Krurovit

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CRUROVIT (CRUROVIT®)

Composition:

Active substance: cilostazol;

One tablet contains 50 mg or 100 mg of cilostazol;

Excipients: maize starch, hypromellose, microcrystalline cellulose, magnesium stearate, calcium carmellose.

Pharmaceutical form. Tablets.

Main physico-chemical properties:

50 mg tablets: white or almost white, round, flat tablets with a bevel, engraved with a stylized letter E on one side and number 601 on the other side of the tablet, odorless or nearly odorless;

100 mg tablets: white or almost white, round, flat tablets with a bevel, engraved with a stylized letter E and number 602 on one side of the tablet, odorless or nearly odorless.

Pharmacotherapeutic group. Platelet aggregation inhibitors, excluding heparin.

ATC code B01A C23.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Cilostazol is an inhibitor of platelet aggregation. The drug improves the ability to tolerate physical exertion, assessed by absolute walking distance in intermittent claudication (or maximum walking distance, MWD) and initial claudication distance (or pain-free walking distance, PFWD) in treadmill testing. Study results under various exercise loads demonstrated a significant absolute improvement of 42 meters in maximum walking distance (MWD) compared to placebo. This corresponds to a relative improvement of 100% over placebo. This effect was somewhat lower in patients with diabetes mellitus.

Cilostazol has a vasodilatory effect, confirmed by measurement of lower limb blood flow using strain-gauge plethysmography. Cilostazol also inhibits smooth muscle cell proliferation and inhibits the release reaction of platelet-derived growth factor and PF-4 from human platelets.

Studies have demonstrated that cilostazol causes reversible inhibition of platelet aggregation. Inhibition is effective against a range of aggregating agents (including arachidonic acid, collagen, ADP, and epinephrine). In patients, inhibition lasts up to 12 hours, and recovery of aggregation occurs within 48–96 hours after discontinuation of cilostazol, without rebound effect (hyperaggregation). An effect of cilostazol on circulating plasma lipids has also been established. The drug reduces triglyceride levels and increases HDL-cholesterol levels. Long-term use of the drug did not result in increased mortality among patients compared to placebo.

Pharmacokinetics.

Absorption. With regular administration of cilostazol at a dose of 100 mg twice daily in patients with peripheral vascular disease, steady-state levels are achieved within 4 days. The Cmax of cilostazol and its primary metabolites increases less than proportionally with dose escalation. However, the AUC of cilostazol and its metabolites increases approximately proportionally with dosage. The apparent elimination half-life of cilostazol is 10.5 hours. Two major metabolites exist—dehydrocilostazol and 4'-trans-hydroxycilostazol—with similar elimination half-lives. The dehydro metabolite has 4–7 times higher antithrombotic activity than the parent compound, while the 4'-trans-hydroxy metabolite has approximately 1/5 the activity of cilostazol. Plasma concentrations (measured by AUC) of dehydro- and 4'-trans-hydroxy metabolites are approximately 41% and 12% of cilostazol concentration, respectively.

Metabolism. Cilostazol is primarily eliminated via metabolism, with subsequent excretion of metabolites in urine. The primary cytochrome P450 isoenzymes involved in its metabolism are CYP3A4, to a lesser extent CYP2C19, and even less so CYP1A2.

Excretion. The main excretion route is via urine (74%), with residual amounts eliminated in feces. Small quantities of unchanged cilostazol are excreted in urine, and less than 2% of the dose is excreted as dehydrocilostazol. Approximately 30% of the initial dose is excreted in urine as the 4'-trans-hydroxy metabolite. The remainder is excreted as a sum of metabolites, none of which exceeds 5% of the total amount.

Distribution. Cilostazol is 95–98% protein-bound, primarily to albumin. The dehydro metabolite and 4'-trans-hydroxy metabolite are protein-bound by 97.4% and 66%, respectively.

There is no evidence that cilostazol induces hepatic microsomal enzymes. The pharmacokinetics of cilostazol and its metabolites were not significantly affected by age or gender in patients aged 50–80 years.

In individuals with severe renal impairment, the free fraction of cilostazol was 27% higher, while Cmax and AUC were 29% and 39% lower, respectively, compared to individuals with normal renal function. Cmax and AUC of the dehydro metabolite were 41% and 47% lower, respectively, in patients with severe renal impairment compared to those with normal renal function. Cmax and AUC of 4'-trans-hydroxycilostazol were 173% and 209% higher in individuals with severe renal impairment. There are no data available for patients with moderate or severe hepatic impairment.

Clinical characteristics.

Indications.

To increase the maximum pain-free walking distance in patients with intermittent claudication who do not have rest pain or signs of peripheral tissue necrosis (peripheral arterial disease, Fontaine stage II).

Contraindications.

