Composition, form of production and packaging
The tablets covered with a film cover from pink to dark pink color, round, biconcave.
Clopidogrel (in the form of hydrogen sulfate or bisulfate) 75 mg
Excipients: lactose monohydrate (sugar milk) - 38.4 mg, microcrystalline cellulose - 129.48 mg, croscarmellose sodium (impellose) - 12 mg, silicon dioxide colloid (aerosil) - 3.12 mg, sodium stearyl fumarate - 2 mg.
The composition of the shell: Opadrai II - 8 mg (alcohol polyvinyl, partially hydrolysed - 3.52 mg, talc 1.6 mg, titanium dioxide (E171) 1.5336 mg, macrogol (polyethylene glycol 3350) 0.988 mg, soy lecithin (E322) 0.28 mg, aluminum varnish based on the dye azorubin - 0.0408 mg, aluminum lacquer based on the dye crimson [Ponso 4R] - 0.0328 mg, aluminum lacquer based on the dye indigo carmine - 0.0048 mg).
10 pieces. - packings cellular planimetric (3) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
14 pcs. - packings of cellular contour (1) - packs cardboard.
14 pcs. - packings cellular planimetric (2) - packs cardboard.
14 pcs. - packings cellular planimetric (4) - packs cardboard.
30 pcs. - packings of cellular contour (1) - packs cardboard.
30 pcs. - packings cellular planimetric (2) - packs cardboard.
30 pcs. - packings cellular planimetric (3) - packs cardboard.
30 pcs. - polymer cans (1) - packs of cardboard.
30 pcs. - vials polymeric (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
Antiaggregant. 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 adenosine diphosphate (ADP) to the P2Y12 receptor of platelets and subsequent ADP-mediated activation of the GPIIb / IIIa complex, leading to suppression of platelet aggregation. Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal. Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP. Because the formation of an active metabolite occurs with the isoenzymes of the P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, not all patients can adequately suppress platelets.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in the lesions of the cerebral, coronary or peripheral arteries.
With daily use of clopidogrel at a dose of 75 mg from the first day of admission, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.
With a course of oral administration at a dose of 75 mg / day clopidogrel quickly absorbed. The mean C max of unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) is reached approximately 45 minutes after administration. According to the excretion of metabolites of clopidogrel with kidneys, its absorption is approximately 50%.
In vitro clopidogrel and its main circulating inactive inactive metabolite bind reversibly to plasma proteins (98% and 94%, respectively) and this bond is unsaturated up to a concentration of 100 mg / l.
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 with the formation of an inactive derivative of carboxylic acid (85% of the circulating metabolites), and the second pathway through the cytochrome P450 system.Initially, clopidogrel is metabolized to 2-oxoklopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxoclopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this pathway of metabolism occurs with the help of isoenzymes CYP2C19, CYP1A2 and CYP2B6. The active thiol clopidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking the platelet aggregation.
Within 120 hours after ingestion of 14 C-labeled clopidogrel, about 50% of the radioactivity is released by the kidneys and approximately 46% of the radioactivity - through the intestine. After a single oral intake in a dose of 75 mg of T 1/2, clopidogrel is approximately 6 hours. After a single administration and reception of repeated doses of T 1/2, the main circulating inactive inactive metabolite is 8 hours.
Pharmacokinetics in specific patient groups
The pharmacokinetics of the active metabolite of clopidogrel in elderly patients, children, patients with kidney and liver diseases have not been studied.
With the help of the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel in the study of platelet aggregation ex vivo vary depending on the genotype of the isoenzyme CYP2C19. The allele of the CYP2C19 * 1 gene corresponds to a fully functional metabolism, while the CYP2C19 * 2 and CYP2C19 * 3 gene alleles are non-functional. Alleles of CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the CYP2C19 * 4, * 5, * 6, * 7, and * 8 genes. Patients with a low activity of the CYP2C19 isoenzyme should have the two alleles of the loss-of-function gene indicated above. Published frequency of occurrence of phenotypes of persons with low activity of the isoenzyme CYP2C19 is 2% for Caucasians, 4% for Negroid people and 14% for Chinese. There are corresponding tests to determine the patient's genotype of the CYP2C19 isoenzyme.
