics of cilostazol has not been studied. Theoretically, the antithrombotic effect may be altered, therefore monitoring is necessary when cilostazol is used with P450 inducers.
In studies, smoking (which induces CYP1A2) reduced the plasma concentration of cilostazol by 18%.
Application features
Patients should be advised to seek medical advice if bleeding or bruising occurs during therapy. Cilostazol should be discontinued if ocular bleeding occurs.
Since the drug is able to inhibit platelet aggregation, the risk of bleeding during surgical interventions (including minor interventions, such as tooth extraction) increases. If the patient needs to undergo surgery and the antiaggregatory effect is undesirable, cilostazol should be discontinued 5 days before surgery.
There have been isolated reports of hematological abnormalities, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, and aplastic anemia. Most patients recovered after discontinuation of cilostazol. However, a few cases of pancytopenia and aplastic anemia were fatal.
Patients should be advised to report promptly any signs that may indicate the early development of blood abnormalities, such as fever and sore throat. A complete blood count should be performed if infection is suspected or any other clinical signs of blood abnormalities are present. Cilostazol should be discontinued if clinical or laboratory evidence of blood abnormalities is present.
Caution is required when cilostazol is co-administered with inhibitors or inducers of CYP 3A4, CYP 2C19, or CYP 3A4 substrates.
The drug should be prescribed with caution to patients with atrial or ventricular ectopy, atrial fibrillation or flutter.
Caution is required when co-administering cilostazol with any other agents that may lower blood pressure, as there is a risk of additive hypotensive effects with reflex tachycardia.
Caution should be exercised when prescribing cilostazol with any other antithrombotic agents.
The stroke-inhibiting effect of this drug has not been studied in asymptomatic ischemic stroke.
Use during pregnancy or breastfeeding
There are no confirmed data on the use of cilostazol in pregnant women, the potential risk is unknown. The drug should not be used in pregnant women.
Cilostazol may pass into breast milk, but there are no precise data. Given the possible negative effects on newborns, the use of the drug during breastfeeding is not recommended.
Ability to influence reaction speed when driving vehicles or other mechanisms
Caution should be exercised, as dizziness is possible when taking the medication.
Method of administration and doses
The recommended dose of the drug is 100 mg 2 times a day. Take the tablets 30 minutes before meals or 2 hours after meals in the morning and evening.
Taking the drug with food may increase its maximum plasma concentrations, which increases the risk of adverse reactions. Significant improvement in the patient's condition is observed after taking the drug for 16-24 weeks, sometimes improvement was noted after 4-12 weeks of treatment. If treatment has not been effective within 6 months, the doctor should prescribe another therapy.
A dose reduction to 50 mg twice daily is recommended for patients receiving drugs that strongly inhibit CYP3A4, such as some macrolides, azole fungicides, protease inhibitors, or drugs that strongly inhibit CYP2C19, such as omeprazole (see section 4.5).
Patients with renal insufficiency. No specific dosage adjustment is required for patients with creatinine clearance > 25 ml/min. Cilostazol is contraindicated in patients with creatinine clearance ≤ 25 ml/min.
Patients with hepatic impairment. No specific dosage adjustment is required for patients with mild hepatic disease. There are no data available for patients with moderate or severe hepatic impairment. Since cilostazol is extensively metabolized by hepatic enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.
Elderly patients: No dose adjustment is necessary for this category of patients.
Children
The drug is not recommended for use in children due to the lack of data on safety and efficacy.
Overdose
Information on acute overdose is limited. Severe headache, diarrhea, tachycardia, and cardiac arrhythmias may occur. Patients should be monitored and given supportive therapy. Gastric emptying should be attempted by inducing emesis or lavage.
Side effects
When using cilostazol, unwanted effects may sometimes occur, as listed below.
From the side of the circulatory and lymphatic system: bruising; anemia; prolonged bleeding time, thrombocytosis; rare - bleeding tendency, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia.
On the part of the immune system: allergic reactions.
Digestive and metabolic disorders: edema (peripheral or facial edema); hyperglycemia, diabetes mellitus; anorexia.
From the mental system: anxiety.
Nervous system: headache; dizziness; insomnia, unusual dreams; paresis, hypoesthesia.
From the organs of vision: conjunctivitis.
On the part of the auditory system: tinnitus.
Cardiovascular system: palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles; myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, loss of consciousness, ocular hemorrhages, epistaxis, gastrointestinal hemorrhages, unspecified bleeding, orthostatic hypotension; hot flashes, hypertension, hypotension, cerebral hemorrhages, pulmonary hemorrhages, muscle hemorrhages, hemorrhages in the respiratory tract, subcutaneous hemorrhages.
Respiratory tract: rhinitis, pharyngitis; dyspnea, pneumonia, cough; interstitial pneumonia.
Gastrointestinal: diarrhea, bowel movements; nausea, vomiting, dyspepsia, flatulence, abdominal pain; gastritis.
From the hepatobiliary system: hepatitis, liver dysfunction, jaundice.
Skin and subcutaneous tissue disorders: rash, itching; eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Musculoskeletal and connective tissue disorders: myalgia.
Renal and urinary disorders: renal failure, renal dysfunction; hematuria, pollakiuria.
General disorders: chest pain, asthenia; chills, hyperthermia, malaise, pain.
Laboratory tests: increased levels of uric acid, blood urea, creatinine.
An increased incidence of palpitations and peripheral edema has been observed when cilostazol is used concomitantly with other vasodilators that may cause reflex tachycardia, such as dihydropyridine calcium channel blockers.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 or 6 blisters in a pack.
Leave category. By prescription.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Address
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua.
