PLAVIKS

Active material: Clopidogrel
When ATH: B01AC04
CCF: Antiplatelet
ICD-10 codes (testimony): I20.0, I21, I63, I73.0, I73.1, I73.9, I74, I79.2, I82
When CSF: 01.12.11.06.01
Manufacturer: SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC (France)

Pharmaceutical form, composition and packaging

Pills, Film-coated Pink colour, round, slightly biconcave, Engraved “75” on one side and “(II) 7I” – another.

Excipients: mannitol, macrogol 6000, microcrystalline cellulose (with low water content, 90 m), giproloza low substituted, Hydrogenated castor oil, opadraj pink (lactose monohydrate, gipromelloza, Titanium dioxide (E171), triacetine, iron oxide red dye (E172)), carnauba wax.

10 PC. – blisters (1) – cardboard boxes.
10 PC. – blisters (2) – cardboard boxes.
10 PC. – blisters (3) – cardboard boxes.
14 PC. – blisters (1) – cardboard boxes.
14 PC. – blisters (2) – cardboard boxes.
14 PC. – blisters (3) – cardboard boxes.

Pharmacological action

Platelet aggregation inhibitor. Clopidogrel (or rather its active metabolite) irreversibly binds to the trombocitarnymi ADP-receptors (ADP receptors) and selectively ingibiruet binding of ADP ADP-receptors on platelets and subsequent activation of the glycoprotein IIb/IIIa complex under the influence of ADP, thereby suppressed ADP-induced by platelet aggregation. Clopidogrel also inhibits platelet aggregation, induced by other agonists, due to the fact, that blocks the activation of platelets dismissed ADP. Clopidogrel irreversibly binds to ADP-receptors of thrombocyte. Hence, platelets, entered with him into interaction, immune to ADP stimulation throughout their life, and normal platelet function is restored with a speed, the proper speed updates platelets.

Clopidogrel is able to prevent the development of aterotromboza in all locations atherosclerotic vessels, in particular cerebral lesions, coronary or peripheral arteries.

Daily admission klopidogrela dose 75 mg the first day receiving significant inhibition of ADP-mediated platelet aggregation, which gradually increases over 3-7 days and then goes on a constant level (when the equilibrium state). In equilibrium platelet aggregation is inhibited by an average of 40-60%. After you stop taking klopidogrela platelet aggregation and bleeding time returned to the original level within an average of 5 days.

Pharmacokinetics

Absorption and distribution

With regular ingestion Plavixa^® dose 75 mg/day, Clopidogrel is rapidly absorbed. On the basis of data on excretion of metabolite of clopidogrel with urine, absorption is at least klopidogrela 50%. However, its concentration in the blood plasma is low and through the 2 h after administration reaches the measurement limit (0.25 ug / l).

In vitro, Clopidogrel and the main metabolite bind reversibly to plasma proteins (98% and 94% respectively), This link is nenasyshhaemoj in a wide range of concentrations.

Metabolism

As prolekarstvom Clopidogrel intensively metabolised in the liver. Its active metabolite, thiol derivative, formed by oxidation of clopidogrel in 2-oxo-clopidogrel and subsequent hydrolysis. Klopidogrela oxidation occurs mainly with the participation by CYP2B6 and CYP3A4 Isoenzymes, and to a lesser extent – CYP1A1, 1A2 and 1S19. Tiolnyj active metabolite quickly and irreversibly binds to the trombocitarnymi receptor, suppressing agregatia platelets thus. This metabolite in plasma is not detected.

The main metabolite klopidogrela, (karboksilnoe derivative), is about 85% circulating plasma metabolites klopidogrela and pharmacological activity, However, he is capable of in vitro inhibition activity of izofermenta 2s9 family of cytochrome p 450. C_max This metabolite in blood plasma after repeated receptions Plavixa^® dose 75 mg is about 3 mg/l and is observed in approximately 1 h after administration. The main metabolite pharmacokinetics is linear (plasma concentrations are increasing in proportion to the dose) in applying klopidogrela in the range of doses from 50 to 150 mg.

Deduction

During 120 hours after intake man ¹⁴P-klopidogrela-about 50% radioactive tags excreted in the urine and approximately 46% – with feces. T_1/2 the main circulating metabolite is 8 h after a single and repeated receptions.

Pharmacokinetics in special clinical situations

The concentration of the main circulating metabolite in plasma with regular admission to the dose of 75 mg/day were lower in patients with severe renal insufficiency (CC 5-15 ml / min) compared with patients with moderate renal insufficiency (CC 30-60 ml / min) and healthy volunteers. Although ingibiruty effect on the ADF-inducyrovannuu agregatia platelets turned out to be reduced (25%) compared to the same effect in healthy volunteers, bleeding time was lengthened to the same extent, as in healthy volunteers, treated with Plavix^® dose 75 mg / day. Clinical tolerability of klopidogrela in patients with renal insufficiency is practically does not differ from that of healthy persons.

