Cilostazol - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antiaggregants

Included in the formulation

Aducil®

pills inwards

SEM Pharmaceuticals Limited Cyprus

Pletasol®

pills inwards

ESCO PHARMA, LLC

АТХ:

B.01.A.C.23 Cilostazolum

Pharmacodynamics:

Cilostazol - a selective inhibitor of phosphodiesterase III - has a vasodilator, antiplatelet and antithrombotic effect.

The quinolinone derivative.

The primary mechanism of pharmacological action of cilostazol is inhibition of type 3 phosphodiesterase and, consequently, an increase in the intracellular content of cAMP. In the liver, cilystazole is metabolized by the main isoenzyme of the cytochrome P450-CYP3A4 system and, to a lesser extent, CYP2C19 and CYP1A2.

Cilostazol reversibly inhibits platelet aggregation, caused by various stimuli, surpassing in this respect aspirin, dipyridamole, ticlopidine and pentoxifylline. It also inhibits the formation of arterial thrombi and the proliferation of smooth muscle cells, has a vasodilating effect.

Additional potentially useful effects of cilostazol found in clinical trials were a decrease in serum triglyceride levels and an increase in cholesterol concentrations in the high-density lipoprotein fraction.

Pharmacokinetics:

With regular administration of cilostazol at a dose of 100 mg twice a day in patients with peripheral vascular disease, a stable condition is achieved within 4 days. Maximum concentrationCilostazol and its primary metabolites increase in less proportion to the increase in dose. Nevertheless, the systemic exposure of cilostazol and its metabolites increases approximately in proportion to the dosage. The apparent half-life of cilostazol is 10.5 hours. There are 2 main metabolites - dehydroxylostazole and 4'-trans-hydroxycilostazole, which have similar half-life values. Dehydrometabolite has a 4-7 times higher antithrombotic activity than the starting material, and 4'-trans-hydroxymetabolite - ¹/₅ activity of cilostazol. Plasma concentrations (obtained by systemic exposure) of dehydro- and 4'-trans-hydroxymetabolites approximately constitute 41% and 12% of the concentration of cilostazol, respectively.

Cilostazol is excreted primarily by metabolism and further excretion of its metabolites in the urine. Primary isoenzymes of cytochrome P450, which are involved in its metabolism, CYP 3A4, to a lesser extent - CYP 2C19 and, to an even lesser extent, CYP 1A2. The main way of excretion is with urine (74%), residual amounts are excreted with feces. Insignificant amounts of unchanged cilostazol are excreted in the urine and less than 2% of the dose in the form of dehydroxylostasol. About 30% of the initial dose is excreted in the urine as 4'-trans-hydroxymetabolite.Residual amount is allocated as the sum of metabolites, none of which exceeds 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 are no data on the ability of cilostazol to induce microsomal liver enzymes. The pharmacokinetics of cilostazol and its metabolites did not depend to a large extent on the age or sex of patients 50-80 years old.

In persons with severe renal insufficiency, the free fraction of cilostazol was 27% higher, the maximum concentration29% lower and system exposure 39% less than those with normal kidney function. Maximum concentrationdihydrometabolite was 41% lower, and systemic exposure was 47% less in patients with severe renal impairment compared with patients with normal renal function. The maximum concentration of 4'-trans-hydroxycilostazol was 173% higher, and systemic exposure was 209% greater in those with severe renal insufficiency. There is no data on patients with moderate or severe hepatic insufficiency.

Indications:

After stenting (in combination with aspirin).

To increase the maximum painless walking distance in patients with intermittent claudication, who do not have pain at rest and signs of necrosis of peripheral tissues (peripheral arterial disease, stage II according to Fontaine).

Currently, the prospects of its use for the prevention of recurrent stroke, thrombosis and restenosis after reconstructive vascular surgeries, as well as for the treatment of post-stroke syndrome are estimated.

ICD-10

IX.I20-I25.I22 Repeated myocardial infarction

IX.I20-I25.I21 Acute myocardial infarction

IX.I70-I79.I70.2 Atherosclerosis of the arteries of the extremities

IX.I70-I79.I73.0 Raynaud's syndrome

IX.I70-I79.I73.1 Obliterating thromboangitis [Berger's disease]

IX.I70-I79.I79 * Disorders of arteries, arterioles and capillaries in diseases classified elsewhere

IX.I80-I89.I87.2 Venous insufficiency (chronic) (peripheral)

Contraindications:

Known hypersensitivity to cilostazol or any component of the drug, severe renal failure (creatinine clearance ≤ 25 mL / min), moderate or severe hepatic insufficiency, congestive heart failure,pregnancy, lactation, any known tendency to bleeding (eg, stomach or duodenal ulcer in the acute stage, recent hemorrhagic stroke (up to 6 months), proliferative form of diabetic retinopathy, poorly controlled hypertension).

