Clopidogrel-SZ, 75 mg, 90 pcs.

Pharmacotherapeutic group:

anti-aggregant.

The ATX code: [B01AC04]

Pharmacological Properties

Pharmacodynamics

Clopidogrel is a prodrug, one of whose active metabolites is a platelet aggregation inhibitor. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor of platelets and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation. Due to 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. Platelet aggregation 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 P450 system isoenzymes, some of which may be polymorphic or may be inhibited by other drugs, adequate platelet suppression is not possible in all patients. Clopidogrel is 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.

When clopidogrel is taken daily at a dose of 75 mg a 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 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.

Pharmacokinetics

Eabsorption

In a course of oral administration at a dose of 75 mg daily, clopidogrel is rapidly absorbed. Mean maximum 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 minutes after the administration. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

Distribution

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

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo clopidogrel is metabolized in two ways: the first – through enzymes and subsequent hydrolysis to form inactive carboxylic acid derivative (85 % of circulating metabolites), and the second way – through 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 occurs via the isoenzymes CYP2CI9, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, which has been isolated in in vitro studies, binds rapidly and irreversibly to platelet receptors, thus blocking platelet aggregation.

Elimination

For 120 hours after oral human ingestion 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 half-life of clopidogrel is about 6 hours. After a single dose and repeated doses, the half-life 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 the CYP2C19 isoenzyme. The pharmacokinetics and antiaggregant effect 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 gene alleles.

Patients with low CYP2C19 isoenzyme activity, must have the two loss-of-function gene alleles listed above. Published frequencies of phenotypes of individuals with low CYP2C19 isoenzyme activity are 2% in Caucasians, 4% in non-Hispanics, and 14% in Chinese. There are appropriate tests to determine the CYP2C19 isoenzyme genotype of a patient.

Based on a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers). which included persons with very high, high, intermediate and low CYP2C19 isoenzyme activity, no significant differences in exposure to the active metabolite and in the mean values of platelet aggregation inhibition (IAT) (induced by ADP) were found in volunteers with very high, high and intermediate CYP2C19 isoenzyme activity.

Volunteers with low CYP2C19 isoenzyme activity had decreased exposure to the active metabolite compared with volunteers with high CYP2C19 isoenzyme activity. When volunteers with low CYP2C19 isoenzyme activity received the 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg) treatment regimen, exposure of the active metabolite was higher than when receiving the 300 mg/75 mg treatment regimen. In addition, IAT was similar to that in the groups of patients with higher metabolism rates by the CYP2C19 isoenzyme receiving the 300 mg/75 mg treatment regimen.

But the dosing regimen of clopidogrel for patients in this group (patients with low CYP2C19 isoenzyme activity) has not yet been established in studies considering clinical outcomes. Clinical studies conducted to date have not had sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.

Particular patient groups

The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with renal and hepatic diseases have not been studied.

Indications

– Prevention of atherothrombotic events in patients with myocardial infarction (from several days to 35 days), ischemic stroke (from 7 days to 6 months) or with diagnosed peripheral artery occlusive disease.

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

– Without ST-segment elevation (unstable angina or myocardial infarction without a Q-wave), including patients who have had stenting for percutaneous coronary intervention;

– With ST-segment elevation (acute myocardial infarction) with medication-assisted treatment and thrombolysis options.

Active ingredient

Composition

Active substance:

clopidogrel (in the form of clopidogrel hydrosulfate) 75 mg (97.875 mg);

Associates:

Lactose monohydrate (200 mesh) 60.0 mg,

Microcrystalline cellulose (Avicel PH-101) 40.125 mg,

Hyprolose 3.0 mg,

Microcrystalline cellulose (Avicel PH-112) 26.0 mg,

Crospovidone 6.0 mg,

hydrogenated vegetable oil type I (Sterotex-Dritex) 10.0 mg,

sodium lauryl sulfate 7.0 mg.

How to take, the dosage

Adults and elderly patients with normal CYP2C19 isoenzyme activity

Clopidogrel-SZ should be taken orally, regardless of meals.

