Description
Pharmacological action
Pharmacodynamics:
Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active clopidogrel metabolite selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 platelet receptor and 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 rest of their life (approximately 7-10 days), and the restoration of normal platelet function occurs at a speed corresponding to the platelet renewal rate. Platelet aggregation caused by agonists other than ADP is also inhibited by the blockade of increased platelet activation by the released ADP. Since the formation of the active metabolite occurs using P450 isoenzymes, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients may have adequate platelet suppression.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular with cerebral lesions, coronary or peripheral arteries.
With daily intake of clopidogrel at a dose of 75 mg from the first day of administration, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (upon reaching equilibrium). In equilibrium, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline for an average of 5 days.
Pharmacokinetics:
Absorption
When administered orally at a dose of 75 mg per day, clopidogrel is rapidly absorbed.
Average maximum plasma concentrations of unchanged clopidogrel (approximately 2.2-2, 5 ng / ml after oral administration of a single dose of 75 mg) are achieved approximately 45 minutes after administration. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.
In vitro distribution of
clopidogrel and its main inactive metabolite circulating in the blood bind reversibly to plasma proteins (by 98% and 94%, respectively) and this bond 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 an inactive derivative of carboxylic acid (85% of the circulating metabolites), and the second through the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, being an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel – a thiol derivative of clopidogrel. In vitro, this metabolic pathway occurs with the help of the isoenzymes CYP2CI9, CYP1A2 and CYP2B6. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking platelet aggregation.
Excretion of
Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestines. After a single oral dose of 75 mg, the elimination half-life of clopidogrel is approximately 6 hours. After a single dose and repeated doses, the half-life of the main inactive metabolite circulating in the blood is 8 hours.
Pharmacogenetics
Using the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite, 2-oxo-clopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active clopidogrel metabolite, when examining platelet aggregation ex vivo, vary depending on the genotype of CYP2C19 isoenzyme. The allele of the YP2C19 * 1 gene corresponds to a fully functional metabolism, while the alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes are non-functional. Alleles of the CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in most representatives of the Caucasoid (85%) and Mongoloid race (99%). Other alleles associated with a lack or decrease in metabolism, are less common and include, but are not limited to, alleles of the CYP2C19 * 4, * 5, * 6, * 7 and * 8 genes. Patients with low activity of the CYP2C19 isoenzyme should have the two aforementioned gene alleles with loss of function. Published phenotypic frequencies of individuals with low CYP2C19 isoenzyme activity are 2% in Caucasians, 4% in Negroid people and 14% in Chinese. There are relevant tests to determine the patient ² ¢s genotype for the CYP2C19 isoenzyme.
According to a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers). Which included individuals with very high, high, intermediate and low activity of the CYP2C19 isoenzyme, There were no significant differences in the exposure of the active metabolite and in the mean values ² ¹ ² ¹of inhibition of platelet aggregation (IAT) (induced by ADP) in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme. In volunteers with low activity of the CYP2C19 isoenzyme, the exposure of the active metabolite was reduced compared with volunteers with high activity of the CYP2C19 isoenzyme.
When volunteers with low CYP2C19 isoenzyme activity received a 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the exposure of the active metabolite was higher than with a 300 mg / 75 mg treatment regimen. In addition, IAT was similar to that in groups of patients with a higher metabolic rate using the CYP2C19 isoenzyme receiving a treatment regimen of 300 mg / 75 mg. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients of this group (patients with low activity of the CYP2C19 isoenzyme) has not yet been established.
Clinical trials conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 isoenzyme activity.
Selected patient groups
The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with kidney and liver diseases has not been studied.
Indications
Prevention of atherothrombotic events in patients after myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or those with a diagnosed peripheral arterial 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 Q wave), including patients who underwent stenting with percutaneous coronary surgery with
segment elevation acute myocardial infarction) with medical treatment and the possibility of thrombolysis.
Contraindications
Hypersensitivity to clopidogrel or any of the excipients of the drug.
Severe liver failure.
Acute bleeding, such as peptic ulcer bleeding or intracranial hemorrhage.
Rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption.
Pregnancy and lactation (see “Pregnancy and the period of breastfeeding”).
