Pletax^® (Tablets) Instructions for Use

Marketing Authorization Holder

Esko Pharma, LLC (Russia)

Manufactured By

Oxford Laboratories, Pvt. Ltd. (India)

Labeled By

JODAS EXPOIM, Pvt. Ltd. (India)

Quality Control Release

OXFORD Laboratories, Pvt. Ltd. (India)

ATC Code

B01AC23 (Cilostazol)

Active Substance

Cilostazol (Rec.INN registered by WHO)

Dosage Forms

	Pletax®	Tablets 50 mg: 30, 40, 42, 56, 60 or 84 pcs.
		Tablets 100 mg: 30, 40, 42, 56, 60 or 84 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex, with a score on one side and smooth on the other side.

Excipients : pregelatinized potato starch – 81.8 mg, microcrystalline cellulose (M102) – 26 mg, sodium carboxymethylcellulose – 1.5 mg, magnesium stearate – 1.7 mg, hypromellose – 19 mg.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (4) – carton packs.
10 pcs. – blisters (6) – carton packs.
14 pcs. – blisters (3) – carton packs.
14 pcs. – blisters (4) – carton packs.
14 pcs. – blisters (6) – carton packs.
30 pcs. – bottles (1) – carton packs.
40 pcs. – bottles (1) – carton packs.
42 pcs. – bottles (1) – carton packs.
56 pcs. – bottles (1) – carton packs.
60 pcs. – bottles (1) – carton packs.
84 pcs. – bottles (1) – carton packs.

Tablets white or almost white, round, biconvex, with a score on one side and smooth on the other side.

Excipients : pregelatinized potato starch – 84 mg, microcrystalline cellulose (M102) – 35 mg, sodium carboxymethylcellulose – 2.2 mg, magnesium stearate – 2.3 mg, hypromellose – 26.5 mg.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (4) – carton packs.
10 pcs. – blisters (6) – carton packs.
14 pcs. – blisters (3) – carton packs.
14 pcs. – blisters (4) – carton packs.
14 pcs. – blisters (6) – carton packs.
30 pcs. – bottles (1) – carton packs.
40 pcs. – bottles (1) – carton packs.
42 pcs. – bottles (1) – carton packs.
56 pcs. – bottles (1) – carton packs.
60 pcs. – bottles (1) – carton packs.
84 pcs. – bottles (1) – carton packs.

Clinical-Pharmacological Group

Antiplatelet agent

Pharmacotherapeutic Group

Antiaggregant agent

Pharmacological Action

Type 3 phosphodiesterase (PDE3) inhibitor. It increases the intracellular content of cyclic adenosine monophosphate (cAMP) in various organs and tissues.

Experimental and small clinical studies have established that Cilostazol has a vasodilating effect. Cilostazol inhibits the proliferation of human and rat smooth muscle cells in vitro.

Experimental and clinical studies in vivo and ex vivo have established that Cilostazol increases cAMP content in platelets and causes a reversible antiplatelet effect. In addition, Cilostazol blocks the release of platelet-derived growth factor and platelet factor 4 (PF-4) from human platelets.

In addition, Cilostazol reduces serum TG concentrations and increases HDL cholesterol concentration. In a clinical study, taking cilostazol at a dose of 100 mg 2 times/day for 12 weeks compared with placebo reduced blood triglyceride levels by an average of 0.33 mmol/L (by 15%) and increased blood HDL cholesterol levels by an average of 0.10 mmol/L (by 10%).

Cilostazol has a positive inotropic effect. In experimental studies, Cilostazol exerted a species-specific damaging effect on the cardiovascular system.

It has been established that therapy with cilostazol at a dose of 100 mg 2 times/day for 24 weeks approximately doubles the maximum walking distance (from 60.4 m to 129.1 m; the mean absolute increase in maximum walking distance is 42 m) and the distance walked until pain appears (from 47.3 m to 93.6 m).

Cilostazol dilates mainly the femoral arteries, to a lesser extent the vertebral, carotid and superior mesenteric arteries. The renal arteries are not sensitive to the effects of cilostazol.