Contraindicated in patients with ventricular tachycardia, ventricular fibrillation, or multilocular ventricular ectopia, who have or have not received appropriate therapy; with an extension of the interval Q-T.

Carefully:

The drug is not recommended for prescribing to children because of the lack of data regarding safety and efficacy of the application.

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

Pregnancy and lactation:

Category of recommendations for FDA - C. There are no confirmed data on the use of cilostazol in pregnant women, the potential risk is unknown. The drug is not used in pregnant women.

Cilostazol can penetrate into breast milk, accurate data are absent. Given the possible negative impact on newborns,the use of the drug in the period of breastfeeding is not recommended.

Dosing and Administration:

The initial dose: 100 mg 2 times a day. Accepted on an empty stomach, for 30 minutes or 2 hours before or after breakfast or dinner. Taking the drug during meals can increase its maximum concentration in the blood plasma, which increases the risk of adverse reactions.

The course of treatment can last from 16 to 24 weeks.

The first improvements can occur only after 4 - 12 weeks.

Side effects:

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

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

From the side immune system: infrequently, allergic reactions.

From the side digestive system and metabolism: often - edema (peripheral or swelling of the face); infrequently - hyperglycemia, diabetes mellitus; single cases - anorexia.

Disorders of the psyche: infrequently - anxiety.

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

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

From the side the organ of hearing: single cases, noise in the ears.

From the side of cardio-vascular system: often - palpitation, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles; infrequently - myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, unconsciousness, eye hemorrhages, nosebleeds, gastrointestinal bleeding, vague bleeding, orthostatic hypotension; single cases - hot flashes, hypertension, hypotension, cerebral hemorrhages, pulmonary hemorrhages, muscle hemorrhages, hemorrhages in the respiratory tract, subcutaneous hemorrhages.

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

From the side GIT: very often - diarrhea, stool; often - nausea, vomiting, indigestion, flatulence, abdominal pain; infrequently - a gastritis.

From the side hepatobiliary system: single cases - hepatitis, a violation of the liver, jaundice.

From the side skin and subcutaneous tissues: often - a rash, itching; single cases - eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

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

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

Laboratory research: single cases - increased levels of uric acid, urea, creatinine.

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

Overdose:

Information on acute overdose is limited. Possible severe headache, diarrhea, tachycardia and arrhythmia. Patients should be observed and maintained maintenance therapy. It is necessary to empty the stomach by inducing vomiting or rinsing.

Interaction:

In the liver cilostazol metabolized under the influence of the main isoenzyme of the cytochrome P450 - CYP3A4 system and to a lesser extent - CYP2C19 and CYP1A2. In this connection, the drug interaction of cilostazol with numerous drugs, also metabolized by CYP3A4, is possible. These include some antibiotics (erythromycin, clarithromycin), antifungal drugs (ketoconazole, itraconazole), calcium antagonists, benzodiazepines, etc.

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

Special instructions:

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

Because the drug is able to inhibit platelet aggregation, the risk of bleeding during surgical interventions (including minor, for example, tooth extraction) increases. If the patient needs to do this and the anti-aggregation effect is undesirable, the use of cilostazol should be discontinued 5 days before the surgery.

There have been individual reports of hematological abnormalities, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia and aplastic anemia. Most patients recovered after cessation of cilostazol. 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 the early development of pathological changes in the blood, such as hyperthermia and sore throat. It is necessary to conduct a complete blood test if there is a suspicion of infection or any other clinical signs of pathological changes in the blood. The use of cilostazol should be discontinued if there is clinical or laboratory evidence of pathological changes in the blood.

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

Precautions should be taken when concomitant administration of cilostazol with any other medicines that can reduce blood pressure, as there is a risk of additive hypotensive effect with reflex tachycardia.

It should be used with caution cilostazol with any other anticoagulants.

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

Care should be taken when managing transport, since dizziness may occur when taking the medication.

Instructions

Cilostazolum (Cilostazolum)