Composition
Active ingredient:
clopidogrel hydrosulfate in the form of II97.875 mg (in terms of clopidogrel-75 mg);
Auxiliary substances:
mannitol-68.925 mg;
macrogol 6000-34 mg;
MCC (with a low water content-90 microns) – 31 mg;
low-substituted hyprolose-12.9 mg;
hydrogenated castor oil-3.3 mg;
Film shell:
Opadry pink (lactose monohydrate, hypromellose, titanium dioxide (E171), triacetin, iron oxide dye red (E172 — – 7.5 mg; Carnauba wax-traces
of Pharmacological action
Plavix – anti-aggregation medicine.
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 binding ADP with 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 stimulation. ADP lasts for the rest of its life (approximately 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.
Platelet aggregation caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by released ADP.
Since the formation of the active metabolite occurs with the help of P450 enzymes, some of which may differ in polymorphism or be inhibited by other drugs, not all patients can adequately inhibit platelet aggregation.
When taking clopidogrel daily at a dose of 75 mg from the first day of use, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (when an equilibrium state is reached). At steady state, platelet aggregation is suppressed by an average of 40-60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually return to baseline, on average within 5 days.
Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular damage, in particular in lesions of the cerebral, coronary or peripheral arteries.
The ACTIVE-A clinical trial showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel in combination with acetylsalicylic acid (ASA) (compared to taking ASA alone) reduced the combined incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system or vascular death, to a greater extent by reducing the risk of stroke.
The effectiveness of taking 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 taking 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 was reduced when taking clopidogrel in combination with ASA, and there was a tendency to reduce the 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 thromboembolism or vascular death. In addition, taking clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular reasons.
Pharmacokinetics
Suction. With a single and repeated oral dose of 75 mg/day, clopidogrel is rapidly absorbed.
Average peak plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng / ml after oral use of a single 75 mg dose) are reached approximately 45 minutes after use. According to the urinary excretion of clopidogrel metabolites, its absorption is approximately 50%.
Distribution. In vitro, clopidogrel and its main circulating inactive metabolite reversibly bind to plasma proteins (by 98 and 94%, respectively), and this bond is unsaturated in 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 is via esterases and subsequent hydrolysis to form an inactive metabolite, a carboxylic acid derivative (85% of the circulating metabolites), and the second is via the cytochrome P450 system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. In vitro, this pathway is metabolized by the P450 isoenzymes CYP2C19, CYP1A2, and CYP2B6. The active thiol metabolite of clopidogrel, which has been isolated in vitro studies, binds rapidly and irreversibly to platelet receptors, blocking platelet aggregation.
Output. Within 120 hours after human ingestion of 14C-labeled clopidogrel, about 50% of the radioactivity is excreted in the urine and approximately 46% of the 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 inactive metabolite circulating in the blood is 8 hours
. Pharmacogenetics. Both the active metabolite and the intermediate metabolite 2 — oxo-clopidogrel are formed by the CYP2C19 isoenzyme. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel in the study of platelet aggregation ex vivo vary depending on the genotype of the CYP2C19 isoenzyme.
The allele of the CYP2C19*1 gene corresponds to a fully functional metabolism, whereas the alleles of the CYP2C19 genes correspond to a fully functional metabolism. *2 and CYP2C19*3 are non-functional. Alleles of the CYP2C19 genes*2 ISR2C19 * 3 is the cause of decreased metabolism in most representatives of the Caucasian (85%) and Mongoloid race (99%). Other alleles associated with an absence or decrease in metabolism are less common and include, but are not limited to, alleles of the CYP2C19 genes*4, *5, *6, *7 and *8. Patients with low activity of the CYP2C19 isoenzyme should have the two above-mentioned alleles of the gene with loss of function.
The published frequencies of phenotypes of individuals with low activity of the CYP2C19 isoenzyme are 2% in Caucasians,4% in Negroes, and 14% in Chinese.