The efficacy of cilostazol in patients with intermittent claudication was confirmed in 9 placebo-controlled clinical studies.

The efficacy of cilostazol in patients with diabetes mellitus was lower than in persons without carbohydrate metabolism disorders.

Pharmacokinetics

In patients with occlusive peripheral arterial disease with regular intake of cilostazol at a dose of 100 mg twice a day, the equilibrium concentration of the drug in the blood is reached after 4 days.
The maximum plasma concentration (C_max) of cilostazol and its main metabolites increases less than proportionally to the dose increase. At the same time, the AUC of cilostazol and its main metabolites increases approximately proportionally to the dose increase.

The binding of cilostazol to plasma proteins, mainly albumin, is 95-98%. It is metabolized in the liver mainly by the action of the CYP3A4 isoenzyme, to a lesser extent by the CYP2C19 isoenzyme, and to an even lesser extent by the CYP1A2 isoenzyme. Cilostazol is not an inducer of hepatic microsomal peroxidation enzymes.

The plasma concentration of dehydrocilostazol and 4′-trans-hydroxycilostazol (estimated based on AUC) is approximately 41% and approximately 12% of the unchanged cilostazol concentration, respectively. The binding to blood proteins of dehydrocilostazol and 4′-trans-hydroxycilostazol is 97.4% and 66%, respectively.

Cilostazol is eliminated from the body mainly by the kidneys (74%), the remaining drug is eliminated through the intestines. Unchanged Cilostazol is practically not detected in the urine. Less than 2% of the administered dose of the drug is excreted by the kidneys in the form of dehydrocilostazol. Approximately 30% of the administered dose is excreted by the kidneys in the form of 4′-trans-hydroxycilostazol. The remaining drug is excreted in the form of various metabolites, each of which accounts for no more than 5% of the administered dose.

The elimination half-life (T_1/2) of cilostazol is 10.5 hours. The two main metabolites, dehydrocilostazol and 4′-trans-hydroxycilostazol, have similar T_1/2 values.

In patients with severe renal failure, the free fraction of cilostazol is 27% higher, and the C_max and AUC of unchanged cilostazol are 29% and 39% lower, respectively, than in persons with normal renal function. The C_max and AUC of dehydrocilostazol in patients with severe renal failure are 41% and 47% lower, respectively, than in patients with normal renal function. At the same time, the C_max and AUC of 4′-trans-hydroxycilostazol (the main metabolite excreted by the kidneys) in patients with severe renal failure increase by 173% and 209%, respectively, compared with patients with normal renal function.

In patients with moderate hepatic impairment, C_max in blood plasma and AUC increased by 25% and 10%, respectively, compared with healthy people. In patients with moderate renal impairment, C_max and AUC increased by 50% and 16%, respectively, compared with healthy people.

Indications

Symptomatic treatment of intermittent claudication.
Cilostazol is used to increase the maximum distance and pain-free walking distance in patients with intermittent claudication who have no pain at rest and no signs of necrosis of peripheral tissues (chronic lower limb ischemia of Fontaine stage II).

Cilostazol is intended for use as second-line therapy in patients with intermittent claudication in whom lifestyle changes (including smoking cessation and physical rehabilitation programs) and other appropriate interventions have been insufficient to reduce the symptoms of intermittent claudication.

ICD codes

Dosage Regimen

Orally.

Patients receiving treatment with cilostazol should continue to follow lifestyle modification recommendations (smoking cessation, exercise) and drug therapy (taking lipid-lowering and antiplatelet drugs) aimed at reducing the risk of cardiovascular complications. Cilostazol is not a substitute for this treatment.

Therapy with cilostazol should be started under the supervision of a physician experienced in the treatment of intermittent claudication.

The recommended dose is 100 mg 2 times/day.

The physician should re-evaluate the patient’s condition after 3 months of treatment. If cilostazol therapy does not have an adequate effect or no reduction in the severity of intermittent claudication symptoms is observed, Cilostazol should be discontinued and other treatment methods should be considered.