In patients with liver cirrhosis (class a or b on a scale Child-Pugh) daily during the 10 days admission klopidogrela dose 75 mg/day was safe and also well tolerated, as in healthy individuals. In patients with liver cirrhosis (class a or b on a scale Child-Pugh) C_max klopidogrela after his one reception and (C)_ss^max klopidogrela after taking regular doses of the drug against the backdrop of a course of treatment was many times higher, than in individuals without cirrhosis. However, the plasma concentration of the primary metabolite, circulating in the blood and the degree of suppression of klopidogrelom ADP-induced platelet aggregation, as well as the time of bleeding in patients with cirrhosis and without it would be comparable.

Testimony

Prevention of aterotromboticheskih events in patients with myocardial infarction, ischemic stroke or peripheral artery Occlusive disease diagnosed.

Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:

- ST segment elevation(unstable angina or myocardial infarction without Q wave), including patients, which was held stenting for percutaneous coronary intervention;

- C ST-segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis.

Dosage regimen

Plaviks^® appointed adults and elderly patients.

The drug is taken orally, regardless of the meal.

Myocardial infarction, ischemic stroke and diagnosed occlusal peripheral arterial disease

The drug is prescribed in a dose 75 mg 1 time / day. Treatment can be started from the early days until 35 the day after myocardial infarction; in terms of 7 days before 6 months – at ischemic stroke.

Acute coronary syndrome without ST segment recovery (unstable angina, myocardial infarction, non-Q wave)

Treatment Plaviksom^® should begin with receiving a single loading dose 300 mg, and then continue at a dose 75 mg 1 time / day (in combination with acetylsalicylic acid at doses 75-325 mg / day). Since the use of acetylsalicylic acid in higher doses associated with an increased risk of bleeding, The recommended dose in this indication acetylsalicylic acid does not exceed 100 mg. The maximum beneficial effect observed in 3 month of treatment. A course of treatment – to 1 year.

Acute coronary syndrome with the rise of ST segment (acute myocardial infarction with ST-segment elevation )

Plaviks^® prescribe a single dose 75 mg 1 times / day with an initial loading dose once-daily in combination with acetylsalicylic acid, thrombolytics (or without thrombolytics). Combination therapy is started as early as possible after the onset of symptoms and continued for, at least, 4 weeks. In older patients 75 years treatment Plaviksom^® should start without receiving loading dose.

Side effect

Safety klopidogrela has been investigated in clinical trials more than 42 000 patients, including over 9000 patients, taking the drug for a year or more. The following are clinically important side effects, observed in clinical studies of CAPRIE, CURE, CLARITY and COMMIT. Portability klopidogrela the dose 75 mg/day in the CAPRIE study is consistent with the portability of acetylsalicylic acid in a dose 325 mg / day. General tolerance of the drug was similar tolerability of acetylsalicylic acid, irrespective of age, sex and race of patients.

From the blood coagulation system: in CAPRIE study – the overall frequency of bleeding in patients, treated with Clopidogrel or acetylsalicylic acid, was 9.3%; the frequency of severe cases when applying klopidogrela was 1.4%, and in the application of acetylsalicylic acid – 1.6%. Patients, treated with Clopidogrel, gastrointestinal bleeding met in 2.0% cases, and in 0.7% cases required hospitalization. Patients, treated with Clopidogrel, and patients, treated with acetylsalicylic acid, gastrointestinal bleeding met respectively in 2% and 2.7% cases, and hospitalization needed in 0.7% and 1.1% cases. The frequency of other bleeding was higher in patients, treated with Clopidogrel, than patients, treated with acetylsalicylic acid (7.3% against 6.5% respectively). However, the frequency of severe bleeding in both groups was the same (0,6% against 0,4%). The most commonly observed in both groups/purple bruises and nosebleeds. Rarely met hematoma, hematuria and eye hemorrhage (primarily, conjunctive). The frequency of intracranial hemorrhage was 0.4% patients, treated with Clopidogrel, and 0.5% – patients, treated with acetylsalicylic acid.