According to a cross-sectional study (40 volunteers) and according to a meta-analysis of six studies (335 volunteers), which included individuals with very high, high, intermediate and low activity of the isoenzyme CYP2C19, no significant differences in the exposure of the active metabolite and in the mean the values вЂ‹вЂ‹of inhibition of platelet aggregation (IAT) (induced by ADP) in volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme were not revealed. In volunteers with a low activity of the isoenzyme CYP2C19, the exposure of the active metabolite decreased compared to volunteers with a high activity of the isoenzyme CYP2C19. When volunteers with a low activity of the CYP2C19 isoenzyme received a 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen. In addition, the IAT was similar to that in groups of patients with a higher metabolic rate with the CYP2C19 isoenzyme receiving a 300 mg / 75 mg treatment regimen. However, in studies with clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low activity of the isoenzyme CYP2C19) has not yet been established.
The clinical trials conducted to date did not have a sufficient sample size to detect differences in the clinical outcome in patients with a low activity of the CYP2C19 isoenzyme.
Prevention of atherothrombotic events in patients who underwent myocardial infarction (with a duration of several days to 35 days), ischemic stroke (with a duration of 7 days to 6 months) or having peripheral arteries diagnosed with 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 in percutaneous coronary intervention;
- with the rise of the ST segment (acute myocardial infarction) with medical treatment and the possibility of carrying out thrombolysis.
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 occlusive disease
The drug is taken 75 mg once a day.
In patients with myocardial infarction (MI) treatment can start from the first days to 35 days of MI, and in patients with ischemic stroke (AI) - in the period from 7 days to 6 months after the AI.
Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without Q-wave)
Treatment with Clopidogrel-SZ should be started with a single dose of 300 mg, and then continued at a dose of 75 mg once a day (in combination with acetylsalicylic acid as antiplatelet agent in doses 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 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 is prescribed in a dose of 75 mg 1 time / day with the initial single loading dose in combination with acetylsalicylic acid as an antiaggregant and thrombolytic agents (or without thrombolytics). Combination therapy starts as soon as possible after the onset of symptoms and lasts for at least 4 weeks. In patients over the age of 75 years, treatment with Clopidogrel-SZ should be started without taking a loading dose.
Patients with a genetically determined decrease in the isoenzyme function of CYP2C19
The weakening of metabolism by means of the CYP2C19 isoenzyme may lead to a decrease in the antiplatelet effect of clopidogrel. The optimal dosage regimen for patients with metabolic weakening with the CYP2C19 isoenzyme is not yet established.
After repeated administration of Clopidogrel-SZ at a dose of 75 mg / day in patients with severe renal disease (SC from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation (25%) was lower than that of healthy volunteers, however , the lengthening of bleeding time was similar to that of healthy volunteers who received clopidogrel-SZ at a dose of 75 mg / day. In addition, all patients had good tolerability of the drug.
After daily administration of Clopidogrel-SZ at a dose of 75 mg for patients with severe liver damage during 10 days , the inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.
The prevalence of the alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite differs among representatives of different ethnic groups. There are only limited data for representatives of the Mongoloid race on the impact of the genotype of the isoenzyme CYP2C19 on the clinical outcome events.
Classification of the incidence of adverse events (WHO): often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10 000 and <1/1000), very rarely (<1/10 000).
From the central and peripheral nervous system: infrequently - headache, dizziness and paresthesia; rarely - vertigo; very rarely - a violation of taste.
Mental disorders: very rarely - confusion, hallucinations.
From the cardiovascular system: very rarely - vasculitis, marked decrease in blood pressure, intracranial hemorrhage, eye hemorrhages (conjunctival, in the tissue and retina of the eye), hematoma, epistaxis, bleeding from the respiratory tract, gastrointestinal bleeding, retroperitoneal hemorrhage with a fatal outcome, hemorrhage in the muscles and joints, hematuria.
From the respiratory system: very rarely - bronchospasm, interstitial pneumonitis.
From the digestive system: often - diarrhea, abdominal pain, dyspepsia; infrequently - ulcers of the stomach and duodenum, gastritis, vomiting, nausea, constipation, flatulence; very rarely - pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, acute hepatic insufficiency, hepatitis.
From the side of the urinary system: very rarely - glomerulonephritis.