Concomitant use of potent CYP3A4 and CYP2C19 inhibitors In patients taking drugs that have a strong blocking effect on CYP3A4 (for example, some macrolides), or drugs that have a strong blocking effect on CYP2C19 (for example, omeprazole), the dose of cilostazol should be reduced to 50 mg twice a day.

Adverse Reactions

Cardiovascular system: common – palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystole, orthostatic hypotension; uncommon – myocardial infarction, atrial fibrillation, chronic heart failure, supraventricular tachycardia, ventricular tachycardia, syncope, hot flushes, arterial hypertension, arterial hypotension; frequency unknown – polymorphic ventricular tachycardia of the “torsades de pointes” type and QT interval prolongation (in patients with cardiovascular diseases).

Respiratory system common – rhinitis, pharyngitis; uncommon – dyspnea, pneumonia, cough; frequency unknown – interstitial pneumonia.

Digestive system very common – diarrhea, stool disorders; common – nausea, vomiting, dyspepsia, flatulence, abdominal pain; uncommon – gastritis.

Hepatobiliary system frequency unknown – hepatitis, abnormal liver function tests, jaundice.

Nervous system and psyche very common – headache; common – dizziness; uncommon – insomnia, sleep disorder (unusual dreams), anxiety; frequency unknown – paresis, hyperesthesia.

Blood clotting system common – ecchymoses, eye hemorrhage, epistaxis, gastrointestinal bleeding; uncommon – intracranial bleeding, pulmonary hemorrhage, intramuscular hematomas, respiratory tract bleeding, subcutaneous hemorrhage; rare – increased bleeding time; frequency unknown – bleeding tendency.

Hematopoietic system uncommon – anemia; rare – thrombocytosis; frequency unknown – thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia.

Organ of vision frequency unknown – conjunctivitis.

Hearing and labyrinthine disorders frequency unknown – tinnitus.

Skin and subcutaneous tissues common – skin rash, skin itching; uncommon – eczema, skin eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Immune system uncommon – allergic reactions.

Metabolism common – edema (peripheral edema, facial edema), anorexia; uncommon – hyperglycemia, diabetes mellitus; frequency unknown – increased blood uric acid, increased blood urea, increased blood creatinine.

Musculoskeletal system uncommon – myalgia.

Urinary system rare – renal failure, renal function disorders; frequency unknown – hematuria, pollakiuria.

General reactions common – chest pain, asthenia; uncommon – chills, malaise; frequency unknown – hyperthermia, pain.

Contraindications

Hypersensitivity to cilostazol,
Severe renal failure (CrCl ≤25 ml/min); moderate or severe hepatic impairment; chronic heart failure; predisposition to bleeding (for example, peptic ulcer of the stomach or duodenum in the acute phase, recent (within the last 6 months) hemorrhagic stroke, proliferative diabetic retinopathy, poorly controlled arterial hypertension); history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular extrasystole (regardless of the presence or absence of adequate antiarrhythmic therapy); prolonged QT interval on ECG; history of severe tachyarrhythmia; unstable angina or myocardial infarction within the last 6 months; invasive intervention on the coronary arteries within the last 6 months; simultaneous use of two or more antiplatelet or anticoagulant drugs (for example, acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban); simultaneous use of potent inhibitors of CYP3A4 or CYP2C19 (for example, cimetidine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole and HIV-1 protease inhibitors); pregnancy; breastfeeding period; age under 18 years.

With caution: mild hepatic impairment; chronic coronary artery disease (in particular, stable exertional angina); atrial or ventricular extrasystole, atrial fibrillation and flutter; diabetes mellitus; simultaneous use of drugs that reduce blood pressure; simultaneous use of drugs that reduce blood clotting; simultaneous use of substrates of CYP3A4 or CYP2C19 (for example, cisapride, midazolam, nifedipine, verapamil); elderly patients.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Before starting therapy with cilostazol, the possibility of prescribing other treatment methods, such as surgical revascularization or conservative therapy, should be assessed.

