Plavix, 75 mg 28 pcs.

Plavix is an antiaggregative.

Pharmacodynamics

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of ADP to the P2Y12-receptor of platelets and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation. Through irreversible binding, platelets remain immune to ADP stimulation for the remainder of their lives (approximately 7-10 days), and recovery of normal platelet function occurs at a rate consistent with the rate of platelet renewal.

The aggregation of platelets caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by the released ADP.

Since the formation of the active metabolite occurs via enzymes of the P450 system, some of which may be polymorphic or inhibited by other drugs, not all patients may have adequate inhibition of platelet aggregation.

When clopidogrel is taken daily at a dose of 75 mg, significant suppression of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases over 3-7 days and then reaches a constant level (when an 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.

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in lesions of the cerebral, coronary or peripheral arteries.

. The ACTIVE-A clinical trial showed that patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel combined with acetylsalicylic acid (ASA) (compared with taking ASA alone) reduced the incidence of combined stroke, myocardial infarction, systemic thromboembolism outside the CNS vessels, or vascular death, more by reducing the risk of stroke.

The efficacy of clopidogrel in combination with acetylsalicylic acid was detected early and persisted for up to 5 years. The reduction in the risk of major vascular complications in the group of patients who took clopidogrel in combination with acetylsalicylic acid was mainly due to a greater reduction in the incidence of strokes. The risk of stroke of any severity when receiving clopidogrel in combination with ASA decreased, and there was a tendency to a lower incidence of myocardial infarction in the group treated with clopidogrel in combination with ASA, but there were no differences in the frequency of non-CNS vascular thromboembolism or vascular death. In addition, receiving clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular causes.

Pharmacokinetics

Intake. Clopidogrel is rapidly absorbed at a single and repeated oral dose of 75 mg/day.

The mean peak plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after oral administration of a single dose of 75 mg) are reached approximately 45 min after administration. According to the urinary excretion of clopidogrel metabolites, its absorption is approximately 50%.

Distribution. In vitro, clopidogrel and its main circulating inactive metabolite are reversibly bound to plasma proteins (by 98% and 94%, respectively), and this binding is unsaturated over a wide range of concentrations.

Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo clopidogrel is metabolized in two ways: the first – through esterases and subsequent hydrolysis to form an inactive metabolite, carboxylic acid derivative (85% of circulating metabolites), and the second way – through the cytochrome P450 system. 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 P450 isoenzymes CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, which has been isolated in in vitro studies, binds rapidly and irreversibly to platelet receptors, blocking platelet aggregation.

Elimination. Within 120 hours after human oral administration of 14C-labeled clopidogrel about 50% of radioactivity is excreted in the urine and approximately 46% of radioactivity is excreted in the feces. After a single oral dose of 75 mg, the T1/2 of clopidogrel is approximately 6 hours. After a single dose and repeated doses, the T1/2 of the main circulating inactive metabolite in blood is 8 hours.

Pharmacogenetics. Both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel are formed using CYP2C19 isoenzyme. The pharmacokinetics and antiaggregant effects of the active metabolite clopidogrel, in an ex vivo study of platelet aggregation, vary depending on the genotype of the CYP2C19 isoenzyme.

The CYP2C19*1 gene allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 gene alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 gene alleles are responsible for reduced metabolism in the majority of Caucasoid (85%) and Mongoloid races (99%). Other alleles that are associated with absence or reduced metabolism are less common and include, but are not limited to, CYP2C19*4, *5, *6, *7, and *8 alleles. Patients with low CYP2C19 isoenzyme activity must have the two loss-of-function gene alleles listed above.

The published incidence of phenotypes of individuals with low CYP2C19 isoenzyme activity is 2% in Caucasians, 4% in non-Hispanics, and 14% in Chinese.

Tests are available to determine if a patient has the CYP2C19 isoenzyme genotype. According to a cross-sectional study (40 healthy volunteers) and a meta-analysis of six studies (335 healthy volunteers) taking clopidogrel that included healthy volunteers with very high, high, intermediate and low CYP2C19 isoenzyme activity, no significant differences in the exposure of the active metabolite and in the mean values of platelet aggregation inhibition (IAT) (induced ADP) in healthy volunteers with very high, high, and intermediate CYP2C19 isoenzyme activity were found. In healthy volunteers with low CYP2C19 isoenzyme activity, exposure to the active metabolite was decreased compared to healthy volunteers with high CYP2C19 isoenzyme activity.