From the coagulation system of the blood: infrequently - prolongation of bleeding time.
On the part of the hematopoiesis system: infrequently - thrombocytopenia, leukopenia, neutropenia and eosinophilia; very rarely thrombocytopenic thrombohemolytic purpura, severe thrombocytopenia (platelet count? 30? 10 9 / L), agranulocytosis, granulocytopenia, aplastic anemia (pancytopenia), anemia.
From the skin and subcutaneous tissues: infrequently - skin rash and itching; very rarely - angioedema, urticaria, erythematous rash (associated with clopidogrel or acetylsalicylic acid); very rarely - bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema and flat lichen.
From the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia.
From the side of the immune system: very rarely - anaphylactoid reactions, serum sickness.
From the laboratory: very rarely - a change in liver samples, an increase in the concentration of serum creatinine.
Other: very rarely - fever.
hepatic failure of severe degree;
- Acute bleeding (eg, bleeding from a peptic ulcer or intracranial hemorrhage);
- rare hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
- lactation period;
- children and adolescents under 18 years of age (safety and efficacy not established);
- Hypersensitivity to clopidogrel or any of the excipients of the drug.
- moderate hepatic insufficiency, which can predispose to bleeding (limited clinical experience of use);
- renal failure (limited clinical experience of use);
- trauma, surgical interventions;
- diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular);
- simultaneous reception of non-steroidal anti-inflammatory drugs, incl. selective COX-2 inhibitors;
- simultaneous use of warfarin, heparin, glycoprotein IIb / IIIa inhibitors;
- in patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme at the recommended doses (there are published data indicating that patients with a genetically determined decrease in the function of the CYP2C19 isoenzyme undergo less systemic exposure to the active metabolite of clopidogrel and have a less pronounced effect of the drug, there is a greater incidence of cardiovascular complications after myocardial infarction compared with patients with normal CYP2C19 isoenzyme function).
PREGNANCY AND LACTATION
As a precaution, it is not recommended to use clopidogrel in pregnancy because of the lack of clinical data on its use in pregnant women, although animal studies have revealed neither direct nor indirect adverse effects during pregnancy, embryonic development, childbirth and postnatal development.
Breastfeeding in case of treatment with clopidogrel should be discontinued, because in studies on rats, it has been shown that clopidogrel and / or its metabolites are excreted in breast milk. Whether clopidogrel penetrates the human milk is unknown.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should prescribe the drug for kidney failure (limited clinical experience of use).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated use of the drug for severe hepatic failure.
Caution should be given to the drug when moderate hepatic insufficiency, which can predispose to bleeding (limited clinical experience of use).
APPLICATION FOR CHILDREN
The drug is contraindicated for use in children and adolescents under 18 years of age (safety and efficacy have not been established).
In the treatment with Clopidogrel-SZ, especially during the first weeks of therapy and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients should be conducted to exclude signs of bleeding, incl. and hidden.
In connection with the risk of bleeding and hematological adverse effects, if clinical symptoms appearing during treatment, suspicious for bleeding, it is urgent to do a clinical blood test, determine APTT, the number of platelets, the platelet function and perform other necessary studies.
Clopidogrel-SZ, as well as other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding due to trauma, surgery or other pathological conditions, as well as in patients receiving acetylsalicylic acid, NSAIDs, incl. inhibitors of COX-2, heparin or inhibitors of glycoprotein IIb / IIIa.
The combined use of clopidogrel with warfarin can enhance the intensity of bleeding, however, except for special rare clinical situations (such as the presence of floating thrombus in the left ventricle, stenting for patients with atrial fibrillation), the combined use of warfarin and clopidogrel is not recommended.
If the patient will have elective surgery, and thus there is no need for antiplatelet effect, then 7 days prior to the operation taking the drug Clopidogrel NW should be discontinued.
Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (particularly gastrointestinal and intraocular).
Patients should be warned about the fact that when using the drug Clopidogrel-SOC (alone or in combination with acetylsalicylic acid) may require more time to stop bleeding, as well as that in the case they have unusual (localization or duration) bleeding them You should inform your doctor. Before any forthcoming operation and before starting any new drug to patients need to inform the doctor (including dentist) about taking the drug Clopidogrel-NW.