Due to its mechanism of pharmacological action, Cilostazol may cause tachycardia, palpitations, tachyarrhythmia and/or arterial hypotension. When taking cilostazol, heart rate may increase by 5-7 beats/min. In patients at risk (for example, patients with stable angina), an increase in heart rate may provoke an angina attack. Such patients should be carefully monitored.

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

Patients should be warned about the need to report any case of bleeding or bruising (subcutaneous hematoma) with minor trauma. In case of development of retinal hemorrhage, cilostazol should be discontinued.

Since Cilostazol is a platelet aggregation inhibitor, the risk of bleeding during surgical interventions (including minor invasive procedures such as tooth extraction) increases. For planned surgical interventions (if the antiplatelet effect is undesirable), Cilostazol should be discontinued 5 days before surgery.

Rare or very rare cases of hematological disorders, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia or aplastic anemia, have been reported. In most cases, these disorders resolved after discontinuation of cilostazol. However, in several cases, pancytopenia and aplastic anemia were fatal.

The patient should be warned to immediately inform the doctor of any symptoms that may be early manifestations of hematological complications, such as high fever (pyrexia) and sore throat. A complete blood count should be performed if an infection is suspected or if clinical symptoms of hematological complications appear. Cilostazol should be discontinued immediately if clinical symptoms or laboratory signs of hematological complications appear.

Caution should be exercised when using cilostazol concomitantly with drugs that reduce blood pressure (possibility of an additive hypotensive effect with the development of reflex tachycardia) as well as those that reduce blood clotting or inhibit platelet aggregation.

Effect on ability to drive vehicles and mechanisms

Cilostazol may cause dizziness. It is recommended to exercise caution when driving vehicles or operating machinery during treatment.

Drug Interactions

Short-term (for < 4 days) simultaneous use of cilostazol and acetylsalicylic acid leads to an increase in the blockade of ADP-induced platelet aggregation by 23-25% in ex vivo conditions compared with acetylsalicylic acid monotherapy. No obvious trend of increased hemorrhagic adverse events was detected in patients receiving Cilostazol and aspirin compared with patients taking placebo and an equivalent dose of acetylsalicylic acid.

In a study in healthy volunteers, simultaneous use of cilostazol with clopidogrel had no effect on platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT). When using clopidogrel both as monotherapy and in combination with cilostazol, bleeding time increased in healthy volunteers. Taking cilostazol did not lead to additional significant prolongation of bleeding time. Nevertheless, caution is recommended when using cilostazol concomitantly with any drug that inhibits platelet aggregation. Regular monitoring of bleeding time is recommended. The use of cilostazol is contraindicated in patients simultaneously receiving two or more antiplatelet and/or anticoagulant drugs.

In a clinical study, a single dose of cilostazol did not inhibit the metabolism of warfarin and did not affect blood coagulation parameters (PT, aPTT, bleeding time). Nevertheless, caution is recommended when using cilostazol concomitantly with any anticoagulant drug. The use of cilostazol is contraindicated in patients receiving two or more antiplatelet and/or anticoagulant drugs simultaneously.

In the liver, Cilostazol is primarily metabolized by cytochrome P450 enzymes, mainly CYP3A4 and CYP2C19 and, to a lesser extent, CYP1A2. It is believed that dehydrocilostazol, which is 4-7 times more potent than Cilostazol in inhibiting platelet aggregation, is formed primarily via CYP3A4. 4′-trans-Hydroxycilostazol, which has five times less potent platelet aggregation inhibitory activity, is formed mainly under the action of CYP2C19. Accordingly, drugs that inhibit CYP3A4 (e.g., some macrolides [erythromycin, clarithromycin], azole antifungals [ketoconazole, itraconazole], protease inhibitors) and CYP2C19 (e.g., proton pump inhibitors [omeprazole, esomeprazole]) increase the overall pharmacological activity of cilostazol and may contribute to an increase in its adverse effects. Accordingly, for patients receiving potent inhibitors of CYP3A4 or CYP2C19, it is recommended to prescribe Cilostazol at a dose of 50 mg twice daily.