Myocardial infarction, ischemic stroke and diagnosed peripheral artery occlusive disease

The drug is taken at 75 mg once daily.

In patients with myocardial infarction (MI), treatment can be started from the first days to day 35 of MI, and in patients with ischemic stroke (IS) from 7 days to 6 months after IS.

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

The treatment with Klopidopil® can be started in the first days before the 35th day of MI. Treatment with Clopidogrel-SZ 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 acetylsalicylic acid as an antiplatelet agent at a dose of 75-325 mg/day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid in this indication should not exceed 100 mg. Maximum therapeutic effect is observed by the third month of treatment. The course of treatment is up to 1 year.

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

Clopidogrel is administered at a dose of 75 mg once daily with an initial single loading dose in combination with acetylsalicylic acid as an antiplatelet agent and thrombolytics (or without thrombolytics). Combination therapy is started as soon as possible after the onset of symptoms and is continued for at least 4 weeks. In patients aged over 75 years, treatment with Clopidogrel-SZ should be started without a loading dose.

Patients with genetically determined decreased CYP2C19 isoenzyme function

The impairment of metabolism by CYP2C19 isoenzyme may lead to decreased antiaggregant effect of clopidogrel. The optimal dosing regimen for patients with impaired metabolism by the CYP2C19 isoenzyme has not yet been established.

. After alternate doses of Clopidogrel-SZ at dose 75 mg/day in patients with severe renal impairment (CKR from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation (25%) was lower in comparison with that in healthy volunteers, however prolongation of bleeding time was similar to that in healthy volunteers who received Clopidogrel-SZ at dose 75 mg/day. In addition, all patients had good tolerability of the drug.

After 10 days of daily administration of Clopidogrel-SZ at a dose of 75 mg in patients with severe liver injury, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.

The prevalence of CYP2C19 isoenzyme gene alleles responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite varies among ethnic groups. Limited data are available for members of the Mongoloid race to assess the effect of CYP2C19 isoenzyme genotype on clinical outcome events.

Interaction

Warfarin

Simultaneous use with clopidogrel may increase bleeding severity, so this combination is not recommended.

IIb/IIIa-receptor blockers

The use 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).

Acetylsalicylic acid

Acetylsalicylic acid does not alter the effect of clopidogrel inhibiting ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of acetylsalicylic acid with clopidogrel as an antipyretic at 500 mg 2 times/day for 1 day did not significantly increase the bleeding time caused by clopidogrel administration. Pharmacodynamic interaction is possible between clopidogrel and acetylsalicylic acid, 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 acetylsalicylic acid for up to one year.

Heparin

In a clinical study conducted with healthy volunteers, no change in heparin dose was required when taking clopidogrel and its anticoagulant effect was not altered. Concomitant use of heparin did not change the antiaggregant effect of clopidogrel. There is a possible pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.

Trombolytics

The safety of concomitant use of clopidogrel, fibrin-specific or fibrin-nonspecific 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 simultaneously with acetylsalicylic acid.

NSAIDs

In a clinical study conducted with healthy volunteers, concomitant use 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 clopidogrel is taken with other NSAIDs. Therefore, administration of NSAIDs, including selective COX-2 inhibitors, in combination with clopidogrel should be performed with caution.

Other combination therapy

To the extent that clopidogrel is metabolized to its active metabolite partially by the CYP2C19 isoenzyme, the use of drugs that inhibit this system may decrease the concentration of active clopidogrel metabolite and decrease its clinical effectiveness. Concomitant use of drugs that inhibit CYP2C19 isoenzyme (e.g., omeprazole) is not recommended.

A number of clinical studies have been performed with clopidogrel and other concomitantly administered drugs to investigate possible pharmacodynamic and pharmacokinetic interactions, which showed that:

– no clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with atenolol, nifedipine, or both drugs simultaneously;

– the concurrent 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 the absorption of clopidogrel;

– phenytoin and tolbutamide can safely be used concomitantly with clopidogrel, even though data from human liver microsomal studies suggest that the carboxyl metabolite of clopidogrel may inhibit CYP2C9 isoenzyme activity, which may lead to increased plasma concentrations of some drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized by CYP2C9 isoenzyme;

– ACE inhibitors, diuretics, beta-adrenoblockers, slow calcium channel blockers, hypoglycemic agents (including insulin), hypoglycemic agents.including insulin, hypolipidemic agents, antiepileptic agents, GGT and GP IIb/IIIa-receptor blockers – no clinically significant adverse interactions were found in clinical studies.

