Plestazol of the tab. of 50 mg No. 60

Pharmacological properties

Pharmacodynamics. tsilostazol is inhibitor of aggregation of thrombocytes. medicament improves ability to transfer physical activities which is estimated on an absolute distance at the alternating lameness (or the maximum distance of walking — mdh) and on an initial distance at the alternating lameness (or a painless distance of walking — bdh) in testing on the racetrack. by results of researches at various loadings the considerable absolute improvement on 42 meters mdh in comparison with placebo was established. it corresponds to relative improvement of 100% in comparison with placebo. this effect was slightly lower at patients with diabetes.

Tsilostazol has vazodilatatorny effect that is confirmed with blood flow measurement of the lower extremities by means of a tensometric pletizmografiya. Tsilostazol also inhibits proliferation of cells of unstriated muscles and reaction of release of thrombocytes of a platelet growth factor and PF-4 in thrombocytes of the person.

Research was shown that tsilostazol causes reversible oppression of aggregation of thrombocytes. The inhibition is effective against a number of agregant (including arachidonic acid, collagen, ADF and adrenaline), at patients it lasts up to 12 h, and upon completion of reception of a tsilostazol the restoration of aggregation happened within 48–96 h without effect of a ricochet (hyper aggregation). Influence of a tsilostazol on the lipids circulating in blood plasma is also established. Administration of medicament reduces the TG level and raises — the XC LPVP. Prolonged use of medicament did not cause increase in lethality among patients in comparison with placebo.

Pharmacokinetics. At regular reception of a tsilostazol in a dose of 100 mg 2 times a day at patients with diseases of peripheral vessels the stable state is reached within 4 days. With _max a tsilostazol and its primary metabolites raises less in proportion to increase in a dose. Nevertheless AUC of a tsilostazol and its metabolites increases approximately in proportion to dosing. Obvious T _½ tsilostazola makes 10.5 h. There are 2 main metabolites — degidrotsilostazol and the 4th '-trance-hydroksitsilostazol which have close indicators of T _½ . Degidrometabolit has by 4–7 times higher antitrombotichesky activity, than initial substance, and the 4th '-trance-hydroxymetabolite — ¹ / ₅ activities of a tsilostazol. Concentration in blood plasma (received by means of AUC) degidro- and 4 '-trances-hydroxymetabolites approximately make 41 and 12% of concentration of a tsilostazol respectively.

Tsilostazol is brought by

mainly by means of metabolism and further removal of its metabolites with urine. Primary isoenzymes of P450 cytochrome which take part in his metabolism, CYP 3A4, to a lesser extent — CYP 2C19 and in a smaller degree — CYP 1A2. The main way of removal — with urine (74%), residual quantities are removed with a stake. Insignificant quantities of not changed tsilostazol are removed with urine and less than 2% of a dose — in the form of a degidrotsilostazol. About 30% of an initial dose are removed with urine as the 4th '-trance-hydroxymetabolite. The residual quantity is distinguished as the sum of metabolites, any of which does not exceed 5% of total.

Tsilostazol contacts proteins of blood plasma for 95–98%, mainly albumine. Degidrometabolit also the 4th '-trance-hydroxymetabolite — for 97.4 and 66% respectively.

do not have the abilities of a tsilostazol given relatively to induce microsomal enzymes of a liver. The pharmacokinetics of a tsilostazol and its metabolites did not depend substantially on age or a sex of patients of 50-80 years.

free fraction of a tsilostazol was 27% higher than

At persons with a heavy renal failure, With _max also AUC 39% less, than at persons with normal function of kidneys is 29% lower. With _max was 41% lower than the degidrometabolit, and AUC — is 47% less at patients with heavy disturbances of kidneys in comparison with patients with normal function of kidneys. With _max 4th '-trance-hydroksitsilostazola was 173% higher, and AUC 209% more at persons with a heavy renal failure. There are no data on patients with a moderate and heavy liver failure.