• Hypersensitivity to cilostazol or any component of the medicinal product.
• Severe renal impairment (creatinine clearance ≤ 25 mL/min).
• Moderate or severe hepatic impairment.
• Congestive heart failure.
• Pregnancy.
• Any predisposition to bleeding (e.g., active gastric or duodenal ulcer, recent hemorrhagic stroke (within 6 months), proliferative diabetic retinopathy, poorly controlled arterial hypertension).
• Ventricular tachycardia, ventricular fibrillation, or multifocal ventricular ectopy; QT interval prolongation.
• Severe tachyarrhythmia.
• Unstable angina, myocardial infarction within the past 6 months, or coronary intervention within the past 6 months.
• Concomitant treatment with two or more antiplatelet or anticoagulant agents (e.g., acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban, or apixaban).

Special precautions.

Patients should be advised to consult a physician if bleeding or bruising occurs during therapy. If ocular bleeding occurs, cilostazol should be discontinued.

Since cilostazol inhibits platelet aggregation, the risk of bleeding is increased during surgical procedures (including minor procedures such as tooth extraction). If a surgical procedure is required and antiplatelet effect is undesirable, cilostazol should be discontinued 5 days prior to surgery.

Isolated reports of hematological abnormalities, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, and aplastic anemia, have been reported. Most patients recovered after discontinuation of cilostazol. However, several cases of pancytopenia and aplastic anemia were fatal.

Patients should be advised to promptly report any symptoms suggestive of early development of blood disorders, such as hyperthermia and sore throat. A complete blood count should be performed if infection is suspected or if any other clinical signs of blood disorders are present. Cilostazol should be discontinued if clinical or laboratory evidence of blood disorders is detected.

Caution is required when co-administering cilostazol with inhibitors or inducers of CYP3A4, CYP2C19, or substrates of CYP3A4.

Cilostazol should be used with caution in patients with atrial or ventricular ectopy, atrial fibrillation, or atrial flutter.

Caution is required when co-administering cilostazol with any agents that may lower blood pressure, as there is a risk of additive hypotensive effect with reflex tachycardia.

Caution should be exercised when prescribing cilostazol with any other antithrombotic agents.

The stroke-preventing effect of this drug has not been studied in asymptomatic ischemic stroke.

Interaction with other medicinal products and other forms of interaction.

Antithrombotic agents

Cilostazol is a phosphodiesterase III inhibitor with antiplatelet activity. Administration to healthy volunteers at a dose of 150 mg for 5 days did not prolong bleeding time.

Acetylsalicylic acid (ASA)

Short-term co-administration (≤ 4 days) with ASA was associated with a 23–25% greater inhibition of ADP-induced platelet aggregation compared to ASA alone. No clear trends toward increased incidence of hemorrhagic adverse effects were observed in patients receiving aspirin and cilostazol compared to those receiving placebo and equivalent doses of ASA.

Clopidogrel and other antiplatelet agents

Concomitant administration of cilostazol and clopidogrel did not affect platelet count, prothrombin time (PT), or activated partial thromboplastin time (aPTT). All healthy study participants had prolonged bleeding time when receiving clopidogrel as monotherapy and in combination with cilostazol, but no significant cumulative effect on bleeding time was observed. However, caution should be exercised when combining cilostazol with any antithrombotic agents. Periodic monitoring of bleeding time should be considered. Particular attention is required for patients receiving multi-component antithrombotic therapy.

Oral anticoagulants (e.g., warfarin)

After single-dose administration, no inhibition of warfarin metabolism or effect on coagulation parameters (PT, aPTT, bleeding time) was observed. However, caution is recommended for patients taking cilostazol with any anticoagulant, and periodic monitoring should be performed to minimize the risk 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 dehydro metabolite, which has antiplatelet activity 4–7 times higher than cilostazol, is likely formed primarily by CYP3A4. The 4'-trans-hydroxy metabolite, with activity equal to 1/5 that of cilostazol, is likely formed via CYP2C19. Therefore, agents that inhibit CYP3A4 (e.g., certain macrolides, azole antifungals, protease inhibitors) or CYP2C19 (e.g., proton pump inhibitors) increase overall pharmacological activity by 32% and 42%, respectively, and may increase cilostazol's adverse effects. Dose reduction of cilostazol to 50 mg twice daily may be necessary depending on individual efficacy and tolerability.

Administration of 100 mg cilostazol on day 7 of erythromycin (moderate CYP3A4 inhibitor) 500 mg three times daily resulted in a 74% increase in cilostazol AUC, accompanied by a 24% decrease in AUC of its dehydro metabolite, but a notable increase in AUC of the 4'-trans-hydroxy metabolite.

Concomitant administration of single doses of ketoconazole (strong CYP3A4 inhibitor) 400 mg and cilostazol 100 mg resulted in a 117% increase in cilostazol AUC, accompanied by a 15% decrease in AUC of the dehydro metabolite and an 87% increase in AUC of the 4'-trans-hydroxy metabolite, resulting in an overall 32% increase in total pharmacological activity compared to cilostazol monotherapy.

Administration of 100 mg cilostazol twice daily with diltiazem (CYP3A4 inhibitor) 180 mg once daily resulted in a 44% increase in cilostazol AUC. Concomitant administration did not affect exposure to the dehydro metabolite but increased AUC of the 4'-trans-hydroxy metabolite by 40%. In patients, co-administration with diltiazem led to a 53% increase in cilostazol AUC.

