Claudex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLAUDIEX (CLAUDIEX)

Composition:

Active ingredient: cilostazol;

1 tablet contains 100 mg of cilostazol;

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round-shaped tablets with a score line on one side. Diameter approximately 8 mm. The tablet can be divided into two equal doses.

Pharmacotherapeutic group. Antithrombotic agents. Antiaggregants.

ATC code B01A C23.

Pharmacological Properties.

Pharmacodynamics.

Cilostazol is an inhibitor of platelet aggregation. The drug improves the ability to tolerate physical exertion, assessed by the absolute distance in intermittent claudication (or maximum walking distance (MWD)) and initial claudication distance (or pain-free walking distance (PFWD)) in treadmill testing. According to study results under various loads, a significant absolute improvement of 42 meters in maximum walking distance (MWD) was established compared to placebo, corresponding 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 in human platelets.

Studies have demonstrated that cilostazol causes reversible inhibition of platelet aggregation. The 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 plasma circulating 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 rates 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. Cmax of cilostazol and its primary metabolites increases less than proportionally with dose escalation. However, AUC of cilostazol and its metabolites increases approximately proportionally with dosage. The apparent elimination half-life of cilostazol is 10.5 hours. There are two major metabolites – 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 about 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 its metabolites in urine. The primary cytochrome P450 isoenzymes involved in its metabolism are CYP3A4, to a lesser extent CYP2C19, and even less significantly CYP1A2.

Excretion.

The main route of elimination is via urine (74%), with residual amounts excreted in feces. Minimal 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% bound to plasma proteins, primarily albumin. The dehydro metabolite and the 4'-trans-hydroxy metabolite are protein-bound by 97.4% and 66%, respectively.

There is no evidence that cilostazol induces liver 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 resting pain or signs of peripheral tissue necrosis (peripheral arterial disease, Fontaine stage II).

Use as a second-line therapy in patients in whom lifestyle modifications (including smoking cessation and supervised exercise programs) and other appropriate measures have not led to significant symptom relief of intermittent claudication.

Contraindications.

• Known 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 known predisposition to bleeding (e.g., active peptic ulcer of the stomach or duodenum, recent hemorrhagic stroke (within 6 months), proliferative diabetic retinopathy, poorly controlled hypertension);
• contraindicated in patients with ventricular tachycardia, ventricular fibrillation, or multifocal ventricular ectopy, whether or not they have received appropriate therapy; patients with prolonged QT interval;
• severe tachyarrhythmia in medical history;
• concomitant treatment with two or more additional antiplatelet agents or anticoagulants (e.g., acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban, or apixaban);
• unstable angina, myocardial infarction within the last 6 months, or coronary intervention within the last 6 months.

Interaction with other medicinal products and other types of interactions.

Antithrombotic agents. Cilostazol is a phosphodiesterase III inhibitor with antiplatelet activity. Administration to healthy individuals at a dose of 150 mg for 5 days did not lead to prolonged bleeding time.

Acetylsalicylic acid (ASA). Short-term co-administration (up to 4 days) with ASA was associated with a 23–25% increase in inhibition of ADP-induced platelet aggregation compared to ASA alone. No obvious trends toward increased incidence of hemorrhagic adverse effects were observed in patients receiving aspirin and cilostazol compared to patients 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 monotherapy and when clopidogrel was combined with cilostazol, but this did not result in a significant additive effect on bleeding time. However, caution should be exercised when combining cilostazol with any antithrombotic agents. Periodic monitoring of bleeding time should be considered. Treatment with cilostazol is contraindicated in patients taking two or more additional antiplatelet/anticoagulant agents. A higher frequency of bleeding events was observed during concomitant use of clopidogrel, ASA, and cilostazol in the CASTLE study.

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. Treatment with cilostazol is contraindicated in patients taking two or more additional antiplatelet/anticoagulant agents.

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 4–7 times higher antiplatelet activity than cilostazol, is likely formed primarily via CYP3A4. The 4'-trans-hydroxy metabolite, with activity 1/5 that of cilostazol, is likely formed via CYP2C19. Thus, agents that inhibit CYP3A4 (e.g., certain macrolides, azole antifungals, protease inhibitors) or CYP2C19 (e.g., proton pump inhibitors) increase the overall pharmacological activity of cilostazol by 32% and 42%, respectively, and may increase cilostazol-related 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 treatment with erythromycin (a 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. Based on AUC values, the overall pharmacological activity of cilostazol increases by 34% when co-administered with erythromycin. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when used concomitantly with erythromycin and similar agents (e.g., clarithromycin).

Concomitant use of ketoconazole (a CYP3A4 inhibitor) with cilostazol resulted in a 117% increase in cilostazol AUC, accompanied by a 15% decrease in dehydro metabolite AUC and an 87% increase in 4'-trans-hydroxy metabolite AUC. Based on AUC values, the overall pharmacological activity of cilostazol increases by 35% when used concomitantly with ketoconazole. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when used concomitantly with ketoconazole and similar agents (e.g., itraconazole).

Administration of cilostazol with diltiazem (a weak CYP3A4 inhibitor) resulted in a 44% increase in cilostazol AUC, accompanied by a 4% increase in dehydro metabolite AUC and a 43% increase in 4'-trans-hydroxy metabolite AUC. Based on AUC values, the overall pharmacological activity of cilostazol increases by 19% when co-administered with diltiazem. Based on these data, dose adjustment is not required.

Single-dose administration of 100 mg cilostazol with 240 mL grapefruit juice (an intestinal CYP3A4 inhibitor) did not show a notable effect on cilostazol pharmacokinetics. Therefore, dose adjustment is not required. However, consumption of large quantities of grapefruit juice may have a clinically significant effect on cilostazol pharmacokinetics.