Indication

For increase in the maximum painless distance of walking at the patients with the alternating lameness who do not have pain at rest and symptoms of necrosis of peripheral fabrics (a disease of peripheral arteries, ii stage according to Fontaine).

Use

Recommended dose — on 100 mg 2 times a day. a pill is taken in 30 min. prior to or in 2 h after meal of morning and in the evening.

Administration of medicament at meal time can raise it With _max in blood plasma that increases risk of side reactions. Considerable improvement of a condition of patients is observed after administration of medicament during 16–24 weeks, sometimes it was noted after 4–12 weeks of treatment. If within 6 months the therapy was not effective, the doctor has to appoint other treatment.

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

Patients of advanced age. There is no need for dose adjustment for this category of patients.

Children. Children are not recommended to appoint medicament due to the lack of data on safety and efficiency of use.

Contraindication

Known hypersensitivity to a tsilostazol or any component of drug, a heavy renal failure (clearance of creatinine of ≤25 ml/min.), a moderate or heavy liver failure, stagnant heart failure, pregnancy, any known tendency to bleeding (for example ulcer of stomach or duodenum in aggravation stages, a recent hemorrhagic stroke (up to 6 months), a proliferative form of a diabetic retinopathy, poorly controllable ag). it is contraindicated to appoint to patients with ventricular tachycardia, ventricular fibrillation or a multilokulyarny ventricular ectopia which passed or did not undergo the corresponding therapy; with lengthening of an interval of q-t.

Side effects

At use of a tsilostazol can sometimes arise the undesirable effects which are listed below.

from blood and lymphatic system: often — hematomas; infrequently — anemia; seldom — the extended bleeding time, a thrombocytosis; single — tendency to bleeding, thrombocytopenia, a granulocytopenia, an agranulocytosis, a leukopenia, a pancytopenia, aplastic anemia.

from the immune system: infrequently — allergic reactions.

from digestive system and metabolism: often — hypostasis (peripheral or a face edema); infrequently — a hyperglycemia, diabetes; isolated cases — anorexia.

Disturbance of mentality: infrequently — alarm.

from nervous system: very often — a headache; often — dizziness; infrequently — insomnia, unusual dreams; isolated cases — paresis, a hypesthesia.

from an organ of sight: isolated cases — conjunctivitis.

from an organ of hearing: isolated cases — sonitus.

from a cardiovascular system: often — heartbeat, tachycardia, stenocardia, arrhythmia, ventricular extrasystoles; infrequently — a myocardial infarction, fibrillation of auricles, stagnant heart failure, supraventricular tachycardia, ventricular tachycardia, a loss of consciousness, hematopsias, nasal bleedings, gastrointestinal bleedings, uncertain bleedings, orthostatic hypotension; isolated cases — inflows, hypertensia, hypotension, brain hemorrhages, pulmonary hemorrhages, muscular hemorrhages, hemorrhages in airways, hypodermic hemorrhages.

from airways: often — rhinitis, pharyngitis; infrequently — short wind, pneumonia, cough; isolated cases — interstitial pneumonia.

from a GIT: very often — diarrhea, disturbance of a chair; often — nausea, vomiting, dyspepsia, a meteorism, an abdominal pain; infrequently — gastritis.

from a gepatobiliarny system: isolated cases — hepatitis, an abnormal liver function, jaundice.

from skin and hypodermic fabrics: often — rash, an itching; isolated cases — eczema, Stephens's syndrome — Johnson, a toxic epidermal necrolysis, a small tortoiseshell.

from kidneys and urinary tract: seldom — a renal failure, a renal failure; isolated cases — a hamaturia, a pollakiuria.

General disturbances: often — a stethalgia, an asthenia; infrequently — myalgia, a fever; isolated cases — a hyperthermia, an indisposition, pain.

Laboratory researches: isolated cases — increase in level of uric acid, urea, creatinine.

