Endastazole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Endastazol (Endastazol®)

Composition:

Active substance: cilostazol;

1 tablet contains cilostazol 100 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with a score line on one side, approximately 8 mm in diameter. The tablet can be divided into two equal doses.

Pharmacotherapeutic group. Antiplatelet agents, excluding heparin.

ATC code B01AC23.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Cilostazol is an inhibitor of platelet aggregation. The drug improves exercise tolerance, assessed by absolute distance in intermittent claudication (or maximum walking distance, MWD) and initial claudication distance (or pain-free walking distance, PFWD) in treadmill testing. Studies under various loads have 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 platelet release of platelet-derived growth factor and PF-4 in human platelets.

Studies have shown 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 persists for 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 demonstrated.

Drug administration 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 concentrations 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. There are two major metabolites – dehydrocilostazol and 4'-trans-hydroxycilostazol – which have 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 (as measured by AUC) of dehydro- and 4'-trans-hydroxy metabolites are approximately 41% and 12% of the 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 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 excreted amount.

Distribution.

Cilostazol is 95–98% bound to plasma proteins, primarily albumin. The dehydro metabolite and 4'-trans-hydroxy metabolite are protein-bound at 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 influenced by age or gender in patients aged 50–80 years.

In patients 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 patients 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 pain at rest or signs of peripheral tissue necrosis (peripheral arterial disease, Fontaine stage II).

As second-line therapy in patients in whom lifestyle modifications (including smoking cessation and [supervised] exercise programs) and other appropriate interventions have not led to sufficient symptom improvement of intermittent claudication.

Contraindications.

• Known hypersensitivity to cilostazol or to 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 gastric or duodenal peptic ulcer, recent hemorrhagic stroke (within 6 months), proliferative diabetic retinopathy, poorly controlled arterial hypertension);
• ventricular tachycardia, ventricular fibrillation, or multifocal ventricular ectopy in medical history in patients who have or have not received appropriate therapy, as well as QT interval prolongation;
• 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 volunteers at a dose of 150 mg twice daily for 5 days did not lead to prolonged bleeding time.

Acetylsalicylic acid (ASA)

Short-term co-administration (≤ 4 days) with ASA was associated with a 23–25% increase in ex vivo ADP-induced platelet aggregation inhibition compared to ASA alone. No apparent 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 as monotherapy and in combination with cilostazol, without resulting 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 receiving two or more additional antiplatelet/anticoagulant agents.

A higher frequency of bleeding events was observed during concomitant administration 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 receiving cilostazol with any anticoagulant, and periodic monitoring should be performed to minimize the risk of bleeding. Treatment with cilostazol is contraindicated in patients receiving 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 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 enhance cilostazol's adverse effects. Dose reduction of cilostazol to 50 mg twice daily may be necessary depending on individual efficacy and tolerability.

Administration of cilostazol with erythromycin (a CYP3A4 inhibitor) 500 mg three times daily resulted in a 72% increase in cilostazol AUC, accompanied by a 6% increase in dehydro metabolite AUC and a 119% increase in 4'-trans-hydroxy metabolite AUC.

Considering AUC values, the total pharmacological activity of cilostazol increases by 34% when administered concomitantly with erythromycin. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when co-administered with erythromycin and similar agents (e.g. clarithromycin).

Concomitant administration 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. Considering AUC values, the total pharmacological activity of cilostazol increases by 35% when co-administered with ketoconazole. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when co-administered 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. Considering AUC values, the total 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 of grapefruit juice (an intestinal CYP3A4 inhibitor) showed no significant 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. Considering AUC values, the total 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 co-administered with omeprazole.

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 reported 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 should also be exercised when co-administering cilostazol with statins metabolized by cytochrome 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 effects may be altered; therefore, monitoring is required when cilostazol is used concomitantly with CYP3A4 and CYP2C19 inducers.

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

Other potential interactions

Caution should be exercised when co-administering cilostazol 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 cilostazol treatment 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 cilostazol therapy. 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 those with atrial fibrillation or atrial flutter.

Patients should be advised to seek medical attention if bleeding or bruising occurs during therapy. If ocular hemorrhage occurs, cilostazol must be discontinued.

Since the drug is capable of inhibiting platelet aggregation, the risk of bleeding is increased during surgical procedures (including minor procedures such as tooth extraction). If a patient requires surgery and antiplatelet effects are undesirable, cilostazol should be discontinued at least 5 days prior to the operation.

Isolated reports of hematological abnormalities have been reported, 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 warned to promptly report any signs 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 hematological abnormalities are present. Cilostazol should be discontinued if there are clinical or laboratory signs of blood disorders.

In patients taking potent inhibitors of CYP3A4 or CYP2C19, increased plasma levels of cilostazol have been observed. 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 with any other antithrombotic agents.

The stroke-preventive 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 excretion of cilostazol into human breast milk. Given the potential for adverse effects on the infant, the use of cilostazol during breastfeeding is not recommended.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Dosing.

The recommended dose of the drug is 100 mg twice daily. Tablets should be taken 30 minutes before or 2 hours after meals, 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. Cilostazol should be prescribed by physicians experienced in the treatment of intermittent claudication. If treatment has not been effective within 3 months, the physician should initiate alternative therapy. Patients receiving cilostazol treatment 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 forms of treatment.

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

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.

Dose adjustment is not required for 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 drug 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 provided with supportive therapy. Gastric emptying should be performed by inducing vomiting or gastric lavage.

Adverse Reactions

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

Undesirable effects that may occasionally occur during cilostazol administration 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); unknown (cannot be estimated based on available data).

The frequency of adverse reactions observed during the post-marketing period is considered unknown (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 effect requiring 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%).

Cilostazol itself may be associated with an increased risk of bleeding, and this risk may increase when the drug is taken concomitantly with any other medicinal product 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 adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

This medicinal product does not require special storage temperature conditions.

Keep out of reach and sight of children.

Packaging.

30 tablets in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription-only.

Manufacturer.

ALKALOID AD Skopje /
ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.