Plestazol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PLESTAZOL (PLESTAZOL)

Composition:

Active substance: cilostazol;

1 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, flat cylindrical tablets with beveled edges;

100 mg tablets: white or almost white, flat cylindrical tablets with beveled edges and a score line.

Pharmacotherapeutic group. Antithrombotic agents. Antiplatelet agents.

ATC code B01AC23.

Pharmacological Properties

Pharmacodynamics

Cilostazol is an inhibitor of platelet aggregation. The drug improves exercise tolerance, assessed as absolute claudication distance (or maximum walking distance [MWD]) and initial claudication distance (or pain-free walking distance [PFWD]) in treadmill testing. Clinical studies 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 suppresses the release of platelet-derived growth factor and PF-4 from human platelets.

Studies have shown 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, the inhibitory effect lasts up to 12 hours, and after discontinuation of cilostazol, platelet aggregation returns to baseline within 48–96 hours without rebound effect (hyperaggregation). Cilostazol has also been shown to affect plasma lipids. 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

With regular administration of cilostazol at a dose of 100 mg twice daily in patients with peripheral vascular disease, steady-state plasma concentrations are achieved within 4 days. The Cmax of cilostazol and its primary metabolites increases less than proportionally with increasing dose. However, the AUC of cilostazol and its metabolites increases approximately in proportion to the administered dose. 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- to 7-fold higher antithrombotic activity than the parent compound, while the 4'-trans-hydroxy metabolite has approximately 1/5 the activity of cilostazol. Plasma concentrations (based on AUC) of the dehydro and 4'-trans-hydroxy metabolites are approximately 41% and 12% of the parent cilostazol concentration, respectively.

Cilostazol is primarily eliminated via metabolism, with subsequent excretion of metabolites in urine. The main cytochrome P450 isoenzymes involved in its metabolism are CYP3A4, to a lesser extent CYP2C19, and even less significantly CYP1A2. The primary route of excretion is via urine (74%), with the remainder excreted in feces. Only negligible amounts 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 mixture of metabolites, none of which exceeds 5% of total excreted material.

Cilostazol is 95–98% bound to plasma proteins, primarily 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 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 regarding 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).

Use as 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 multiform ventricular ectopy, whether or not appropriately treated; patients with QT interval 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 forms of interaction.

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

Acetylsalicylic acid (ASA). Short-term co-administration (up to 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 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, but there was no 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. Particular attention is required for patients receiving complex 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 4–7 times greater antiplatelet activity than cilostazol, is likely formed primarily by CYP3A4. The 4'-trans-hydroxy metabolite, with activity approximately 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) may increase the overall pharmacological activity of cilostazol by 32% and 42%, respectively, and may enhance 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 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 with 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 led to 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) did not show a 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 metabolite by up to 70% has been observed with cilostazol. Caution is advised when co-administering cilostazol with CYP3A4 substrates that have a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivatives). Caution is also required when co-administering with simvastatin.

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

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

Special precautions for use

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 is increased during surgical procedures (including minor procedures such as tooth extraction). If a patient requires surgery and antiplatelet effect is undesirable, cilostazol should be discontinued at least 5 days prior to the operation.

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 resulted in fatal outcomes.

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 are clinical or laboratory findings indicating hematological abnormalities.

Caution is required when cilostazol is used concomitantly with inhibitors or inducers of CYP3A4, CYP2C19, or substrates of CYP3A4.

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

Caution is required when cilostazol is co-administered with any other 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 together 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

There are no confirmed data on the use of cilostazol in pregnant women; the potential risk is unknown. The drug should not be used during pregnancy.

Cilostazol may pass into breast milk; exact data are lacking. Considering the potential adverse effects on the newborn, the use of this medicinal product during breastfeeding is not recommended.

Ability to influence the speed of reactions when driving or operating machinery

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

Dosage and Administration

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

Administration of the medicinal product with food may increase its maximum plasma concentrations, thereby increasing the risk of adverse reactions. Significant improvement in patients is observed after 16–24 weeks of treatment; however, improvement has sometimes been noted as early as 4–12 weeks of therapy. If no therapeutic effect is achieved within 6 months, the physician should consider initiating an alternative 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 forms of interaction").

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. No special dose 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 liver enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.

Elderly patients. No dose adjustment is necessary for this patient group.

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 provided with supportive treatment. Gastric decontamination by induction of emesis or gastric lavage should be performed.

Adverse Reactions

During cilostazol administration, the following undesirable effects may occasionally occur.

Blood and lymphatic system disorders: bruising; anemia; prolonged bleeding time, thrombocytosis; rare – tendency to bleeding, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia.

Immune system disorders: allergic reactions.

Gastrointestinal and metabolic disorders: edema (peripheral or facial edema); hyperglycemia, diabetes mellitus; anorexia.

Psychiatric disorders: anxiety.

Nervous system disorders: headache; dizziness; insomnia, unusual dreams; paresis, paresthesia.

Eye disorders: conjunctivitis.

Ear and labyrinth disorders: tinnitus.