The study of CURE – application of combination of clopidogrel + acetylsalicylic acid compared to placebo combination + acetylsalicylic acid, does not lead to a statistically insignificant improvement of life-threatening bleeding (frequency 2.2% compared with 1.8%) or fatal bleeding (frequency 0.2% compared with 0.2% respectively). However, the risk of major, small and other bleeding was significantly higher when applying a combination of clopidogrel + acetylsalicylic acid: major bleeding, do not pose danger to life (1.6% – Clopidogrel + acetylsalicylic acid, 1.0% – placebo + acetylsalicylic acid), first and foremost, gastrointestinal bleeding and bleeding at the injection site, as well as small bleeding (5.1% – Clopidogrel + acetylsalicylic acid, 2.4% – placebo + acetylsalicylic acid). The frequency of intracranial bleeding in both groups 0.1%. Frequency of major bleeding when you apply a combination of clopidogrel + acetylsalicylic acid is dependent on dose last (<100 mg – 2.6%; 100-200 mg – 3.5%; >200 mg – 4.9%), same, as and when you apply a combination of acetylsalicylic acid with placebo (<100 mg – 2%; 100-200 mg – 2.3%; >200 mg – 4%). In the course of the study, the risk of bleeding (danger to life, large, small, other) decreased: 0-1 month of treatment [Clopidogrel: 599/6259 (9.6%); placebo: 413/6303 (6.6%)], 1-3 month of treatment [Clopidogrel: 276/6123 (4.5%); placebo: 144/6168 (2.3%)], 3-6 months of treatment [Clopidogrel: 228/6037 (3.8%); placebo: 99/6048 (1.6%)], 6-9 months of treatment[Clopidogrel: 162/5005 (3.2%); placebo: 74/4972 (1.5%)], 9-12 months of treatment [Clopidogrel: 73/3841 (1.9%); placebo: 40/3844 (1.0%)].

Patients, stopped taking the drug for more than 5 days before coronary artery bypass surgery, There was no increase in the frequency of major bleeding during the 7 days after surgery for coronary bypass surgery (4.4% in the case of clopidogrel + acetylsalicylic acid and 5.3% in the case of placebo + acetylsalicylic acid). Patients, continued to take the drug for five days before coronary bypass surgery, Frequency was 9.6% in the case of clopidogrel + acetylsalicylic acid and 6.3% – If I receive one of acetylsalicylic acid.

The study observed overall improvement in CLARITY, frequency of bleeding in the Clopidogrel group + acetylsalicylic acid (17.4%) compared with the placebo group + acetylsalicylic acid (12.9%). Frequency of major bleeding was similar in both gpyppax (1.3% and 1.1% in gpyppax Clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) and practically does not depend on the on the original characteristics of patients and types of fibrinolytic or geparinova therapy. The frequency of fatal bleeding (0.8% and 0.6% in the groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) and intracranial hemorrhage (0.5% and 0.7% in the groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively) was low and not reliably differed in both gpyppax.

The COMMIT study total rate necerebralnyh major bleeding or cerebral bleeding was low and similar in both groups (0.6% and 0.5% in the groups of clopidogrel + acetylsalicylic acid and placebo + acetylsalicylic acid, respectively).

From the hematopoietic system: in CAPRIE study – severe neutropenia (<0.45x10⁹/l) I observed in 4 patients (0.04%), treated with Clopidogrel, and 2 patients (0.02%), treated with acetylsalicylic acid. In 2 patients 9599, treated with Clopidogrel, the number of neutrophils was zero, and none of the 9586, treated with acetylsalicylic acid, such a value is not indicated. During treatment klopidogrelom there was one case of aplastic anemia. The frequency of severe trombopitopenii (<80 000/l) was 0.2% in the Group klopidogrela and 0.1% in the Group of acetylsalicylic acid.

In research for a CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups.

Other clinically important side effects, marked in CAPRIE studies, CURE, CLARITY and COMMIT with frequency ≥ 0.1%, as well as any severe side effects listed below, in accordance with the classification of the who. Their frequency is defined as follows:: often (> 1/100, <1/10); sometimes (> 1/1000, < 1/100); rarely (>1/10 000, < 1/1000).

From the central and peripheral nervous system: sometimes – headache, dizziness, paresthesia; rarely – vertigo.

From the digestive system: often – dyspepsia, diarrhea, abdominal pain; sometimes – nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer and duodenal ulcer.

From the blood coagulation system: sometimes – prolonged bleeding.

From the hematopoietic system: sometimes – leukopenia, reduce the number of neutrophils and eosinophils, reduction in the number of platelets.

Dermatological reactions: sometimes – rash and itching.