Children under 18 years of age (safety and efficacy not established).
Precautions:
Moderate hepatic failure in which a predisposition to bleeding is possible (limited clinical experience).
Renal failure (limited clinical experience).
Trauma, surgery (see “Special instructions”).
Diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular).
Concomitant use of non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors (COX-2).
Concomitant use of warfarin, heparin, glycoprotein IIb / IIIa inhibitors.
In patients with a genetically determined decrease in the function of the ¡Y 2 ¡19 isoenzyme in the recommended doses (there are literature data indicating that that patients with a genetically determined decrease in the function of the ¡Y 2 ¡19 isoenzyme undergo a less systemic exposure by the active metabolite of clopidogrel and have a less pronounced effect of the drug, in addition, they may have a higher frequency of cardiovascular complications after myocardial infarction compared with patients with normal function of the ¡Y 2 ¡19 isoenzyme).
Use during pregnancy and lactation
As a precaution, clopidogrel during pregnancy is not recommended due to the lack of clinical data on its use by pregnant women, although animal studies have not revealed any direct, nor indirect adverse effects on pregnancy, embryonic development, childbirth and postnatal development. Breastfeeding should be discontinued if treated with clopidogrel, as studies in rats have shown that clopidogrel and / or its metabolites are excreted in breast milk. Whether clopidogrel passes into human breast milk is not known.
Special instructions
When treating with clopidogrel-SZ, especially during the first weeks of treatment and / or after invasive cardiological procedures / surgical interventions, careful monitoring of patients should be carried out to exclude signs of bleeding, including hidden.
Due to the risk of bleeding and hematologic adverse effects (see section ² ÑSide effects ² Ñ) in the event of the appearance of clinical symptoms that are suspicious of bleeding during treatment, an urgent clinical blood test should be performed, activated partial thromboplastin time (APTT), platelet count, platelet functional activity indicators and other necessary studies should be performed.
Clopidogrel-SZ, as well as other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients receiving acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including including COX-2 inhibitors, heparin, or IIb / IIIa glycoprotein inhibitors.
Concomitant use of clopidogrel with warfarin, can increase the intensity of bleeding (see ² ÑInteraction with other drugs ² Ñ), therefore, with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), the combined use of clopidogrel and warfarin is not recommended.
If the patient has planned surgery, and there is no need for an antiplatelet effect, then 7 days before surgery, the drug Clopidogrel-SZ should be discontinued.
Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular).
Patients should be warned that that when taking Clopidogrel-SZ (alone or in combination with acetylsalicylic acid), it may take longer to stop the bleeding, and that if they have unusual (by location or duration) bleeding, they should inform their doctor to the doctor. Before any upcoming surgery and before starting to take any new drug, patients should inform the doctor (including the dentist) about taking Clopidogrel-SZ.
Very rarely, after the use of the drug Clopidogrel-SZ (sometimes even short-lived), there have been cases of thrombocytopenic thrombohemolytic purpura (TGP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and TGP is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.
During the treatment period, it is necessary to monitor the functional activity of the liver. In severe violations of liver function, remember the risk of developing hemorrhagic diathesis. Clopidogrel-SZ is not recommended for acute stroke with a duration of less than 7 days (since there is no data on its use in this condition). Clopidogrel-SZ should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome ( see “Composition”).
INFLUENCE ON ABILITY TO DRIVING MOTOR TRANSPORT AND MANAGEMENT OF MECHANISMS
Clopidogrel-SZ does not significantly affect the ability required to drive vehicles or work with mechanisms.
Composition
Film-coated tablets, 75 mg.
Composition (1 table): active substance: clopidogrel hydrosulfate in terms of clopidogrel or clopidogrel bisulfate in terms of clopidogrel – 75 mg
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 fumarate – 2.0 mg
excipients (shell): Opadry 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 dye azorubine – 0.0408 mg, aluminum varnish based on dye crimson [Ponceau 4R] – 0.0328 mg, aluminum varnish based on dye indigo carmine – 0.0048 mg).
Dosage and administration of
Adults and elderly patients with normal activity of the isoenzyme CYP2C19
Clopidogrel-SZ should be taken orally, regardless of food intake.
myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusion disease
The drug is taken 75 mg once a day.