Special Instructions

When treating with Clopidogrel-SZ, especially during the first weeks of therapy 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, 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-CS, as well as other antiplatelet agents, should be used with caution in patients with increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients receiving acetylsalicylic acid, NSAIDs, including COPD inhibitors, and in those receiving antiplatelet agents.COX-2 inhibitors, heparin, or glycoprotein IIb/IIIa inhibitors.

The co-administration of clopidogrel with warfarin may increase the intensity of bleeding, therefore, except for special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), co-administration of clopidogrel and warfarin is not recommended.

If the patient is scheduled for surgery, and there is no need for antiplatelet effect, then 7 days prior to surgery, the drug Clopidogrel-SZ should be discontinued.

Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposed to bleeding (especially gastrointestinal and intraocular).

Patients should be warned that it may take longer to stop bleeding when using Clopidogrel-SZ (alone or in combination with acetylsalicylic acid) and that if they have unusual bleeding (in location or duration) they should inform the attending physician. Patients should tell their physician (including their dentist) about taking Clopidogrel-SZ before any upcoming surgery and before starting any new medication.

Very rarely, after using Clopidogrel-SZ (sometimes even short-term) there have been cases of thrombocytopenic thrombohemolytic purpura (THP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. DVT is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Hypatic function should be monitored during treatment. If liver function is severely impaired, the risk of hemorrhagic diathesis should be kept in mind.

The use of Clopidogrel-SZ is not recommended for acute stroke less than 7 days old (since there are no data on its use for this condition).

Clopidogrel-SZ should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

Impact on the ability to drive and operate machinery

Clopidogrel-SZ has no significant effect on the ability to drive or operate machinery.

Contraindications

Side effects

The frequency classification of side effects (WHO):

frequently more than 1/100 and less than 1/10,

infrequently more than 1/1000 and less than 1/100,

rarely more than 1/10000 and less than 1/1000,

very rarely less than 1/10000).

Anxiety of the central and peripheral nervous system:

infrequent – headache, dizziness and paresthesias:

rarely – vertigo;

very rarely – impairment of taste sensation.

Digestive system disorders:

often – diarrhea, abdominal pain, dyspepsia;

infrequently – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence;

very rarely – pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.

Hemostasis disorders:

infrequently – prolongation of bleeding time.

Hemopoiesis disorders:

infrequent – thrombocytopenia, leukopenia, neutropenia and eosinophilia,

very rarely – thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count ≤ 30×109/l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.

Dermal and subcutaneous tissue disorders:

infrequent – skin rash and itching;

very rare – angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid);

very rarely – bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus.

Disorders of the immune system:

very rarely – anaphylactoid reactions, serum sickness.

Mental disorders:

very rarely – confusion, hallucinations.

Vascular system disorders:

very rarely – vasculitis, marked decrease of blood pressure (BP), intracranial hemorrhage, ocular hemorrhage (conjunctival, tissue and retina), hematoma, nasal bleeding, respiratory bleeding, gastrointestinal bleeding, retroperitoneal bleeding with fatal outcome, muscle and joint hemorrhage, hematuria, etc.

Respiratory disorders:

very rarely – bronchospasm, interstitial pneumonitis.

Hepato-biliary system disorders:

very rarely – acute liver failure, hepatitis.

Musculoskeletal system disorders:

very rarely – arthralgia, arthritis, myalgia.

Renal and urinary tract disorders:

very rarely – glomerulonephritis.

General disorders:

very rarely – fever.

Changes in laboratory parameters:

very rarely – change in hepatic tests, increased serum creatinine concentration.

Overdose

Symptoms: prolongation of bleeding time and subsequent complications.

Treatment: If bleeding occurs, appropriate therapy must be given. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended. There is no specific antidote.

Similarities