Pestazole 100 mg tablet number 30
Author Ольга Кияница
|Amount in a package
|Kiev vitamin plant PAT (Ukraine, Kiev)
|The main medicament
Pleistazol (Cilostazol) user manual
Composition of the medicinal product:
active ingredient: cilostazol; 1 tablet contains cilostazol 50 mg or 100 mg;
auxiliary substances: corn starch, hypromelose, microcrystalline cellulose, magnesium stearate, calcium carmelose.
Basic physical and chemical properties:
tablets of 50 mg: tablets of flat-cylindrical form with a bevel, white or almost white;
tablets of 100 mg: tablets of flat-cylindrical form with a facet and a risk, white or almost white.
ATX code. Antithrombotic agents. Antiaggregants. ATX Code B01A C23.
Cilostazol is an inhibitor of platelet aggregation. The drug improves the ability to withstand physical activity, which is evaluated at absolute distance with intermittent claudication (or maximum walking distance, MDC) and the initial distance of intermittent claudication (or painless walking distance, BDH) in testing on the treadmill. According to the results of the studies under different loads, a significant absolute improvement was found at 42 meters of the maximum walking distance (MDC) in comparison with placebo. This corresponds to a relative improvement of 100% compared to placebo. This effect was somewhat weaker in patients with diabetes mellitus.
Cilostazol has a vasodilating effect, which has been confirmed by measuring the blood flow of the lower limbs with the help of tensometric plethysmography. Cilostazol also inhibits the proliferation of smooth muscle cells and inhibits the release of platelet platelets from platelet growth factor and PF-4 in human platelets.
Studies have demonstrated that cilostazol causes reversible inhibition of platelet aggregation. Inhibition is effective against a number of aggregates (including arachidonic acid, collagen, ADP and epinephrine), in patients the inhibition lasts up to 12 hours, and upon completion of cilostazol administration, aggregation was restored within 48-96 hours, without the effect of rebounding (hyperaggregation). Also, the effect of cilostazol on the lipids circulating in the blood plasma was established. Taking the drug reduces triglyceride levels and increases the level of HDL-cholesterol. Long-term use of the drug did not cause an increase in the level of mortality in patients compared with placebo.
With regular administration of cilostazol at a dose of 100 mg twice daily in patients with peripheral vascular disease, a stable condition is achieved within 4 days. Cmax of cilostazol and its primary metabolites increases less proportionately with increasing doses. Nevertheless, the AUC of cilostazol and its metabolites increases approximately in proportion to the dosage. The apparent half-life of cilostazol is 10.5 hours. There are two main metabolites, ̶ dehydrocystostazol and 4'-trans-hydroxycilostazol, which have similar half-lives. Dehydrometabolite has a 4-7 times higher antithrombotic activity than the starting material, and 4'-trans-hydroxymetabolite - 1/5 of the activity of cilostazol. Plasma concentrations (obtained with AUC) 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. The primary isoenzymes of cytochrome P450 that participate in its metabolism are ̶ CYP3A4, to a lesser extent ̶ CYP2C19 and to an even lesser extent CYP1A2. The main way of excretion ̶ with urine (74%), residual amounts are excreted with feces.Insignificant amounts of unchanged cilostazol are excreted in the urine, and less than 2% of its dose is released as dehydrozylostazole. Approximately 30% of the initial dose is excreted in the urine as 4'-trans-hydroxymetabolite.Residual amounts are allocated as the sum of metabolites, none of which exceeds 5% of the total.
Cilostazol binds to proteins by 95-98%, mainly with albumin. Dehydrometabolite and 4'-trans-hydroxymetabolite bind to proteins at 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 patients with severe renal insufficiency, the free fraction of cilostazol was 27% higher, and Cmax and AUC were 29% and 39%, respectively, than those with normal kidney function, respectively. Cmax and AUC of dehydrometabolite were respectively 41% and 47% lower in patients with severe renal impairment compared with patients with normal renal function. Cmax and AUC of 4'-trans-hydroxycilostazole were 173% and 209% higher in those with severe renal insufficiency. There is no data on patients with moderate or severe hepatic insufficiency.
To increase the maximum painless walking distance in patients with intermittent claudication that do not have resting pain and signs of necrosis of peripheral tissues (peripheral arterial disease, stage II Fontaine).
Known hypersensitivity to cilostazol or to any component of the drug, severe renal failure (creatinine clearance ≤ 25 mL / min), moderate or severe hepatic impairment, congestive heart failure, pregnancy, any known tendency to bleeding (eg, gastric or duodenal ulcer in stage exacerbations, 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; patients with an extension of the QT interval.
