Cilostazol

Pharmacological properties

cilostazol is an inhibitor of platelet aggregation. the drug improves the ability to tolerate physical exertion, which is assessed by the absolute distance with intermittent claudication (or maximum walking distance - mdx) and by the initial distance with intermittent claudication (or painless walking distance - bdh) in testing on a treadmill. according to the results of studies at various loads, a significant absolute improvement of 42 meters mdh was found compared with placebo. this corresponds to a relative improvement of 100% compared with placebo. this effect was slightly lower in patients with diabetes mellitus.

Cilostazol has a vasodilator effect, which is confirmed by measuring the blood flow of the lower extremities using tensometric plethysmography. Cilostazol also inhibits the proliferation of smooth muscle cells and the platelet release reaction 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 number of aggregates (including arachidonic acid, collagen, ADP and adrenaline), in patients it lasts up to 12 hours, and upon completion of cilostazol administration, recovery of aggregation occurred within 48–96 hours without rebound effect (hyperaggregation). The effect of cilostazol on lipids circulating in blood plasma was also established. Taking the drug reduces TG and increases HDL cholesterol. Long-term use of the drug did not cause an increase in mortality among patients compared with placebo.

Pharmacokinetics With regular use of cilostazol in a dose of 100 mg 2 times a day in patients with peripheral vascular disease, a stable state is achieved within 4 days. WITH_max cilostazol and its primary metabolites increase less in proportion to the dose increase. However, the AUC of cilostazol and its metabolites increases approximately in proportion to dosage. Explicit T_½ cilostazol is 10.5 hours. There are 2 main metabolites - dehydrocylostazole and 4’-trans-hydroxycylostazole, which have close T_½. Dehydrometabolite has 4–7 times higher antithrombotic activity than the starting material, and 4’-trans-hydroxymetabolite - ¹/₅ cilostazol activity. Plasma concentrations (obtained using AUC) of dehydro- and 4’-trans-hydroxymetabolites are approximately 41 and 12% of the concentration of cilostazol, respectively.

Cilostazol is excreted primarily through metabolism and the subsequent excretion of its metabolites in the urine. The primary isoenzymes of cytochrome P450, which are involved in its metabolism, are CYP 3A4, to a lesser extent - CYP 2C19 and to an even lesser extent - CYP 1A2. The main route of excretion is with urine (74%), residual amounts are excreted in the feces. Minor amounts of unchanged cilostazol are excreted in the urine and less than 2% of the dose in the form of dehydrocylostazol. About 30% of the initial dose is excreted in the urine as 4’-trans-hydroxymetabolite. The residual amount is allocated as the sum of the metabolites, none of which exceed 5% of the total.

Cilostazol binds to plasma proteins by 95–98%, mainly with albumin. Dehydrometabolite and 4’-trans-hydroxymetabolite - by 97.4 and 66%, respectively.

There is no data on the ability of cilostazol to induce microsomal liver enzymes. The pharmacokinetics of cilostazol and its metabolites did not depend significantly on the age or gender of patients 50–80 years old.

In patients with severe renal failure, the free fraction of cilostazol was 27% higher, C_max 29% lower and AUC 39% less than those with normal renal function. WITH_max dehydromethabolite was 41% lower, and AUC was 47% less in patients with severe renal impairment compared with patients with normal renal function. WITH_max 4’-trans-hydroxycylostazole was 173% higher, and the AUC was 209% higher in people with severe renal failure. No data are available for patients with moderate to severe hepatic impairment.

Indications

To increase the maximum painless walking distance in patients with intermittent claudication, without pain at rest and signs of peripheral tissue necrosis (peripheral arterial disease, stage II by fountain).

Application

The recommended dose is 100 mg 2 times a day. tablets are taken 30 minutes before or 2 hours after a meal in the morning and evening.

Taking the drug with food can increase it._max in blood plasma, which increases the risk of adverse reactions. A significant improvement in the condition of patients is observed after taking the drug for 16-24 weeks, sometimes it was noted after 4-12 weeks of treatment. If within 6 months the therapy was not effective, the doctor should prescribe another treatment.

Renal and liver failure. For patients with creatinine clearance of 25 ml / min and mild liver failure, special dose adjustment is not required.

Elderly patients. There is no need for dose adjustment for this category of patients.

Children. The drug is not recommended for children due to lack of data regarding the safety and effectiveness of use.

Contraindications

Known hypersensitivity to cilostazol or any component of the drug, severe renal failure (creatinine clearance ≤25 ml / min), moderate or severe liver failure, congestive heart failure, pregnancy, any known tendency to bleed (for example, stomach or duodenal ulcer in the acute stage , recent hemorrhagic stroke (up to 6 months), proliferative form of diabetic retinopathy, poorly controlled ag). it is contraindicated in patients with ventricular tachycardia, ventricular fibrillation, or multilocular ventricular ectopia who have undergone or have not undergone appropriate therapy; with lengthening of the q – t interval.