Post-marketing data

From the blood coagulation system: common – bleeding (In most cases – during the first month of treatment). Several fatalities (Intracranial, gastrointestinal and retroperitoneal haemorrhage); there are reports of serious cases of skin bleeding (purpura), musculoskeletal bleeding (gemartroz, hematoma), eye haemorrhage (conjunctival, ocular, retinal), nosebleeds, hemoptysis, pulmonary hemorrhage, hematuria and bleeding from the surgical wound; patients, clopidogrel together with acetyl salicylic acid or acetylsalicylic acid and heparin, as there have been cases of severe bleeding.

In addition to these clinical trials were spontaneously declared the following side effects. In each class of (MedDRA classification) they are listed with an indication of the frequency. Term “rarely” corresponds to the frequency <1/10 000. Within each group, the frequency of side effects is presented in descending order of severity.

From the hematopoietic system: rarely – trombogemoliticheskaja Thrombocytopenic Purpura (1 on 200 000 patients), tyazhelaya thrombocytopenia (platelet count ≤ 30 000/l), granulocytopenia, agranulocytosis, anemia and aplastic anemia/pancytopenia.

CNS: rarely – confusion, hallucinations.

Cardio-vascular system: rarely – vasculitis, hypotension.

The respiratory system: rarely – bronchospasm, interstitial pneumonitis.

From the digestive system: rarely – colitis (incl. yazvennыy or limfotsitarnыy colitis), pancreatitis, change in taste, stomatitis, hepatitis, acute liver failure, increase in liver enzymes.

On the part of the musculoskeletal system: rarely – arthralgia, arthritis, myalgia.

From the urinary system: rarely – glomerulonephritis, increase of serum creatinine.

Dermatological reactions: rarely – bullous rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), erythematous rash (related to klopidogrelom or acetylsalicylic acid), eczema, lichen planus.

Allergic reactions: rarely – angioedema, hives, anaphylactoid reactions, serum sickness.

Other: rarely – temperature rise.

Contraindications

- Severe hepatic impairment;

— acute pathological bleeding, eg, bleeding from a peptic ulcer or intracranial hemorrhage;

is a rare hereditary Galactose intolerance, deficiency of lactase and glucose-Galactose malabsorption syndrome;

- Pregnancy;

- Lactation (breast-feeding);

- Children up to age 18 years (Safety and efficacy have not been established);

- Hypersensitivity to the drug.

FROM caution assign product with moderate hepatic insufficiency, where possible predisposition to bleeding (limited clinical experience); renal failure (limited clinical experience); trauma, surgery; for diseases, in which there is a predisposition to develop bleeding (especially the gastrointestinal or intraocular); together with the admission NPVS, incl. selective COX-2 inhibitors; together with the appointment of warfarin, geparina, glycoprotein IIb/Iiia inhibitors.

FROM caution should designate product in liver and kidney (incl. moderate hepatic and/or renal failure), injuries, preoperative conditions.

Pregnancy and lactation

Contraindicated drug Plavix^® Pregnancy and lactation (breast-feeding).

Data on the clinical use of the drug during pregnancy are not available.

Unknown, is allocated whether Clopidogrel in breast milk in humans.

IN experimental studies not revealed nor direct, no indirect adverse effects on pregnancy, embryonic development, rodы and development postnatalynoe. It has been shown, that Clopidogrel and/or its metabolites are highlighted with breast milk from lactating rats.

Cautions

When applying Plavixa^®, especially during the first weeks of treatment and / or after invasive cardiological procedures / surgery, necessary to conduct a thorough monitoring of patients for signs of bleeding exceptions, including hidden.

Because of the risk of bleeding and hematologic side effects arise during treatment of clinical symptoms, suspected of bleeding, should urgently make the CBC, define ACTV, platelet count, functional activity of platelets and conduct other necessary investigations.

Plaviks^®, as well as other anti-platelet drugs, should be used with caution in patients, with an increased risk of bleeding, related injuries, surgery or other pathological conditions, as well as in combined therapy with acetylsalicylic acid, NSAIDs (incl. COX-2 inhibitors), heparin or inhibitors of glycoprotein IIb/Iiia.

The combined use of clopidogrel with warfarin may increase the intensity of bleedings, so, except in specific rare clinical situations (such as the presence of a blood clot in the left jeludocke flotirujushhego, stenting in patients with atrial fibrillation) combined use of Plavixa^® and warfarin is not recommended

With the planned course of treatment, surgical Plaviksom^® should be discontinued 7 days before the operation.

Plaviks^® should be used with caution in patients with a risk of bleeding (particularly gastrointestinal and intraocular).

Patients should be warned that, When receiving Plavixa^® (single or in combination with acetylsalicylic acid) to stop bleeding may take longer, as well as, that in case they have unusual (localization or duration) bleeding, they should inform their doctor. Before any upcoming operation and before receiving any new medication patients should inform their doctor (including dentist) for admission to klopidogrela.

Very rarely were There were also cases of development tromboticheskoj trombocitopenicheskoj Purpura (TTP) After taking klopidogrela (sometimes even a short). It was characterized by thrombocytopenia and mikroangiopaticescoy hemolytic anemia in combination with either the neurological symptoms, violations of the kidney or fever. Development of TTP can be life-threatening and require urgent action, including plasmapheresis.

Clopidogrel is not recommended for acute stroke with less prescription 7 days, tk. There is no data on the use of drugs in this State.

The drug should be administered with caution in patients with impaired renal function.

In the period of treatment is necessary to control the functional activity of the liver. Severe liver problems should take into account the risk of hemorrhagic Diathesis.

Effects on ability to drive vehicles and management mechanisms

Plaviks^® There is a significant impact on the ability to drive or working with machinery.

Overdose

Symptoms: prolonged bleeding and subsequent complications in the form of bleeding.

Treatment: in case of bleeding should be held appropriate therapy. If you need a quick correction to lengthen bleeding time, It recommended a transfusion of platelets. No specific antidote.

Drug Interactions

Combined use of klopidogrela with warfarin is not recommended, Since this combination may increase the intensity of bleeding.

Appointment of glycoprotein IIb/Iiia inhibitors in conjunction with Plaviksom^® requires caution, especially in patients with increased risk of bleeding (trauma and surgery or other pathological conditions).

Acetylsalicylic acid does not alter the inhibitory effect of Plavixa^® the ADF-inducyrovannuu agregatia platelets, but Plavix^® potenziruet effect of acetylsalicylic acid on collagen-induced platelet aggregation. Nonetheless, simultaneous with klopidogrelom reception of acetylsalicylic acid on 500 mg 2 times / day for 1 the day did not produce a significant increase in bleeding time, called reception klopidogrela. Between klopidogrelom and acetylsalicylic acid may pharmacodynamic interaction, which leads to an increased risk of bleeding. Therefore, when they are applying with caution, Although clinical trials patients received combination therapy klopidogrelom and acetylsalicylic acid 1 year.

Together with the use of heparin, According to a clinical study, conducted on healthy volunteers, When taking Plavixa^® do not need to change the dose of heparin and did not change its Anticoagulant activity. The simultaneous use of heparin inhibiting action has not changed klopidogrela on platelet aggregation. Between Plaviksom^® and heparin may pharmacodynamic interaction, that can increase the risk of bleeding, Therefore, when the combination of caution.

Safety joint application klopidogrela, fibrin-specific or nonspecific fibrin-thrombolytic drugs and heparin has been investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to the, that was observed in the case of joint use of thrombolytic funds with acetylsalicylic acid and heparin.

Appointment Of NSAIDS (incl. COX-2 inhibitors) in conjunction with Plaviksom^® requires caution. In a clinical study, held with the participation of healthy volunteers, combined use of klopidogrela and naproksena increased the hidden loss of blood through blood. However, due to the lack of research on the interaction of klopidogrela with other NSAIDS is currently unknown, whether there is an increased risk of gastrointestinal bleeding when taking klopidogrela along with other NSAIDS.

There had been a number of clinical studies with klopidogrelom and the other at the same time appointed drugs with a view to exploring possible farmakodinamicheskogo and pharmacokinetic interaction, that showed the following.

In applying klopidogrela in conjunction with atenolol, nifedipine or with both drugs simultaneously clinically meaningful interaction farmakodinamicheskogo not observed.

The simultaneous use of phenobarbital, zimetidina and estrogen had no significant effect on the pharmacodynamic properties of klopidogrela.

Pharmacokinetic performance of Digoxin and theofillina have not changed in their joint application with klopidogrelom.

Antacids means not reduced absorption klopidogrela.

Phenytoin and tolbutamid security can be used in conjunction with klopidogrelom (CAPRIE study), despite, that data, obtained in the course of studies with human liver mikrosomami, indicates, that karboksilnyj metabolite klopidogrela can inhibit the activity of izofermenta CYP2C9, that may lead to increased plasma concentrations of some drugs (phenytoin, tolbutamida and some NSAIDS), which are metabolized via CYP2C9 izofermenta.

In clinical studies showed no clinically significant interactions of klopidogrela with ACE inhibitors, Diuretics, β-adrenergic, calcium channel blockers, lipid-lowering drugs, coronary vazodilatatorami, anti-diabetic means (incl. insulinom), antiepileptic drugs, drugs for hormone replacement therapy, with antagonists of glycoprotein IIb/IIIa.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children at or above 30 ° C. Shelf life – 3 year.