Increase in quantity of cases of heartbeat and peripheral hypostases was observed by

when tsilostazol applied along with other vazodilatator which can cause reflex tachycardia, for example with dihydropyridinic blockers of calcium channels.

Special instructions

Patient needs to warn about need to see a doctor in case of appearance of bleedings or hematomas during therapy. at appearance of eye bleeding the reception of a tsilostazol needs to be stopped.

As medicament is capable to oppress aggregation of thrombocytes, the risk of developing of bleedings increases during surgical interventions (including insignificant, for example odontectomy). If the patient needs to carry out such intervention and anti-aggregation effect is undesirable, reception of a tsilostazol should be stopped in 5 days prior to operation.

separate messages about hematologic deviations, including thrombocytopenia, a leukopenia, an agranulocytosis, a pancytopenia and aplastic anemia Arrived. Most of patients recovered after the termination of reception of a tsilostazol. However several cases of a pancytopenia and aplastic anemia had a lethal outcome.

Patient should warn about need to report immediately about any signs which can demonstrate prematurity of pathological changes of blood, such as hyperthermia and sore throat. It is necessary to carry out complete analysis of blood if there are suspicions of an infection or any other clinical signs of pathological changes of blood. Reception of a tsilostazol should be stopped in case of availability of clinical or laboratory proofs of pathological changes of blood.

care at simultaneous use of a tsilostazol with inhibitors or inductors CYP 3A4, CYP 2C19 or CYP substrates 3A4 Is necessary for

.

Should appoint by

with care medicament to patients with an atrial or ventricular ectopia, fibrillation or an atrial flutter.

needs to observe precautionary measures at the combined reception of a tsilostazol with any other medicines which can lower the arterial blood pressure as there is a risk of additive hypotensive effect with reflex tachycardia.

Should be careful when assigning a tsilostazol with any other antitrombotichesky means.

Effect of slowing down of development of a stroke which shows this drug, did not investigate in an asymptomatic ischemic stroke.

Use during pregnancy and feeding by a breast. There are no confirmed data on use of a tsilostazol for pregnant women, the potential risk is unknown. Drug is not used at pregnant women.

Tsilostazol can get into breast milk, exact data are absent. Taking into account potential negative impact on newborns the use of medicament during feeding by a breast is not recommended.

Ability to influence speed of response at control of vehicles or other mechanisms. It is necessary to be careful as at intake of medicine the dizziness is possible.

Interaction

Antitrombotichesky means. tsilostazol is inhibitor fde ііі with antithrombocytic activity. its use for healthy faces in a dosage of 150 mg within 5 days did not lead to lengthening of a bleeding time

Acetylsalicylic acid (ASK). The combined use with ASK within a short period of time (up to 4 days) was connected with increase for 23–25% of oppression ADF-indutsirovannoy of aggregation of thrombocytes in comparison with reception only of ASK. Obvious tendencies to increase in level of hemorrhagic side effects at patients who accepted ASK and tsilostazol, in comparison with the patients accepting placebo and equivalent doses of ASK were not observed.

Klopidogrel and other antitrombotichesky means. The combined reception of a tsilostazol and klopidogrelya did not affect quantity of thrombocytes, the prothrombin time (PT) or the activated partial tromboplastinovy time (APTT). All healthy participants of researches had the extended bleeding time at reception klopidogrelya as monotherapy and at the combined use with tsilostazoly that did not lead to considerable total influence on a bleeding time. Nevertheless it is necessary to be careful at the combined use of a tsilostazol with any antitrombotichesky medicines. It is necessary to consider the possibility of periodic monitoring of a bleeding time. Special attention should be paid to patients who receive multicomponent antitrombotichesky therapy.

Oral anticoagulants (for example warfarin). At single dose the oppression of metabolism of warfarin or influence on coagulation parameters (PV, AChTV, a bleeding time) was not revealed. Nevertheless it is recommended to be careful at patients who accept tsilostazol with any anti-coagulative medicament and to carry out periodic monitoring for minimization of possibility of bleeding.