Special security measures.
Patients should be warned about the need to consult a doctor in cases of bleeding or bruising during therapy. In the case of eye bleeding, the use of cilostazol should be discontinued.
Since the drug is able to inhibit platelet aggregation, the risk of bleeding increases during surgical interventions (including minor interventions, such as tooth extraction). If a patient needs to undergo surgery and the anti-aggregation effect is undesirable, the cilostazol should be discontinued 5 days before the surgery.
There were isolated reports of hematologic 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.
Patients should be warned about the need to report immediately any signs that may indicate 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 take place.Reception of cilostazol should be discontinued if there are clinical or laboratory evidence of pathological changes in the blood.
Caution is necessary when combined use of cilostazol with inhibitors or inductors CYP 3A4, CYP 2C19 or CYP 3A4 substrates.
It is necessary to prescribe with caution the drug to patients with atrial or ventricular ectopia, fibrillation or atrial flutter.
Caution should be exercised when co-administration of cilostazol with any other means that can reduce 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 an attack of stroke, which shows this drug, was not investigated in asymptomatic ischemic stroke.
Interaction with other drugs and other types of interactions.
Antithrombotic agents. Cilostazol is an inhibitor of phosphodiesterase III with antithrombotic activity. Its use by healthy individuals at a dose of 150 mg for 5 days did not lead to an extended bleeding time.
Acetylsalicylic acid (ASA). Co-administration with ASA for a short time (up to 4 days) was associated with an increase of 23-25% in the inhibition of ADP-induced platelet aggregation in comparison with the use of ASA alone. There were no obvious trends in the level of hemorrhagic side effects in patients who took aspirin and cilostazol, compared with patients who took placebo and equivalent doses of ASA.
Clopidogrel and other antithrombotic agents. The combined administration of cilostazol and clopidogrel did not affect the platelet count, prothrombin time (PT), or activated partial thromboplastin time (APTT). All healthy participants in the studies had an extended bleeding time when taking clopidogrel in monotherapy and in joint use with cilostazol, which did not result in a significant total effect on bleeding time. Nevertheless, caution should be exercised in the combined use of cilostazol with any antithrombotic agents. 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 (eg warfarin). At a single admission, there was no oppression of warfarin metabolism or an effect on coagulation parameters (PV, APTT, bleeding time). Nevertheless, caution is recommended for patients who take cilostazol with any anticoagulant, and perform periodic monitoring to minimize the possibility of bleeding.
Inhibitors of cytochrome P450 (CYP). Cilostazol is largely metabolized by CYP enzymes, especially CYP3A4 and CYP2C19, and to a lesser extent CYP1A2. Dehydrometabolite, which has an antithrombotic activity 4-7 times higher than cilostazol, is probably formed mainly by the action of CYP3A4. 4'-trans-hydroxymetabolite, with an activity of 1/5 of cilostazol, is probably formed by CYP2C19. Thus, agents that inhibit CYP3A4 (eg, some macrolides, azole antifungal agents, protease inhibitors) or CYP2C19 (eg proton pump inhibitors) increase overall pharmacological activity by 32 and 42%, respectively, and may increase the side effects of cilostazol. It may be necessary to reduce the dose of cilostazol to 50 mg twice daily, depending on individual efficacy and tolerability.
Taking 100 mg of cilostazol on the 7th day of the administration of erythromycin (moderate inhibitor of CYP3A4) 500 mg 3 times a day resulted in an increase in AUC of cilostazol up to 74%, which was accompanied by a 24% decrease in the AUC of its dehydrometabolite, but with a marked increase in AUC 4'-trans -hydroxymetabolite.
The simultaneous administration of single doses of ketoconazole (a strong inhibitor of CYP3A4) 400 mg and cilostazol 100 mg resulted in a 117% increase in AUC of cilostazol, which was accompanied by a 15% decrease in the AUC of dehydrometabolite and an 87% increase in AUC 4'- trans-hydroxymetabolite, which generally increased total pharmacological activity by 32% in comparison with monotherapy with cilostazol.
Using 100 mg of cilostazol twice daily with diltiazem (inhibitor CYP3A4) 180 mg once a day resulted in a 44% increase in AUC of cilostazol. The combined administration did not affect the dehydrometabolite exposure, but increased the AUC 4'-trans-hydroxymetabolite by 40%. In patients co-administration with diltiazem led to an increase in AUC of cilostazol by 53%.
The administration of a single dose of 100 mg of cilostazol with 240 ml of grapefruit juice (an inhibitor of intestinal CYP3A4) had no significant effect on the pharmacokinetics of cilostazol.