When cilostazol was taken concomitantly with erythromycin (a potent CYP3A4 inhibitor), the AUC values for cilostazol, dehydrocilostazol, and 4′-trans-hydroxycilostazol increased by 72%, 6%, and 119%, respectively. Based on the changes in AUC values, it was determined that the overall pharmacological activity of cilostazol increases by 34% when used concomitantly with erythromycin. Based on these data, it is recommended to use Cilostazol at a dose of 50 mg twice daily when taken concomitantly with erythromycin or similar drugs (e.g., clarithromycin).

When cilostazol was taken concomitantly with ketoconazole (a potent CYP3A4 inhibitor), the AUC of cilostazol increased by 117%, the AUC of dehydrocilostazol decreased by 15%, and the AUC of 4′-trans-hydroxycilostazol increased by 87%. Based on the changes in AUC values, it was determined that the overall pharmacological activity of cilostazol increases by 35% when used concomitantly with ketoconazole. Based on these data, it is recommended to use Cilostazol at a dose of 50 mg twice daily when taken concomitantly with ketoconazole or similar drugs (e.g., itraconazole).

When cilostazol was taken concomitantly with diltiazem (a weak CYP3A4 inhibitor), the AUC values for cilostazol, dehydrocilostazol, and 4′-trans-hydroxycilostazol increased by 44%, 4%, and 43%, respectively. Based on the changes in AUC values, it was determined that the overall pharmacological activity of cilostazol increases by 19% when used concomitantly with diltiazem. Dose adjustment of cilostazol is not required when used concomitantly with diltiazem.

When a single 100 mg dose of cilostazol was taken with 240 ml of grapefruit juice (an intestinal CYP3A4 inhibitor), no significant changes in the pharmacokinetic parameters of cilostazol were observed. Dose adjustment of cilostazol is not required. However, consuming larger quantities of grapefruit juice may affect the pharmacokinetics of cilostazol.

When cilostazol was taken concomitantly with omeprazole (a potent CYP2C19 inhibitor), the AUC of cilostazol and dehydrocilostazol increased by 22% and 68%, respectively, while the AUC of 4′-trans-hydroxycilostazol decreased by 36%. Based on the changes in AUC values, it was determined that the overall pharmacological activity of cilostazol increases by 47% when used concomitantly with omeprazole. It is recommended to reduce the dose of cilostazol to 50 mg twice daily when used concomitantly with omeprazole.

Cilostazol increases the AUC of lovastatin (a CYP3A4 substrate) and its beta-hydroxy metabolite by 70%. Caution is recommended when using cilostazol concomitantly with HMG-CoA reductase inhibitors (statins) metabolized by CYP3A4 (simvastatin, atorvastatin, and lovastatin).

Caution is recommended when using cilostazol concomitantly with CYP3A4 substrates with a narrow therapeutic range (such as cisapride, halofantrine, pimozide, ergot alkaloids).

The effect of drugs that increase the activity of CYP3A4 and CYP2C19, such as carbamazepine, phenytoin, rifampicin, St. John’s wort preparations, on the pharmacokinetics of cilostazol has not been studied. Concomitant use may theoretically reduce the antiplatelet effect of cilostazol, so bleeding time should be monitored regularly.

Clinical studies have established that smoking (a factor that increases CYP1A2 activity) reduces the plasma concentration of cilostazol by 18%.

Caution should be exercised when using cilostazol concomitantly with antihypertensive drugs, as well as any other drugs that potentially lower blood pressure (including nitrates and PDE5 inhibitors), due to the possibility of an additive hypotensive effect with the development of reflex tachycardia.

An increase in the frequency of palpitations and peripheral edema has been observed with the concomitant use of cilostazol and other vasodilating agents, for example, dihydropyridine calcium channel blockers.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.