P450 cytochrome Inhibitors. Tsilostazol is substantially metabolized by CYP enzymes, especially CYP 3A4 and CYP 2C19, and in smaller — CYP 1A2. Degidrometabolit which has the antitrombotichesky activity, by 4–7 times exceeding that a tsilostazol probably is formed mainly under the influence of CYP 3A4. 4’ - the Trance-hydroxymetabolite with activity ¹ / ₅ tsilostazola is probably formed by means of CYP 2C19. Thus, medicines which suppress CYP 3A4 (for example some macroleads, azolovy antifungal drugs, inhibitors of proteases) or CYP 2C19 (for example inhibitors of the proton pump) increase the general pharmacological activity by 32 and 42% respectively and can enhance side effects of a tsilostazol. Perhaps, it will be necessary to lower a dose of a tsilostazol to 50 mg 2 times a day depending on individual efficiency and shipping.

Reception of 100 mg of a tsilostazol for the 7th day of use of erythromycin (moderate CYP inhibitor 3A4) of 500 mg 3 times a day led

to increase in AUC of a tsilostazol up to 74% which was followed by reduction by 24% of AUC of its degidrometabolit, but with noticeable increase in AUC 4 '-trances-hydroxymetabolites.

Combined reception of single doses of a ketokonazol (strong CYP inhibitor 3A4) of 400 mg and a tsilostazola of 100 mg led

to increase in AUC of a tsilostazol by 117% which was followed by reduction by 15% of the AUC degidrometabolit and increase by 87% of AUC 4 '-trances-hydroxymetabolites that increased the general pharmacological activity by 32% in comparison with monotherapy tsilostazoly.

Use of 100 mg of a tsilostazol 2 times a day with diltiazem led (CYP inhibitor 3A4) of 180 mg of 1 times a day to increase in AUC of a tsilostazol by 44%. The combined reception did not influence exposure of the degidrometabolit, but increased AUC 4 '-trances-hydroxymetabolites by 40%. At patients the concomitant use with diltiazem led to increase in AUC of a tsilostazol by 53%.

Use of a single dose of 100 mg of a tsilostazol from 240 ml of grapefruit juice (inhibitor of intestinal CYP 3A4) did not render to

noticeable effect on pharmacokinetics of a tsilostazol.

Single dose of 100 mg of a tsilostazol for the 7th day of use of omeprazolum (CYP inhibitor 2C19) of 40 mg of 1 times a day increased AUC of a tsilostazol to 26% that 4 '-trances-hydroxymetabolites were followed by increase by 69% of the AUC degidrometabolit and reduction by 31% of AUC that as a result increased the general pharmacological activity by 42% in comparison with monotherapy tsilostazoly.

P450 cytochrome enzyme Substrates. Increase tsilostazoly AUC of a lovastatin (sensitive CYP substrate 3A4) and its β-hydroxyacids to 70% was noted. It is necessary to be careful at the combined reception of a tsilostazol with CYP substrates 3A4 with the narrow therapeutic index (for example tsizaprid, galofantrin, Pimozidum, ergot derivatives). The care in case of the combined use with simvastatiny is necessary.

P450 cytochrome enzyme Inductors. Influence of inductors CYP 3A4 and CYP 2C19 (such as carbamazepine, Phenytoinum, rifampicin and medicaments of a St. John's wort) on pharmacokinetics of a tsilostazol was not investigated. Theoretically antitrombotichesky action can change therefore it is necessary to carry out monitoring in case of use of a tsilostazol with the inductors P450.

during the researches the tobacco smoking (which induces CYP 1A2) reduced concentration of a tsilostazol in blood plasma by 18%.

Overdose

Information on acute overdose is limited to

. the severe headache, diarrhea, tachycardia and arrhythmia are possible. patients it is necessary to observe and carry out maintenance therapy. it is necessary to empty a stomach by means of induction of vomiting or washing.

Storage conditions

At a temperature not above 25 °C.