A single dose of 100 mg of cilostazol on the 7th day of omeprazole (CYP2C19 inhibitor) 40 mg once a day increased the AUC of cilostazol to 26%, which was accompanied by a 69% increase in the AUC of dehydrometabolite and a 31% decrease in the AUC 4'-trans-hydroxymetabolite, that as a result increased the total pharmacological activity by 42% in comparison with monotherapy with cilostazol.
Substrates of the enzyme cytochrome P 450. There was an increase in cuvostazol AUC of lovastatin (sensitive substrate CYP3A4) and its β-hydroxy acid up to 70%. Caution should be exercised when co-administration of cilostazol with CYP3A4 substrates with a narrow therapeutic index (for example, cisapride, halofantrine, pimozide, ergot derivatives). Caution is necessary in the case of joint administration with simvastatin.
Inductors of the enzyme cytochrome P 450. The effect of inducers CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin and St. John's wort preparations) on the pharmacokinetics of cilostazol has not been investigated.Theoretically, the antithrombotic effect can change, therefore it is necessary to monitor the use of cilostazol with inducers P 450.
During studies, tobacco smoking (which induces CYP1A2) reduced the concentration of cilostazol in the blood plasma by 18%.
Features of application.
Use during pregnancy or lactation.
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 during breastfeeding is not recommended.
The ability to influence the reaction rate when driving vehicles or other mechanisms.
Caution should be used, because dizziness may occur when taking the drug.
Method of administration and dose.
The recommended dose of the drug is 100 mg twice a day. Tablets are taken 30 minutes before meals or 2 hours after eating in the morning and evening.
Taking the drug during meals can increase its maximum plasma concentration, which increases the risk of adverse reactions. Significant improvement in the condition of patients is observed after taking the drug for 16-24 weeks, sometimes improvement was noted after 4-12 weeks of therapy. If the treatment was not effective within 6 months, the doctor should prescribe another therapy.
Renal and hepatic insufficiency. For patients with creatinine clearance> 25 ml / min and mild hepatic insufficiency, special dose adjustment is not needed.
Patients of advanced age. There is no need for dose adjustment for this category of patients.
The drug is not recommended for children because of a lack of safety and efficacy data.
Information on acute overdose is limited. Possible severe headache, diarrhea, tachycardia and cardiac arrhythmias.Patients should observe and conduct supportive therapy. It is necessary to empty the stomach by inducing vomiting or rinsing.
When using cilostazol, there may sometimes be undesirable effects, which are listed below.
From the blood and lymphatic systems: often - bruises; 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 swelling of the face); infrequently ̶ hyperglycemia, diabetes mellitus; single - anorexia.
On the part of the mental system: infrequently - anxiety.
From the nervous system: very often - headache; often - dizziness; infrequently - insomnia, unusual dreams; single - paresis, hypoesthesia.
On the part of the organs of vision: single - conjunctivitis.
From the organs of hearing: single - noise in the ears.
From the cardiovascular system: often - palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles;infrequently, myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, syncope, ocular hemorrhages, epistaxis, gastrointestinal bleeding, vague bleeding, orthostatic hypotension;single - hot flashes, hypertension, hypotension, cerebral hemorrhages, pulmonary hemorrhages, muscle hemorrhages, hemorrhages in the airways, subcutaneous hemorrhages.
From the respiratory tract: often - rhinitis, pharyngitis; infrequently - dyspnea, pneumonia, cough; single - interstitial pneumonia.
Gastro-intestinal tract: often - diarrhea, disturbance of bowel movements; often - nausea, vomiting, dyspepsia, flatulence, abdominal pain; rarely - gastritis.
On the part of the hepatobiliary system: single - hepatitis, abnormal liver function, jaundice.
Skin and subcutaneous tissue disorders: often - a rash, itching; single - eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
The kidneys and the urinary tract: rarely - renal failure, renal dysfunction; single - hematuria, pollakiuria.
General disorders: often - pain in the chest, fatigue; rarely - myalgia, chills; single - hyperthermia, malaise, pain.
Laboratory Tests: unit - increased levels of uric acid, blood urea, creatinine.
A higher incidence of heart and peripheral edema observed when cilostazol was used in conjunction with other vasodilators, which can cause reflex tachycardia, for example with the dihydropyridine calcium channel blockers.
Store in the original packaging, at a temperature not higher than 25 ° C. Keep out of the reach of children.
10 tablets in a blister; 3 or 6 of blisters in a pack.
Category of vacation.