Clopidogrel-SZ, 75 mg 28 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. Active metabolite of clopidogrel selectively inhibits binding of adenosine diphosphate (ADP) to P2Y12 receptor of platelets and subsequent ADP-mediated activation of 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 dose. 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 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.

Tests are available to determine if a patient has the CYP2C19 isoenzyme genotype. According to a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers). which included subjects 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 to 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 to 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. However, 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

1 film-coated tablet contains:

the active ingredient:

clopidogrel hydrosulfate converted to clopidogrel or clopidogrel bisulfate converted to clopidogrel – 75 mg

/p>

excipients (core):

Lactose monohydrate (milk sugar) – 38.4 mg, microcrystalline cellulose – 129.48 mg, croscarmellose sodium (primellose) – 12.0 mg, colloidal silicon dioxide (aerosil) – 3.12 mg, sodium stearyl fumarate – 2.0 mg

excipients (coating):

Opadray II – 8 mg (polyvinyl alcohol, partially hydrolyzed – 3.52 mg, talc – 1.6 mg, titanium dioxide E 171 – 1.5336 mg, macrogol (polyethylene glycol 3350) – 0.988 mg, soy lecithin E 322 – 0.28 mg, aluminum varnish based on the dye azorubin – 0.0408 mg, aluminum varnish based on the dye crimson [Ponceau 4R] – 0.0328 mg, aluminum varnish based on the dye indigo carmine – 0.0048 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, but 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

IIb/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).

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 at 500 mg twice daily for 1 day with clopidogrel did not significantly increase the bleeding time caused by clopidogrel administration. There may be pharmacodynamic interaction 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: According to the clinical trial conducted with the participation of healthy subjects when taking clopidogrel no change in the dose of heparin was required and its anticoagulant effect was not changed. Concomitant use of heparin did not alter 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-unspecific drugs 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 acetylsalicylic acid.

Non-steroidal anti-inflammatory drugs (NSAIDs): In a clinical study involving healthy volunteers, the combined 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 not known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be used with caution. Other combination therapy: since clopidogrel is metabolized to form its active metabolite partly by the CYP2C19 system, the use of drugs that inhibit this system (e.g., omeprazole) is not recommended.

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

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 who receive these drugs.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 to have elective 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 driving and operating machinery

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

Contraindications

Side effects

Classification of the frequency of side effects (WHO): frequently (>1/100 and <1/10), infrequently (>1/1000 and <1/100), rarely (>1/10 000 and <1/1000), very rarely (<1/10 000).

Activities of the central and peripheral nervous system: infrequent – headache, dizziness and paresthesias; rare – vertigo; very rare – disorders of taste sensation.

Mental disorders: very rare – confusion, hallucinations.

Cardiovascular system disorders: very rare – vasculitis, marked BP decrease, intracranial hemorrhage, ocular hemorrhages (conjunctival, tissue and retina), hematoma, nasal bleeding, airway bleeding, gastrointestinal bleeding, retroperitoneal bleeding with fatal outcome, muscle and joint hemorrhages, hematuria.

Respiratory system disorders: very rarely – bronchospasm, interstitial pneumonitis.

The digestive system: frequently – diarrhea, abdominal pain, dyspepsia; infrequently – gastric and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; very rarely – pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, acute liver failure, hepatitis.

Urinary system disorders: very rarely – glomerulonephritis.

With the blood coagulation system: infrequent – prolongation of bleeding time.

Hematopoietic system disorders: infrequent – thrombocytopenia, leukopenia, neutropenia and eosinophilia; very rare – thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count ≤30×109/l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.

Skin and subcutaneous tissue disorders: Infrequent – skin rash and itching; very rare – angioneurotic edema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid); very rare – bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and lichen planus.

Muscular system disorders: very rarely – arthralgia, arthritis, myalgia.

Immune system disorders: very rare – anaphylactoid reactions, serum sickness.

Laboratory disorders: very rare – changes in liver function tests, increased serum creatinine concentration.

Other: very rare – fever.

Overdose

A clopidogrel overdose may lead to prolonged bleeding time and hemorrhagic complications.

If bleeding is detected, appropriate treatment should be applied.

No antidotes to the pharmaceutical activity of clopidogrel have been identified.

If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.

Pregnancy use

In the absence of data, it is not recommended to take clopidogrel during pregnancy and lactation.

Similarities