Side effects

When using cilostazol, sometimes the undesirable effects listed below can occur.

From the circulatory and lymphatic systems: often - hematomas; infrequently - anemia; rarely - prolonged bleeding time, thrombocytosis; single - a tendency to bleeding, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia.

From the immune system: infrequently - allergic reactions.

From the digestive system and metabolism: often - edema (peripheral or facial edema); infrequently - hyperglycemia, diabetes mellitus; isolated cases - anorexia.

Mental disorders: infrequently - anxiety.

From the nervous system: very often - headache; often dizziness; infrequently - insomnia, unusual dreams; isolated cases - paresis, hypesthesia.

From the side of the organ of vision: isolated cases - conjunctivitis.

On the part of the hearing organ: isolated cases are tinnitus.

From the cardiovascular system: often - palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles; infrequently - myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, loss of consciousness, eye hemorrhage, nosebleeds, gastrointestinal bleeding, undefined bleeding, orthostatic hypotension; isolated cases - hot flashes, hypertension, hypotension, cerebral hemorrhage, pulmonary hemorrhage, muscle hemorrhage, hemorrhage in the respiratory tract, subcutaneous hemorrhage.

From the respiratory tract: often - rhinitis, pharyngitis; infrequently - shortness of breath, pneumonia, cough; isolated cases - interstitial pneumonia.

From the digestive tract: very often - diarrhea, impaired stool; often - nausea, vomiting, dyspepsia, flatulence, abdominal pain; infrequently - gastritis.

From the hepatobiliary system: isolated cases - hepatitis, impaired liver function, jaundice.

On the part of the skin and subcutaneous tissues: often - rash, itching; isolated cases - eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

From the kidneys and urinary tract: rarely - renal failure, impaired renal function; isolated cases - hematuria, pollakiuria.

General disorders: often - chest pain, asthenia; infrequently - myalgia, chills; isolated cases - hyperthermia, malaise, pain.

Laboratory studies: isolated cases - increased levels of uric acid, urea, creatinine.

An increase in the number of cases of palpitations and peripheral edema was observed when cilostazol was used simultaneously with other vasodilators, which can cause reflex tachycardia, for example, dihydropyridine calcium channel blockers.

special instructions

The patient must be warned about the need to consult a doctor in case of bleeding or hematomas during therapy. when eye bleeding occurs, cilostazol should be discontinued.

Since the drug can inhibit platelet aggregation, the risk of bleeding during surgery (including minor ones, such as tooth extraction) is increased. If the patient needs to undergo such an intervention and the anti-aggregation effect is undesirable, cilostazol should be discontinued 5 days before surgery.

There have been separate reports of hematologic abnormalities, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia and aplastic anemia. Most patients recovered after cilostazol was discontinued. However, several cases of pancytopenia and aplastic anemia have been fatal.

The patient should be warned about the need to immediately report any signs that may indicate an early development of pathological changes in the blood, such as hyperthermia and sore throat. A complete blood count should be performed if there is a suspicion of infection or any other clinical signs of pathological changes in the blood. Cilostazol should be discontinued if there is clinical or laboratory evidence of abnormal blood changes.

Caution is necessary when using cilostazol with inhibitors or inducers of CYP 3A4, CYP 2C19 or substrates of CYP 3A4.

Caution is advised to prescribe the drug to patients with atrial or ventricular ectopia, atrial fibrillation, or flutter.

Precautions must be observed when taking cilostazol with any other drugs that can lower blood pressure, since there is a risk of an additive hypotensive effect with reflex tachycardia.

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

The effect of inhibition of the development of stroke, which this drug exhibits, was not investigated in asymptomatic ischemic stroke.

Use during pregnancy and lactation. There is no confirmed data regarding the use of cilostazol in pregnant women, the potential risk is unknown. The drug is not used in pregnant women.

Cilostazol can pass into breast milk, exact data are not available. Given the possible negative effect on newborns, the use of the drug during lactation is not recommended.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Caution should be exercised, since dizziness is possible when taking the drug.

Interactions

Antithrombotic agents. Cilostazol is an inhibitor of PDE III with antiplatelet activity. its use in healthy individuals at a dosage of 150 mg for 5 days did not lead to an increase in bleeding time

Acetylsalicylic acid (ASA).The combined use with ASA for a short time (up to 4 days) was associated with an increase of 23–25% inhibition of ADP-induced platelet aggregation compared to taking ASA alone. There were no obvious tendencies for an increase in hemorrhagic side effects in patients who took ASA and cilostazol, compared with patients who took placebo and equivalent doses of ASA.