When healthy volunteers with low CYP2C19 isoenzyme activity received the 600 mg – loading dose/150 mg – maintenance dose (600/150 mg) treatment regimen, exposure of the active metabolite was higher than when receiving the 300/75 mg treatment regimen. In addition, IAT was similar to that in groups of healthy volunteers receiving clopidogrel, with higher metabolism by the CYP2C19 isoenzyme receiving the 300/75 mg treatment regimen. Dosing regimen of clopidogrel in low CYP2C19 isoenzyme activity.

Indications

Prevention of atherothrombotic complications:

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation).

Patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications cannot take indirect anticoagulants and have a low risk of bleeding (when combined with ASA).

Active ingredient

Composition

Active substance:

clopidogrel hydrosulfate in form II97.875 mg (in terms of clopidogrel – 75 mg);

Auxiliary substances:

Mannitol, 68.925 mg;

Macrogol 6000, 34 mg;

MCC (low water content – 90 microns) – 31 mg;

Hyprolose low-substituted – 12.9 mg;

hydrogenated castor oil – 3.3 mg;

Film coating:

Opadry pink (lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron oxide red dye (E172) – 7.5 mg; carnauba wax – traces

How to take, the dosage

Ingestion, regardless of meals.

Adults and elderly persons with normal CYP2C19 isoenzyme activity

Myocardial infarction, ischemic stroke and diagnosed peripheral artery occlusive disease. The drug is taken 75 mg once daily.

Acute coronary syndrome without ST-segment elevation (unstable angina pectoris, myocardial infarction without Q-wave). Treatment with clopidogrel should be started with a single loading dose of 300 mg and then continued with a dose of 75 mg once daily (in combination with ASA in doses of 75-325 mg/day). Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. The optimal duration of treatment has not been officially determined. Data from clinical trials support use of the drug for up to 12 months, and the maximum favorable effect was observed by the 3rd month of treatment.

Acute coronary syndrome with ST-segment elevation (acute ST-segment elevation myocardial infarction). Clopidogrel should be taken once daily at a dose of 75 mg with an initial single loading dose of clopidogrel 300 mg in combination with ASA in combination with thrombolytics or without combination with thrombolytics. In patients over 75 years old, treatment with clopidogrel should be started without its loading dose. Combination therapy should be started as soon as possible after the onset of symptoms and continued for at least 4 weeks. The effectiveness of the combination of clopidogrel and ASA for this indication beyond 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation). Clopidogrel should be taken once daily in a dose of 75 mg. In combination with clopidogrel ASA (75-100 mg/day) should be started and then continued.

Missing the next dose

1. If less than 12 hours have passed since the next dose was missed, the missed dose should be taken immediately, and then the next doses should be taken at the usual time.

2. If more than 12 hours have passed since the next dose was missed, the patient should take the next dose at the usual time (do not take a double dose).

Patients with genetically determined reduced CYP2C19 isoenzyme activity

Low CYP2C19 isoenzyme activity is associated with decreased antiplatelet activity of clopidogrel. A regimen of higher doses (600 mg – loading dose, then 150 mg once daily) in patients with low CYP2C19 isoenzyme activity increases the antiplatelet effect of clopidogrel (see “Pharmacokinetics”). However, the optimal dosing regimen for clopidogrel for patients with reduced metabolism due to genetically determined low CYP2C19 isoenzyme activity is not currently established in clinical studies that consider clinical outcomes.

Particular patient groups

Elderly persons. No differences in platelet aggregation and bleeding time were observed in elderly volunteers (over 75 years of age) when compared to younger volunteers. No dose adjustment is required for the elderly.

Children. There is no experience of using the drug in children.

Patients with impaired renal function. After repeated use of clopidogrel in dose 75 mg/day in patients with severe renal impairment (creatinine Cl from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation (25%) was decreased in comparison with healthy volunteers, but prolongation of bleeding time was similar to it in healthy volunteers who received clopidogrel in dose 75 mg/day. In addition, all patients had good tolerability of the drug.