Administration of cilostazol with omeprazole (a CYP2C19 inhibitor) resulted in a 22% increase in cilostazol AUC, accompanied by a 68% increase in dehydro metabolite AUC and a 36% decrease in 4'-trans-hydroxy metabolite AUC. Based on AUC values, the overall pharmacological activity of cilostazol increases by 47% when co-administered with omeprazole. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when used concomitantly with omeprazole.

Cytochrome P450 substrates. Cilostazol has been shown to increase the AUC of lovastatin (a sensitive CYP3A4 substrate) and its β-hydroxy acid metabolite by up to 70%. Caution should be exercised when co-administering cilostazol with CYP3A4 substrates that have a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivatives). Caution should also be exercised when co-administering cilostazol with statins metabolized by CYP3A4 enzymes, such as simvastatin, atorvastatin, and lovastatin.

Cytochrome P450 enzyme inducers. The effect of CYP3A4 and CYP2C19 inducers (such as carbamazepine, phenytoin, rifampicin, and St. John's wort preparations) on cilostazol pharmacokinetics has not been studied. Theoretically, antithrombotic effect may be altered; therefore, monitoring is necessary when cilostazol is used concomitantly with CYP3A4 and CYP2C19 inducers.

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

Other potential interactions

Caution should be exercised when administering cilostazol concomitantly with any other agent capable of lowering blood pressure due to the potential for additive hypotensive effects accompanied by reflex tachycardia.

Special precautions for use.

The appropriateness of treatment with cilostazol should be carefully evaluated alongside other treatment options, such as revascularization.

Due to its mechanism of action, cilostazol may cause tachycardia, palpitations, tachyarrhythmia, and/or arterial hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 beats per minute; therefore, in patients at risk of this effect, the drug may provoke angina.

Patients who may be predisposed to an increased risk of serious cardiac adverse effects due to elevated heart rate, such as those with stable ischemic heart disease, should be closely monitored during treatment with cilostazol. It should be noted that cilostazol is contraindicated in patients who have experienced unstable angina or myocardial infarction/coronary intervention within the previous 6 months, or who have a history of severe tachyarrhythmia.

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

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

Since the drug is capable of inhibiting platelet aggregation, the risk of bleeding during surgical procedures (including minor procedures such as tooth extraction) is increased. If a surgical procedure is required and the antiplatelet effect is undesirable, cilostazol should be discontinued at least 5 days prior to 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, several cases of pancytopenia and aplastic anemia were fatal.

Patients should be advised to promptly report any symptoms that may indicate 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 hematological abnormalities are present. Cilostazol should be discontinued if there is clinical or laboratory evidence of hematological abnormalities.

Increased plasma levels of cilostazol have been observed in patients taking strong inhibitors of CYP3A4 or CYP2C19. In such cases, the recommended dose of cilostazol is 50 mg twice daily.

Cilostazol should be prescribed with caution in patients with atrial or ventricular ectopy, atrial fibrillation, or atrial 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 concomitantly with any other antithrombotic agents.

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

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; therefore, cilostazol should not be used during pregnancy.

Breastfeeding.

Animal studies have shown that cilostazol may pass into breast milk. There are no precise data on the passage of cilostazol into human breast milk. Considering the potential adverse effects on the infant, the use of this drug during breastfeeding is not recommended.

Fertility.

Animal studies have shown that cilostazol does not affect fertility.

Ability to affect reaction speed when driving or operating machinery.

Caution should be exercised, as dizziness may occur during treatment with this drug.

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 meals, in the morning and in the evening.

Administration of the medicinal product with food may increase its maximum plasma concentrations (Cmax), thereby increasing the risk of adverse reactions. Cilostazol should be prescribed by physicians experienced in the treatment of intermittent claudication. If no therapeutic effect is observed within 3 months of treatment, the physician should consider alternative therapy. Patients receiving cilostazol should adhere to lifestyle modifications (smoking cessation and physical exercise) and continue pharmacological interventions (e.g., lipid-lowering and antiplatelet agents) to reduce the risk of cardiovascular events. Cilostazol does not replace these treatment modalities.

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

Elderly patients.

There is no need for dose adjustment in 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 changed 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 provided. Gastric emptying should be performed by inducing vomiting or gastric lavage.

Adverse reactions

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

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

Frequency of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated based on available data). The frequency of adverse reactions observed during post-marketing use is considered not known (cannot be estimated based on available data).

An increased incidence of palpitations and peripheral edema was 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 reaction that led to discontinuation of treatment in ≥3% of patients receiving cilostazol. Other common reasons for treatment discontinuation included strong palpitations and diarrhea (occurring at a frequency of 1.1%).

Use of cilostazol may be associated with an increased risk of bleeding, and this risk may increase when the medicinal product 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 strong palpitations was observed in patients aged 70 years and older.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 28 tablets in a blister; 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. NUCOR HEALTH, S.A.

Manufacturer's location and address of the place of business.

Avinguda Camí Real, 51-57 08184, PALAU-SOLITÀ I PLEGAMANS (Barcelona), Spain.

Manufacturer. GALENIKUM HEALTH, S.L.

Manufacturer's location and address of the place of business.

Avinguda Cornellà 144, 7o-1a Edifici LECLA, Esplugues de Llobregat, Barcelona, 08950, Spain.

Marketing Authorization Holder. JSC "Pharmaceutical Company "Darnytsia".

Address of the Marketing Authorization Holder.

13, Boryspilska Street, Kyiv, 02093, Ukraine.