Cardiovascular system disorders: 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 hemorrhages, orthostatic hypotension; flushing, hypertension, hypotension, cerebral hemorrhages, pulmonary hemorrhages, muscular hemorrhages, hemorrhages in respiratory tract, subcutaneous hemorrhages.

Respiratory system disorders: rhinitis, pharyngitis; dyspnea, pneumonia, cough; interstitial pneumonia.

Gastrointestinal tract disorders: diarrhea, defecation disorders; nausea, vomiting, dyspepsia, flatulence, abdominal pain; gastritis.

Hepatobiliary system disorders: hepatitis, liver function abnormalities, jaundice.

Skin and subcutaneous tissue disorders: rash, pruritus; eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Musculoskeletal and connective tissue disorders: myalgia.

Renal and urinary disorders: renal failure, impaired kidney function; hematuria, pollakiuria.

General disorders: chest pain, asthenia; chills, hyperthermia, malaise, pain.

Laboratory findings: increased levels of uric acid, blood urea nitrogen, 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.

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. 10 tablets per blister; 3 or 6 blisters per pack.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's location and address of business activity.

38 Kopilivska St., Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua.

INSTRUCTION

for medical use of medicinal product

PLESTAZOL

(PLESTAZOL)

Composition:

Active substance: cilostazol;

1 tablet contains cilostazol 50 mg or 100 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

50 mg tablets: flat cylindrical tablets with bevelled edges, white or almost white;

100 mg tablets: flat cylindrical tablets with bevelled edges and a score line, white or almost white.

Pharmacotherapeutic group. Antithrombotic agents. Antiplatelet agents.

ATC code B01AC23.

Pharmacological properties.

Pharmacodynamics.

Cilostazol is an inhibitor of platelet aggregation. The drug improves the ability to tolerate physical exercise, assessed by absolute walking distance in intermittent claudication (or maximum walking distance (MWD)) and initial claudication distance (or pain-free walking distance (PFWD)) during treadmill testing. Clinical studies have demonstrated a significant absolute improvement of 42 meters in maximum walking distance (MWD) compared to placebo. This corresponds to a 100% relative improvement compared to placebo. This effect was somewhat weaker 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 from human platelets.

Studies have shown that cilostazol causes reversible inhibition of platelet aggregation. Inhibition is effective against various aggregating agents (including arachidonic acid, collagen, ADP, and adrenaline). In patients, inhibition lasts up to 12 hours, and platelet aggregation returns to normal within 48–96 hours after cilostazol discontinuation, without rebound hyperaggregation.

Cilostazol also affects plasma lipids. The drug reduces triglyceride levels and increases HDL-cholesterol levels. Long-term use of cilostazol has not been associated with increased mortality compared to placebo.

Pharmacokinetics.

With regular administration of cilostazol 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 increase. However, the AUC of cilostazol and its metabolites increases approximately proportionally with dose. The apparent elimination half-life of cilostazol is 10.5 hours. Two major metabolites are formed: dehydrocilostazol and 4'-trans-hydroxycilostazol, both 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.

Cilostazol is primarily eliminated via metabolism, with subsequent excretion of metabolites in urine. The main cytochrome P450 isoenzymes involved in its metabolism are CYP3A4, to a lesser extent CYP2C19, and even less so CYP1A2. The primary route of excretion is via urine (74%), with residual amounts excreted in feces. Minimal unchanged cilostazol is 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 mixture of metabolites, none exceeding 5% of total excretion.

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 liver microsomal enzymes. The pharmacokinetics of cilostazol and its metabolites are not significantly influenced by age or gender in patients aged 50–80 years.

In patients with severe renal impairment (creatinine clearance ≤ 25 mL/min), the free fraction of cilostazol was 27% higher, while Cmax and AUC were 29% and 39% lower, respectively, compared to patients 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, respectively, in patients with severe renal impairment. No data are 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).

Use as second-line therapy in patients in whom lifestyle modifications (including smoking cessation and supervised exercise programs) and other appropriate measures have not significantly reduced symptoms of intermittent claudication.

Contraindications.

Hypersensitivity to cilostazol or any excipient, 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 ulcer, recent hemorrhagic stroke (within 6 months), proliferative diabetic retinopathy, poorly controlled hypertension). Contraindicated in patients with ventricular tachycardia, ventricular fibrillation, or multiform ventricular ectopy, regardless of whether they have received appropriate therapy; patients with QT interval 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 forms of interaction.

Antithrombotic agents. Cilostazol is a type III phosphodiesterase inhibitor with antithrombotic activity. Administration to healthy subjects at a dose of 150 mg for 5 days did not prolong bleeding time.

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

Clopidogrel and other antithrombotic 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 during clopidogrel monotherapy and combination therapy with cilostazol, without significant additive effect on bleeding time. However, caution is advised 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 receiving cilostazol with any anticoagulant, and periodic monitoring is advised to minimize the risk of bleeding.

Cytochrome P450 (CYP) inhibitors. Cilostazol is extensively metabolized by CYP enzymes, particularly CYP3A4, to a lesser extent CYP2C19, and even less so CYP1A2.