Clopidogrel and other antithrombotic agents. The combined use of cilostazol and clopidogrel did not affect platelet count, prothrombin time (PV) or activated partial thromboplastin time (APTT). All healthy participants in the studies had an extended bleeding time when taking clopidogrel as monotherapy and when combined with cilostazol, which did not lead to a significant total effect on bleeding time. Nevertheless, caution should be exercised in the combined use of cilostazol with any antithrombotic drugs. It is necessary to consider the possibility of periodic monitoring of bleeding time. Particular attention should be given to patients who receive multicomponent antithrombotic therapy.

Oral anticoagulants (e.g. warfarin). With a single dose, there was no inhibition of warfarin metabolism or an effect on coagulation parameters (PV, APTT, bleeding time). Nevertheless, caution is advised in patients who take cilostazol with any anticoagulant drug and periodically monitor it to minimize the possibility of bleeding.

Inhibitors of cytochrome P450. Cilostazol is largely metabolized by CYP enzymes, especially CYP 3A4 and CYP 2C19, and to a lesser extent, CYP 1A2. Dehydrometabolite, which has an antithrombotic activity 4-7 times higher than that of cilostazol, is probably formed mainly under the influence of CYP 3A4. 4’-Trans-hydroxymetabolite with activity ¹/₅ cilostazol is probably formed using CYP 2C19. Thus, drugs that suppress CYP 3A4 (e.g., some macrolides, azole antifungals, protease inhibitors) or CYP 2C19 (e.g., proton pump inhibitors) increase the overall pharmacological activity by 32 and 42%, respectively, and may enhance the side effects of cilostazol. It may be necessary to reduce the dose of cilostazol to 50 mg 2 times a day, depending on individual effectiveness and tolerability.

Reception of 100 mg of cilostazol on the 7th day of the use of erythromycin (moderate inhibitor of CYP 3A4) 500 mg 3 times a day led to an increase in AUC of cilostazol to 74%, which was accompanied by a decrease of 24% AUC of its dehydromethabolite, but with a noticeable increase in AUC 4- trans hydroxymetabolite.

The combined administration of single doses of ketoconazole (a strong CYP 3A4 inhibitor) 400 mg and cilostazol 100 mg led to an increase in AUC of cilostazol by 117%, which was accompanied by a decrease of 15% in AUC of dehydromethabolite and an increase of 87% in AUC of 4-trans-hydroxymethabolite, which increased the total pharmacological activity by 32% compared with monotherapy with cilostazol.

The use of 100 mg of cilostazol 2 times a day with diltiazem (CYP 3A4 inhibitor) 180 mg 1 time per day led to an increase in AUC of cilostazol by 44%. The combined dose did not affect the exposure of dehydromethabolite, but increased the AUC of 4’-trans-hydroxymethabolite by 40%. In patients, concomitant use with diltiazem led to an increase in AUC of cilostazol by 53%.

The use of a single dose of 100 mg of cilostazol with 240 ml of grapefruit juice (an intestinal inhibitor of CYP 3A4) did not have a noticeable effect on the pharmacokinetics of cilostazol.

A single dose of 100 mg of cilostazol on the 7th day of administration of omeprazole (a CYP 2C19 inhibitor) 40 mg once a day increased the AUC of cilostazol to 26%, which was accompanied by an increase of 69% in AUC of dehydromethabolite and a 31% decrease in AUC of 4-trans-hydroxymetabolite , which ultimately increased the overall pharmacological activity by 42% compared with monotherapy with cilostazol.

Substrates of the cytochrome P450 enzyme. An increase in cilostazol AUC of lovastatin (a sensitive substrate of CYP 3A4) and its β-hydroxy acid was noted to increase by up to 70%. Caution should be exercised when taking cilostazol with CYP 3A4 substrates with a narrow therapeutic index (for example, cisapride, halofantrine, pimozide, ergot derivatives).Caution is required in case of combined use with simvastatin.

Inducers of the cytochrome P450 enzyme. The effect of CYP 3A4 and CYP 2C19 inducers (such as carbamazepine, phenytoin, rifampicin and St. Johns wort preparations) on the pharmacokinetics of cilostazol was not investigated. Theoretically, the antithrombotic effect may vary, therefore, it is necessary to monitor if cilostazol with P450 inducers is used.

During the study, smoking (which induces CYP 1A2) reduced the concentration of cilostazol in blood plasma by 18%.

Overdose

Information about acute overdose is limited. severe headache, diarrhea, tachycardia and arrhythmia are possible. Patients should be monitored and given maintenance therapy. it is necessary to empty the stomach by inducing vomiting or washing.

Storage conditions

At a temperature not exceeding 25 ° C.