Very rarely, after treatment Clopidogrel-NW (and sometimes even short) have been reported cases of thrombotic thrombocytopenic purpura (THP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, renal dysfunction and fever. TGP is a potentially life-threatening condition that requires immediate treatment including plasmapheresis.
The period of treatment is necessary to control the functional activity of the liver. In case of severe violations of liver function, one should remember about the risk of hemorrhagic diathesis.
Clopidogrel-SOC formulation is not suitable for acute stroke with prescription of at least 7 days (since there is no data on its application in this condition).
Clopidogrel-SZ should not be taken in patients with rare hereditary galactose intolerance, lactase deficiency and malabsorption glucose-galactose.
Impact on the ability to drive vehicles and manage mechanisms
Clopidogrel-NW has no significant effect on the ability needed for road management or using machinery.
Symptoms: prolonged bleeding time and subsequent complications in the form of bleeding.
Treatment: stop bleeding, transfusion of platelet mass. Antidote is unknown.
Simultaneous treatment with clopidogrel may increase the intensity of the bleeding, therefore, the use of this combination is not recommended.
Blockers IIb / IIIa receptor
blockers IIb / IIIa receptor together with clopidogrel requires caution in patients who have an increased risk of bleeding (with injuries and surgical interventions or other pathological states).
Acetylsalicylic acid does not alter the effect of clopidogrel inhibits ADP-induced platelet aggregation, clopidogrel but potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, simultaneous with clopidogrel acetylsalicylic acid as an antipyretic 500 mg of 2 times / day for 1 day did not cause a significant increase in bleeding time caused by clopidogrel. Between clopidogrel and acetylsalicylic acid may pharmacodynamic interaction, which leads to increased risk of bleeding. Therefore, when simultaneous application of caution, although clinical trials of patients received a combination therapy with clopidogrel and acetylsalicylic acid up to one year.
According to a clinical study conducted in healthy volunteers, while taking clopidogrel did not need to change the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between clopidogrel and heparin possible pharmacodynamic interactions, which may increase the risk of bleeding, so simultaneous use of these preparations requires caution.
Safety simultaneous application of clopidogrel fibrinspetsificheskih fibrinnespetsificheskih or thrombolytic agents and heparin was investigated in patients with acute myocardial infarction. The incidence of clinically relevant bleeding was similar to that observed in the case of simultaneous use of thrombolytic agents and heparin, acetylsalicylic acid.
In a clinical study conducted in healthy volunteers, concurrent use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of research 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, the appointment of NSAIDs, including selective COX-2 inhibitors in combination with clopidogrel should be done with caution.
Another combination therapy
Because Clopidogrel is metabolized to form its active metabolite partially by isoenzyme CYP2C19, use of drugs that inhibit this system can reduce the concentration of the active metabolite of clopidogrel and reduce its clinical efficacy. Simultaneous administration of drugs that inhibit isozyme CYP2C19 (eg omeprazole) is not recommended.
Several clinical studies have been conducted with clopidogrel and other prescribed drugs simultaneously to investigate possible pharmacodynamic and pharmacokinetic interactions, which showed that:
- the application of clopidogrel together with atenolol, nifedipine or both drugs simultaneously clinically significant pharmacodynamic interaction was observed;
- simultaneous administration of phenobarbital, cimetidine and estrogens had no significant effect on the pharmacodynamics of clopidogrel;
- pharmacokinetic parameters of digoxin and theophylline did not change when they are applied simultaneously with clopidogrel;
- Antacids do not reduce the absorption of clopidogrel;
- phenytoin and tolbutamide can be safety applied simultaneously with clopidogrel, despite the fact that the data obtained in studies with human liver microsomes, suggest that carboxylic metabolite of clopidogrel can inhibit isozyme CYP2C9, which can lead to increased plasma concentrations of some drugs (phenytoin, tolbutamide and certain NSAIDs) that are metabolized via isoenzyme CYP2C9;
- ACE inhibitors, diuretics, beta-blockers, calcium channel blockers slow, hypoglycemic agents (including insulin), lipid lowering agents, antiepileptics, HRT blockers and GP IIb / IIIa-receptor - showed no clinically in clinical trials significant adverse interactions.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, dry, protected from light at a temperature of no higher than 25 В° C. Shelf life - 3 years.