The dehydro metabolite, which has 4–7 times higher antithrombotic activity than cilostazol, is likely formed primarily by CYP3A4. The 4'-trans-hydroxy metabolite, with 1/5 the activity of cilostazol, is likely formed by CYP2C19. Therefore, drugs that inhibit CYP3A4 (e.g., certain macrolides, azole antifungals, protease inhibitors) or CYP2C19 (e.g., proton pump inhibitors) may increase the overall pharmacological activity of cilostazol by 32% and 42%, respectively, and may enhance its 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 (a moderate CYP3A4 inhibitor) 500 mg three times daily increased cilostazol AUC by 74%, 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 a single dose of ketoconazole (a strong CYP3A4 inhibitor) 400 mg and cilostazol 100 mg increased cilostazol AUC by 117%, 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 a 32% increase in overall pharmacological activity compared to cilostazol monotherapy.

Administration of 100 mg cilostazol twice daily with diltiazem (a CYP3A4 inhibitor) 180 mg once daily increased cilostazol AUC by 44%. 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 increased cilostazol AUC by 53%.

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

Single administration of 100 mg cilostazol on day 7 of omeprazole (a CYP2C19 inhibitor) 40 mg once daily increased cilostazol AUC by up to 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 a 42% increase in overall pharmacological activity compared to cilostazol monotherapy.

Cytochrome P450 substrates. Cilostazol has been shown to increase AUC of lovastatin (a sensitive CYP3A4 substrate) and its β-hydroxy acid by up to 70%. Caution is advised when co-administering cilostazol with CYP3A4 substrates having a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivatives). Caution is also required when co-administering with simvastatin.

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

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

Special precautions.

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

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

There have been rare 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 immediately report any signs suggestive of early blood disorders, such as hyperthermia and sore throat. A complete blood count should be performed if infection is suspected or any other clinical signs of hematological abnormalities are present. Cilostazol should be discontinued if clinical or laboratory evidence of blood disorders is detected.

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

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

Caution is advised when co-administering cilostazol with other agents that may lower blood pressure, due to the risk of additive hypotensive effect with reflex tachycardia.

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

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

Use during pregnancy or breastfeeding.

There are no confirmed data on cilostazol use during pregnancy; potential risk is unknown. The drug should not be used during pregnancy.

Cilostazol may pass into breast milk; exact data are lacking. Due to possible adverse effects on newborns, use of the drug during breastfeeding is not recommended.

Effect on ability to drive or operate machinery.

Caution is advised, as dizziness may occur during treatment.

Dosage and administration.

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

Administration with food may increase maximum plasma concentrations, increasing the risk of adverse reactions. Significant improvement in patients is observed after 16–24 weeks of treatment, although improvement may be noted as early as 4–12 weeks. If treatment is ineffective after 6 months, the physician should consider alternative therapy.

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

Patients with renal impairment. No 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. No dose adjustment is required for patients with mild liver disease. Data are lacking 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.

Elderly patients. No dose adjustment is necessary for this patient group.

Children. The drug is not recommended for children due to lack of safety and efficacy data.

Overdose.

Information on acute overdose is limited. Possible symptoms include severe headache, diarrhea, tachycardia, and cardiac arrhythmias. Patients should be monitored and supportive therapy administered. Gastric emptying via induced emesis or lavage may be necessary.

Adverse reactions.

During cilostazol administration, the following undesirable effects may occasionally occur.

Blood and lymphatic system disorders: bruising; anemia; prolonged bleeding time, thrombocytosis; rare – tendency to bleeding, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia.

Immune system disorders: allergic reactions.

Gastrointestinal and metabolic disorders: edema (peripheral or facial edema); hyperglycemia, diabetes mellitus; anorexia.

Psychiatric disorders: anxiety.

Nervous system disorders: headache; dizziness; insomnia, unusual dreams; paresis, paresthesia.

Eye disorders: conjunctivitis.

Ear and labyrinth disorders: tinnitus.

Cardiovascular system disorders: palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles; myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, syncope, ocular hemorrhages, epistaxis, gastrointestinal hemorrhages, unspecified hemorrhages, orthostatic hypotension; flushing, hypertension, hypotension, cerebral hemorrhages, pulmonary hemorrhages, muscular hemorrhages, hemorrhages in respiratory tract, subcutaneous hemorrhages.

Respiratory system disorders: rhinitis, pharyngitis; dyspnea, pneumonia, cough; interstitial pneumonia.

Gastrointestinal tract disorders: diarrhea, defecation disorders; nausea, vomiting, dyspepsia, flatulence, abdominal pain; gastritis.

Hepatobiliary system disorders: hepatitis, liver function abnormalities, jaundice.

Skin and subcutaneous tissue disorders: rash, pruritus; eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Musculoskeletal and connective tissue disorders: myalgia.

Renal and urinary disorders: renal failure, impaired kidney function; hematuria, pollakiuria.

General disorders: chest pain, asthenia; chills, hyperthermia, malaise, pain.

Laboratory findings: increased levels of uric acid, blood urea nitrogen, 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.

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. 10 tablets per blister; 3 or 6 blisters per pack.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's location and address of business activity.

38 Kopilivska St., Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua.