Plagril A, 75 mg+75 mg 30 pcs

Pharmacodynamics

Clopidogrel

.Clopidogrel (more precisely, its active metabolite) irreversibly binds to platelet ADP receptors and selectively inhibits the binding of ADP to platelet ADP receptors and the subsequent activation of GPIIb/IIIa complex under the action of ADP, thus suppressing ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation caused by other agonists by blocking the increase in platelet activity by released adenosine diphosphate. Due to the irreversible binding of clopidogrel with platelet ADP-receptors, platelets remain immune to ADP stimulation for the rest of their life, and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

When clopidogrel is taken daily at a dose of 75 mg, there is a significant suppression of ADP-induced platelet aggregation from the first day of administration, which gradually increases over 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed by an average of 40-60%. After stopping clopidogrel administration platelet aggregation and bleeding time gradually return to the initial level
on average within 5 days.

Acetylsalicylic acid (ASA)

ASA suppresses platelet aggregation through irreversible inhibition of cyclooxygenase-1 (COX-1), thereby reducing the formation of thromboxane A2, which is an inducer of platelet aggregation and vasoconstriction. This effect persists throughout the life of platelets.

ASA does not change the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, while clopidogrel increases the effect of acetylsalicylic acid on collagen-induced platelet aggregation.

Both active substances are able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in lesions of the cerebral, coronary or peripheral arteries.

Pharmacokinetics

Assimilation

Clopidogrel
.
Clopidogrel is rapidly absorbed in the intestine at a single and course oral dose of 75 mg per day. Mean maximum plasma concentrations of unchanged clopidogrel (about 2.2-2.5 ng/ml after oral administration of a single dose of
75 mg) are reached approximately 45 minutes after its single administration.

According to the excretion of clopidogrel metabolites by the kidneys its absorption is approximately 50%.

Acetylsalicylic acid

After absorption ASK undergoes hydrolysis to form salicylic acid, the maximum concentrations of which in blood plasma are reached one hour after oral administration. Due to rapid hydrolysis in 1.5-3 hours after oral administration ASK is practically not detected in blood plasma.

Distribution

Clopidogrel

In vitro, clopidogrel and its major circulating inactive metabolite reversibly bind to plasma proteins (by 98% and 94%, respectively) and this binding in vitro is unsaturated up to a concentration of 100 mg/L.
Acetylsalicylic acid

ASK weakly binds to plasma proteins and has a small volume of distribution (10 liters). Its metabolite, salicylic acid, binds well to plasma proteins, but its binding to plasma proteins depends on its plasma concentration
(non-linear relationship).

At low concentrations (< 100 µg/ml) about 90% of salicylic acid binds to plasma albumin. Salicylic acid is well distributed in tissues and body fluids, including the central nervous system, breast milk and fetal tissues.

Metabolism

Clopidogrel

Clopidogrel is rapidly metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized via two metabolic pathways: the first pathway is metabolized by esterases, which leads to hydrolysis to form the inactive metabolite ̶ carboxylic acid derivative (accounting for 85% of the metabolites circulating in the systemic blood stream); the second pathway is carried out by several cytochrome P450 system isozymes. At first, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite.

Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel – thiol derivative of clopidogrel. In vitro, this metabolic pathway is metabolized by the CYP2C19, CYP1A2, CYP3A4, and CYP2B6 isoenzymes. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, rapidly and irreversibly binds to platelet receptors, inhibiting platelet aggregation.

After a loading dose of clopidogrel 300 mg, the maximum concentration (Cmax) of the active metabolite is 2 times higher than that after 4 days of a maintenance dose of clopidogrel 75 mg, while its Cmax is reached approximately 30-60 minutes after clopidogrel administration.

Acetylsalicylic Acid

ASA when taken in combination with clopidogrel is rapidly hydrolyzed in plasma to salicylic acid with a half-life of 0.3 to 0.4 hours for ASA 75-100 mg doses. Salicylic acid mainly undergoes conjugation in the liver to form salicylic acid, phenolic glucuronide and acyl glucuronide, as well as a large number of minor metabolites.

Elevation

Clopidogrel

Within 120 hours of human oral intake of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestine. After a single oral dose of 75 mg, the elimination half-life of clopidogrel is approximately 6 hours. After a single and a course of clopidogrel administration, the half-life of the main circulating inactive metabolite in blood is 8 hours.

Acetylsalicylic Acid

The half-life of salicylic acid from blood plasma is about 2 hours. The metabolism of salicylate is saturable, and total clearance is reduced at higher serum concentrations due to the limited ability of the liver to form salicyluric acid and phenolic glucuronide.

After taking toxic doses of ASA (10-20 g), the plasma elimination half-life may increase up to 20 hours. At high doses of ASA, the elimination of salicylic acid corresponds to zero-order kinetics (that is, the elimination rate depends on the plasma concentration) with a half-life of 6 hours or longer.
Renal excretion of the unchanged active substance depends on urine pH. When pH exceeds 6.5 the renal clearance of free salicylate increases

from <5% to >80%. After administration of therapeutic doses, approximately 10% of the ingested dose as salicylic acid, 75% of the ingested dose ̶ as salicyluric acid, 10% of the ingested dose ̶ as phenolic glucuronides, and 5% of the ingested dose ̶ as acyl glucuronides are detected in the urine.

Pharmacogenetics

Several polymorphic isoenzymes of the cytochrome P450 system are involved in the activation of clopidogrel. The CYP2C19 isoenzyme is involved in the formation of both the active metabolite and the intermediate metabolite ̶ 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effects of the active metabolite clopidogrel studied by in vivo platelet aggregation differ depending on the genotype of CYP2C19 isoenzyme.

The CYP2C19*1 gene allele is responsible for normally functioning metabolism, whereas the CYP2C19*2 and CYP2C19*3 isoenzyme gene alleles are responsible for reduced metabolism. These alleles are responsible for reduced metabolism in approximately 85% of Caucasoid races and 99% of Mongoloid races.

Other alleles responsible for reduced metabolism are represented by CYP2C19*4, *5, *6, *7, and *8 isoenzymes, but they are rare in the general population. Pharmacogenetic testing can identify a genotype with variability in CYP2C19 isoenzyme activity. Genetic variants of other enzymes of P450 system with influence on formation of active clopidogrel metabolites are also possible.

Individual patient groups

Elderly patients. No differences in platelet aggregation and bleeding time were obtained in elderly volunteers (over 75 years old) when compared with younger volunteers. No dose adjustment is required for elderly patients.

Children and adolescents.

No data available.

Renal dysfunction. After repeated administration of clopidogrel at a dose of 75 mg/day in patients with severe renal impairment (creatinine clearance (CK) of 5 to
15 ml/min) inhibition of ADP-induced platelet aggregation was lower (25%) compared to that in healthy volunteers, but prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel at a dose of 75 mg/day.

Impaired liver function. After daily use of clopidogrel in daily dose of 75 mg for 10 days in patients with severe hepatic impairment (Chile-Pugh grades ̶ A and B less than 9 points) inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. Mean bleeding time was comparable in both groups.

Ethnicity. The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and reduced metabolism is different between ethnic groups. There are limited literature data on their prevalence among representatives of the Mongoloid race to assess the clinical significance of the impact of CYP2C19 isoenzyme genotypes on clinical outcomes.

The pharmacokinetics and metabolism of both active substances of Plagril® A exclude clinically significant pharmacokinetic interactions.

Indications

Active ingredient

Composition

How to take, the dosage

Interaction

Thrombolytic agents

The safety of coadministration of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytics and heparin has been analyzed in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed when thrombolytics and heparin were used together with ASA. Due to insufficient clinical data on concomitant use of Plagril® A and thrombolytic drugs, caution should be exercised when prescribing them simultaneously (see section “Cautions”).
Glycoprotein IIb/IIIa inhibitors

There may be pharmacodynamic interaction between glycoprotein IIb/IIIa inhibitors and Plagril® A which requires caution when using them simultaneously in patients with increased risk of bleeding (in injuries and surgical interventions or other pathological conditions) (see section “Special Precautions”).

Heparin
According to a clinical study conducted with healthy volunteers, the administration of clopidogrel did not require changes in the dose of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. There is possible pharmacodynamic interaction between the drug Plagril® A and heparin, which may increase the risk of bleeding and requires caution when using them together (see section “Cautions”).

Direct anticoagulants

The simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, in connection with this combination is not recommended. Clopidogrel at a dose of 75 mg does not affect warfarin pharmacokinetics and does not change the International Normalized Ratio (INR) in patients taking warfarin for a long time. However, concomitant administration of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

Non-steroidal anti-inflammatory drugs (NSAIDs)

In a clinical study with healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the GI tract. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with the drug Plagril® A is not recommended (see section “Cautions”).

Experimental evidence supports that ibuprofen (when administered as a single dose of 400 mg between 8 hours before and 30 minutes after immediate ASA dosing of 81 mg in immediate-release form) may inhibit the effect of low doses of ASA on platelet aggregation. However, when not taken regularly, ibuprofen does not have any clinically significant effects on the antiaggregant effect of ASA.

Selective serotonin reuptake inhibitors (SSRIs)

Because SSRIs disrupt platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be performed with caution.

Other combination therapy with clopidogrel

strong and moderate CYP2C9 isoenzyme inhibitors

. Since clopidogrel is metabolized to its active metabolite partially by the CYP2C19 isoenzyme, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. As a precautionary measure, concomitant use of clopidogrel and strong or moderate inhibitors of CYP2C9 isoenzyme should be avoided.

The strong and moderate inhibitors of CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, variconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol. Concomitant use of proton pump inhibitors that are strong or moderate inhibitors of CYP2C19 isoenzyme (e.g., omeprazole, esomeprazole) with clopidogrel is not recommended. If a patient still needs to use proton pump inhibitors concomitantly with the drug Plagril® A, a proton pump inhibitor with insignificant effect on CYP2C19 isoenzyme activity, such as pantoprazole or lansoprazole, should be used.