Single administration of 100 mg cilostazol with 240 mL of grapefruit juice (intestinal CYP3A4 inhibitor) showed no significant effect on cilostazol pharmacokinetics.

Single administration of 100 mg cilostazol on day 7 of omeprazole (CYP2C19 inhibitor) 40 mg once daily increased cilostazol AUC by 26%, accompanied by a 69% increase in AUC of the dehydro metabolite and a 31% decrease in AUC of the 4'-trans-hydroxy metabolite, resulting in an overall 42% increase in total pharmacological activity compared to cilostazol monotherapy.

Cytochrome P450 enzyme substrates

An increase in AUC of lovastatin (a sensitive CYP3A4 substrate) and its β-hydroxy acid by up to 70% has been observed with cilostazol. Caution should be exercised when co-administering cilostazol with CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivatives). Caution is required when co-administering with simvastatin.

Inducers of cytochrome P450 enzymes

The effect of inducers of CYP3A4 and CYP2C19 (e.g., carbamazepine, phenytoin, rifampicin, St. John's wort) on cilostazol pharmacokinetics has not been studied. Theoretically, antithrombotic effect may be altered; therefore, monitoring is required when cilostazol is used with P450 inducers.

During studies, cigarette smoking (which induces CYP1A2) reduced plasma concentration of cilostazol by 18%.

Use in specific populations.

Use during pregnancy or breastfeeding.

Pregnancy. There are no confirmed data on the use of cilostazol in pregnant women. Animal studies have shown reproductive toxicity. The potential risk is unknown. Cilostazol should not be used during pregnancy.

Breastfeeding. Animal studies have shown that cilostazol may pass into breast milk. There are no adequate data on the excretion of cilostazol in human breast milk. Given the potential for adverse effects on the infant, use of this medicinal product during breastfeeding is not recommended. If treatment is necessary, breastfeeding should be discontinued.

Fertility

Cilostazol reversibly impaired fertility in female mice, but not in other animal species. The clinical significance is unknown.

Ability to influence reaction rate when driving or operating machinery.

Caution should be exercised, as dizziness may occur during use of the medicinal product.

Method of Administration and Dosage.

Dosing.

The recommended dose of the medicinal product is 100 mg twice daily. Tablets should be taken 30 minutes before or 2 hours after a meal, in the morning and evening.

Administration of the drug during meals may increase its maximum plasma concentrations (Cmax), thereby increasing the risk of adverse reactions. If no therapeutic effect is observed within 3 months, the physician should consider alternative therapy.

Dose reduction to 50 mg twice daily is recommended for patients receiving drugs that are strong inhibitors of CYP3A4, for example, certain macrolides, azole antifungals, protease inhibitors, or drugs that are strong inhibitors of CYP2C19, such as omeprazole (see section "Interaction with other medicinal products and other forms of interactions").

Elderly patients.

No dose adjustment is necessary for this patient population.

Patients with renal impairment.

No special dose 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.

The dose does not need to be adjusted in patients with mild liver disease. There are no data available for patients with moderate or severe hepatic impairment. Since cilostazol is extensively metabolized by liver enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.

Children.

The medicinal product is not recommended for use in children due to lack of data on safety and efficacy.

Overdose.

Information on acute overdose is limited. Possible symptoms include severe headache, diarrhea, tachycardia, and cardiac arrhythmias. Patients should be monitored and supportive therapy should be administered. Gastric emptying should be performed by inducing emesis or gastric lavage.

Adverse Reactions

The most commonly observed adverse reactions in clinical trials with the drug were headache (> 30%), diarrhea (> 15%), and gastrointestinal disturbances (> 15%). These reactions were generally mild to moderate in severity and sometimes improved with dose reduction.

Undesirable effects that may occur during cilostazol administration are listed in the table below.

Frequency of adverse reactions:

very common (≥ 1/10);

common (≥ 1/100, < 1/10);

uncommon (≥ 1/1000, < 1/100);

rare (≥ 1/10000, < 1/1000);

very rare (< 1/10000);

not known (available data are insufficient to estimate the frequency).

Adverse reactions observed during the post-marketing period are considered as not known (available data are insufficient to estimate the frequency of adverse reactions).

An increased number of cases of palpitations and peripheral edema were observed when cilostazol was used concomitantly with other vasodilators that may cause reflex tachycardia, such as dihydropyridine calcium channel blockers.

Headache was the only adverse effect leading to discontinuation of treatment in ≥3% of patients receiving cilostazol. Other common reasons for discontinuation included palpitations and diarrhea (occurring at a frequency of 1.1%).

Cilostazol use may be associated with an increased risk of bleeding, and this risk may be increased when the drug is taken concomitantly with any other agent having a similar effect.

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

An increased frequency of diarrhea and palpitations was observed in patients aged 70 years and older.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua».

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging. 14 tablets in a blister; 2 or 4 blisters in a cardboard package.

Prescription category. Prescription only.

Manufacturer. EGIS Pharmaceuticals PLC, Hungary.

Manufacturer's address and location of operations.

1165 Budapest, Bekény utca 118-120, Hungary.