Patients with impaired liver function. After daily use of clopidogrel in daily dose of 75 mg for 10 days in patients with severe hepatic impairment, inhibition of ADF-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

Patients of different ethnicities. The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and reduced metabolism of clopidogrel to its active metabolite varies among different ethnic groups (see “Pharmacogenetics”). Limited data are available for Mongoloid races to assess the effect of CYP2C19 isoenzyme genotype on clinical outcome events.

Female and male patients. In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there were no differences in prolongation of bleeding time. In the large controlled CAPRIE trial (clopidogrel versus ASA in patients at risk for ischemic complications), the incidence of clinical outcomes, other adverse events, and abnormal clinical and laboratory parameters was similar in both men and women.

Interaction

Warfarin: Although clopidogrel administration at a dose of 75 mg/day did not alter the pharmacokinetics of warfarin (a substrate of CYP2C9 isoenzyme) or INR in patients treated with long-term warfarin, concomitant administration of clopidogrel increases bleeding risk due to its independent additional effect on blood clotting. Therefore, caution should be exercised when concomitant administration of warfarin and clopidogrel.

Ib/IIIa-receptor blockers: Administration of IIb/IIIa-receptor blockers together with clopidogrel requires caution in patients with increased risk of bleeding (in trauma and surgery or other pathological conditions) (see “Special Precautions”).

ASA does not change the effect of clopidogrel inhibiting ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of ASA at a dose of 500 mg twice daily for 1 day with clopidogrel did not cause an additional increase in bleeding time due to clopidogrel administration. Pharmacodynamic interaction is possible between clopidogrel and ASA, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them concomitantly, although in clinical trials patients received combined therapy with clopidogrel and ASA for up to one year.

Heparin: According to the clinical trial conducted with healthy subjects, no change in heparin dose was required when taking clopidogrel and its anticoagulant effect was not altered. Concomitant use of heparin did not alter the antiaggregant effect of clopidogrel. Pharmacodynamic interaction is possible between the drug Plavix® and heparin, which may increase the risk of bleeding, therefore, concomitant use of these drugs requires caution.

Trombolytics: The safety of concomitant use of clopidogrel, fibrin-specific or fibrin-unspecific thrombolytics and heparin has been studied 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.

NSAIDs: In a clinical study involving healthy volunteers, coadministration of clopidogrel and naproxen increased latent blood loss through the GI tract. However, due to the lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel with other NSAIDs. Therefore, administration of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be performed with caution (see “Special Precautions”).

Other drug interactions. Since clopidogrel is metabolized to form its active metabolite partially by CYP2C19 isoenzyme, use of drugs that inhibit this isoenzyme may lead to decreased levels of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established.

The concomitant use of strong or moderate inhibitors of CYP2C19 isoenzyme (e.g., omeprazole or esomeprazole – see “Pharmacokinetics of the active metabolite of CYP2C19 isoenzyme”) with clopidogrel should be avoided. “Pharmacokinetics, subsection, Pharmacogenetics; Special Precautions). If proton pump inhibitors are to be taken concomitantly with clopidogrel, proton pump inhibitors with the least CYP2C19 isoenzyme inhibition, 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 have shown that:

– no clinically significant pharmacodynamic interactions were observed when clopidogrel was used concomitantly with atenolol, nifedipine or their combination;

– concomitant use of phenobarbital, cimetidine and estrogen had no significant effect on the pharmacodynamics of clopidogrel;

– the pharmacokinetic parameters of digoxin and theophylline were not altered by their concomitant use with clopidogrel;

– antacids did not decrease absorption of clopidogrel;

Phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study). It is unlikely that clopidogrel can affect metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs, which are metabolized by cytochrome P450 isoenzyme CYP2C9.

– ACE inhibitors, diuretics, beta-adrenoblockers, BKK, hypolipidemic agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic agents, hormone replacement therapy and GPIIb/IIIa-receptor blockers: no clinically significant adverse interactions have been observed in clinical trials.

Special Instructions

When treating with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be closely monitored for signs of bleeding, including hidden bleeding.

Because of the risk of bleeding and hematologic adverse events (see side effects), if clinical symptoms suspicious of bleeding occur during treatment are present, a clinical blood count, ACTV, platelet count, platelet function tests and other necessary tests should be performed promptly.

Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with trauma, surgery or other pathological conditions, as well as in patients receiving ASA, other NSAIDs, including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors.

The co-administration of clopidogrel with warfarin may increase the intensity of bleeding (see “Interactions”), so caution should be exercised when using clopidogrel and warfarin together.

If the patient is to have elective surgery and there is no need for antiplatelet effects, clopidogrel should be discontinued 5-7 days before surgery.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases that predispose to bleeding (especially gastrointestinal and intraocular). Drugs that may cause gastrointestinal mucosal damage (NSAIDs, including ASA) in patients taking clopidogrel should be used with caution.

Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with ASA) and that they should inform their physician if they have unusual bleeding (in location or duration). Patients should tell their doctor (including their dentist) about taking clopidogrel before any upcoming surgery and before starting any new medication.

Very rare cases of TTP, characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever, have been reported after clopidogrel use (sometimes even short-term). TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

The combination of ASA and clopidogrel has been shown to increase the risk of major bleeding in patients with recent transient cerebral haemorrhage or stroke with a high risk of recurrent ischemic complications. Therefore, this combination therapy should be used with caution and only if there is clinical evidence of benefit from its use.

Cases of acquired hemophilia have been reported with clopidogrel administration. If an isolated increase in ACTB is confirmed, with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease and discontinue clopidogrel.

Patients should be questioned about a history of allergy to thienopyridines (such as ticlopidine, prasugrel), since cross-allergy between thienopyridines and clopidogrel has been reported.

Hypatic function should be monitored during treatment. In severe liver lesions it is necessary to remember about the risk of hemorrhagic diathesis. Administration of clopidogrel is not recommended in acute stroke less than 7 days old (since there are no data on its use in this condition).

Impact on the ability to drive and operate machinery. Plavix® has no significant effect on the ability to drive or operate machinery.

Contraindications

Side effects

Nervous system disorders: infrequent – headache, dizziness, paresthesia; rarely – vertigo.

Gastrointestinal disorders: frequent – dyspepsia, abdominal pain, diarrhea; infrequent – nausea, gastritis, bloating, constipation, vomiting, peptic ulcer, duodenal ulcer.

Skin and subcutaneous tissue: infrequent – rash, itching.

Blood and lymphatic system disorders: infrequent – increased bleeding time, decreased number of platelets in peripheral blood, leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.

Postmarketing experience with the drug

Blood and lymphatic system disorders: unknown frequency – cases of serious bleeding, mainly subcutaneous, skeletal-muscular, ocular hemorrhages (conjunctival, tissue and retina), respiratory bleeding (hemoptysis, pulmonary bleeding), nasal bleeding, hematuria and bleeding from postoperative wounds and cases of fatal bleeding (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

Immune system disorders: unknown frequency – anaphylactoid reactions, serum sickness, cross-allergy with other thienopyridines (such as ticlopidine, prasugrel – see “Special Indications”).

Psychiatric disorders: unknown frequency – confusion, hallucinations.

Nervous system disorders: unknown frequency – disorders of taste perception.

Vascular disorders: unknown frequency – vasculitis, decreased BP.

Respiratory system, chest and mediastinum: unknown frequency – bronchospasm, interstitial pneumonia, eosinophilic pneumonia.

Gastrointestinal disorders: unknown frequency – colitis (including ulcerative or lymphocytic), pancreatitis, stomatitis.

Liver and biliary tract disorders: unknown frequency – hepatitis (non-infectious), acute liver failure.

Skin and subcutaneous tissue disorders: unknown frequency – maculopapular erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome), eczema, flat tetter.

Skeletal, muscular and connective tissue disorders: unknown frequency – arthralgia (joint pain), arthritis, myalgia.

Renal and urinary tract: unknown frequency – glomerulopathy (including glomerulonephritis).

General disorders and disorders at the site of administration: unknown frequency – fever.

Laboratory and instrumental data: unknown frequency – abnormal laboratory values of liver function, increased blood creatinine concentration.

Overdose

Symptoms: clopidogrel overdose may lead to increased bleeding time with subsequent complications in the form of bleeding development.

Treatment: If bleeding occurs, appropriate treatment measures are required. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended. An antidote for clopidogrel has not been established.

Similarities