A number of clinical studies have been conducted with clopidogrel and other concomitantly used drugs to examine possible pharmacodynamic and pharmacokinetic interactions, which showed that:

Special Instructions

Contraindications

Side effects

Bleeding and hemorrhage were the most frequently observed adverse events in clinical trials and in post-marketing use of the drug, mostly occurring during the first month of treatment.

Often: major bleeding [life-threatening bleeding requiring a transfusion of 4 or more units of blood; other major bleeding requiring a transfusion of 2-3 units of blood; non-life-threatening major bleeding (according to the COMMIT study, the incidence of major non-cerebral bleeding and intracranial hemorrhage was “infrequent”)]; minor bleeding (according to the ACTIVE-A study, the incidence of minor bleeding was “very frequent”), bleeding in the vascular puncture site; bruising; hematomas. The incidence of major bleeding with the clopidogrel + acetylsalicylic acid combination depended on the dose of acetylsalicylic acid (< 100 mg ̶ 2.6%; 100-200 mg ̶ 3.5%, >200 mg ̶ 4.9%), as did their incidence with ASA alone (< 100 mg ̶ 2.0%, 100-200 mg ̶ 2.3%, >200 mg ̶ 4.0%).

In patients who discontinued treatment more than 5 days before aortocoronary bypass surgery, there was no increase in major bleeding in the 7 days after this intervention (4.4% with clopidogrel + acetylsalicylic acid versus 5.3% with acetylsalicylic acid alone). In patients who remained on antiplatelet therapy for the last five days before aortocoronary bypass surgery, the incidence of these bleeds after intervention was 9.6% (clopidogrel + acetylsalicylic acid) and 6.3% (acetylsalicylic acid alone).

Infrequent: Fatal bleeding; life-threatening bleeding [bleeding with a decrease in blood hemoglobin of more than 5 g/dL (according to the CLARITY clinical trial, the incidence was “often”)1; bleeding requiring surgical intervention; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical trial, the frequency was “often”); bleeding requiring inotropic drugs]; severe bleeding (purpura, nasal bleeding were the most common; hematuria and intraocular hemorrhages, mainly conjunctival, were less common).

Rare: intraocular hemorrhage with significant visual impairment, retroperitoneal hemorrhage.
Frequency unknown (post-marketing experience with use): serious cases of bleeding, primarily bleeding in skin tissue, bone, muscle and joint cavity (hemarthrosis), ocular tissue (conjunctival, internal media and retina), respiratory bleeding, hemoptysis, nasal bleeding, hematuria, bleeding from surgical wounds; intracranial hemorrhage, including fatal cases, particularly in elderly patients; other cases of fatal bleeding (particularly gastrointestinal hemorrhage and retroperitoneal hemorrhage).

Disorders of the blood and lymphatic system:

Infrequently: Reduced peripheral blood platelet count, severe thrombocytopenia with peripheral blood platelet count < 80×109/l, but > 30×109/l; leukopenia; decreased peripheral blood neutrophil count, eosinophilia, prolonged bleeding time.

Rarely: neutropenia, including severe neutropenia (< 0.45×109/l). Although the risk of myelotoxic effects with clopidogrel is quite low, its possibility should be considered when a patient taking clopidogrel develops fever and other infectious manifestations.

Very rare: aplastic anemia, severe thrombocytopenia with peripheral blood platelet count < 30×109/L.
Frequency is unknown (post-marketing experience of use): Thrombocytopenia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, agranulocytosis; aplastic anemia/pancytopenia, bicytopenia, disorders of medullary hematopoiesis, neutropenia, leukopenia, granulocytopenia, anemia, acquired hemophilia A, thrombotic thrombocytopenic purpura (TTP).

Infrequent: headache, dizziness and paresthesias.

Rarely: vertigo.

Frequency unknown (postmarketing experience with use): changes in taste sensation.

Disorders of the digestive system

Often: gastrointestinal bleeding, dyspepsia, abdominal pain, diarrhea.

Infrequent: nausea, gastritis, flatulence, constipation, vomiting, peptic ulcer and duodenal ulcer.

Hepatic and biliary tract disorders

Dermatological and subcutaneous tissue disorders

Infrequent: skin rash, itching.

Frequency unknown (postmarketing experience with use): Maculopapular, erythematous or exfoliative skin rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome), eczema, lichen planus, fixed skin rash (single or multiple skin changes, usually in the form of erythematous plaques of round or oval shape appearing in the same place with successive administration of the drug).

Immune system disorders

Vascular disorders

Cardiac disorders

Disorders of the respiratory system, thorax and mediastinum

Musculoskeletal and connective tissue disorders

Kidney and urinary tract disorders

Gender and breast disorders

General disorders

Laboratory and instrumental data

Overdose

Pregnancy use