In patients with myocardial infarction (MI), treatment can be started from the first days to 35 days of MI, and in patients with ischemic stroke (MI) – from 7 days to 6 months after MI.
Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without Q wave)
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 a day (in combined with acetylsalicylic acid as an antiplatelet agent in doses of 75-325 mg per day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the dose of acetylsalicylic acid recommended for this indication should not exceed 100 mg. The 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-SZ is prescribed once at a dose of 75 mg once a day with the initial single dose of the load 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 continues for at least four weeks. In patients older than 75 years of age, treatment with Clopidogrel-SZ should begin without taking its loading dose.
Patients with a genetically determined decrease in the function of the Y 2 19 isoenzyme
Weakening of the metabolism with the help of the Y 2 19 isoenzyme may lead to a decrease in the antiplatelet effect of clopidogrel. The optimal dosage regimen for patients with weakened metabolism using the Y 2 19 isoenzyme has not yet been established.
Patients with impaired renal function
After repeated doses of Clopidogrel-SZ at a dose of 75 mg / day in patients with severe renal damage (creatinine clearance from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation (25%) was lower compared with that of healthy volunteers, however, the prolongation of bleeding time was similar to that of healthy volunteers who received Clopidogrel-SZ at a dose of 75 mg per day. In addition, all patients had good tolerance to the drug.
Patients with impaired liver function
After daily administration of Clopidogrel-SZ at a dose of 75 mg daily for 10 days in patients with severe liver damage, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. Mean bleeding time was also comparable in both groups.
Patients of different ethnicities
The prevalence of alleles of the CYP2C19 isoenzyme gene genes responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite varies among representatives of different ethnic groups (see the Pharmacogenetics section). There is only limited data for members of the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcome events.
Side effects
Classification of the incidence of side effects (WHO):
often – 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).
From the central and peripheral nervous system:
infrequently – headache, dizziness and paresthesia:
rarely – vertigo
very rarely – taste disturbance. digestive system:
often – diarrhea, abdominal pain, dyspepsia
infrequently – stomach and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence
very rarely – pancreatitis, colitis (including), colitis (including) stomatitis.
Hemostatic disorders:
infrequently – prolonged bleeding time.
Hematopoietic disorders:
infrequently – thrombocytopenia, leukopenia, neutropenia and eosinophilia,
is very rare – thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count? 30×109 / l), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.
Disorders of the skin and subcutaneous tissue:
infrequently – skin rash and pruritus
very rare – angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid)
very rarely – bullemonous dermatitis, Stevens dermatitis, dermatitis toxic epidermal necrolysis), eczema and lichen planus.
Immune system disorders:
is very rare – anaphylactoid reactions, serum sickness.
Mental disorders:
is very rare – confusion, hallucinations.
Disorders of the vascular system:
is very rare – vasculitis, marked decrease in blood pressure (BP), intracranial hemorrhage, ocular hemorrhage (conjunctival, in the tissue and retina), hematoma, nosebleed, airway bleeding, gastrointestinal bleeding fatal retroperitoneal hemorrhage, hemorrhages in muscles and joints, hematuria, etc.
Respiratory disorders:
very rarely – bronchospasm, interstitial pneumonitis.
Disorders from the hepatobiliary system:
is very rare – acute liver failure, hepatitis.
Disorders of the musculoskeletal system:
is very rare – arthralgia, arthritis, myalgia.
Disorders of the kidneys and urinary tract:
is very rare – glomerulonephritis.
General Disorders:
is very rare – fever.
Changes in laboratory parameters:
is very rare – a change in liver samples, an increase in the concentration of serum creatinine.
Overdose
Symptoms: prolonged bleeding time with subsequent complications in the form of bleeding.
Treatment: stopping bleeding, platelet transfusion. The antidote is unknown.
Storage conditions
In a dry, dark place at a temperature of no higher than 25 ° C.
Keep out of the reach of children.
Expiration
3 years.
Deystvuyuschee substances
clopidogrel
Form of Treatment
tablets
Indications
Prevention trombozov, Prevention of acute ynfarkta myocardium, Prevention stroke, angina, Prevention of thromboembolism
Northern Star, Russia