To determine the patient’s genotype of the CYP2C19 isoenzyme, appropriate tests are available. According to a cross-sectional study (40 healthy volunteers) and a meta-analysis of six studies (335 healthy volunteers) taking clopidogrel, which included healthy volunteers 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 average values of inhibition of platelet aggregation (IAT) (induced by ADP) in healthy volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme. In healthy volunteers with low activity of the CYP2C19 isoenzyme, exposure to the active metabolite decreased compared to healthy volunteers with high activity of the CYP2C19 isoenzyme.
When healthy volunteers with low CYP2C19 isoenzyme activity received a 600 mg loading dose/150 mg maintenance dose regimen (600/150 mg), exposure to the active metabolite was higher than when taking the 300/75 mg treatment regimen. In addition, IAT was similar to that in the groups of healthy volunteers treated with clopidogrel, with a higher metabolic rate using the CYP2C19 isoenzyme, receiving the 300/75 mg treatment regimen. Dosage regimen of clopidogrel with low activity of the CYP2C19 isoenzyme.
Indications
Prevention of atherothrombotic complications:
- adult patients with myocardial infarction (with a prescription from a few days to 35 days), ischaemic stroke (with a prescription from 7 days to 6 months) or with diagnosed occlusive peripheral arterial disease;
- adult patients with acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without Q wave), including patients who have held stenting in percutaneous coronary intervention (in combination with ASA); c ST-segment elevation (acute myocardial infarction) with medical treatment and the possibility of thrombolysis (in combination with ASA).
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 (in combination with ASA).
Contraindications
- hypersensitivity to clopidogrel or any of the excipients of the drug;
- severe hepatic insufficiency;
- acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
- rare hereditary problems of lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
- pregnancy and lactation (see “Use during pregnancy and lactation”);
- children under 18 years of age (safety and efficacy of use have not been established).
With caution under the following conditions: moderate liver failure, where a possible propensity to bleed (limited clinical experience); renal failure (limited clinical experience); trauma, surgical intervention (see “Special instructions”); diseases in which there is a predisposition to bleeding (especially gastrointestinal or intraocular); simultaneous reception of NSAIDs, including selective COX-2 inhibitors; co-use of warfarin, heparin, inhibitors of glycoprotein IIb/IIIA; patients with genetically determined decrease in the function of isoenzyme CYP2 19 (there are published data indicating that patients with genetically caused a decrease in the function of the isoenzyme CYP2 19 are exposed to less systemic exposure of the active metabolite of clopidogrel and have less pronounced antiplatelet effect of the drug, in addition, they may experience an increased frequency of cardiovascular complications after myocardial infarction compared with patients with normal function of the isoenzyme CYP2 19); a history of instructions on allergic reactions to thienopyridine (e. g. tiklopidin, has prasugrel — the possibility of cross-Allergy); recent transient ischemic stroke or ischemic stroke in the acute period
Side effects
Nervous system disorders:Â infrequently-headache, dizziness, paresthesia; rarely-vertigo.
From the gastrointestinal tract:Â often-dyspepsia, abdominal pain, diarrhea; infrequently-nausea, gastritis, bloating, constipation, vomiting, stomach ulcer, duodenal ulcer.
Skin and subcutaneous tissue disorders: infrequently — rash, itching.
Blood and lymphatic system disorders:Â infrequently-an increase in bleeding time, a decrease in the number of platelets in peripheral blood, leukopenia, a decrease in the number of neutrophils in peripheral blood, eosinophilia.
Post-marketing experience with the drug
Blood and lymphatic system disorders: unknown frequency — serious cases of bleeding, mainly subcutaneous, musculoskeletal, eye bleeding (conjunctival, in the tissue and the retina of the eye), bleeding from the airway (hemoptysis, pulmonary hemorrhage), nasal bleeding, hematuria, and bleeding from surgical wounds and cases of bleeding with fatal outcome (especially intracranial hemorrhage, gastrointestinal hemorrhage, and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.
From the immune system: unknown frequency — anaphylactoid reactions, serum sickness, cross-allergy with other thienopyridines (such as ticlopidine, prasugrel-see “Special instructions”).
Mental disorders: unknown frequency — confusion, hallucinations.
Nervous system disorders: unknown frequency — disorders of taste perception.
From the side of blood vessels: unknown frequency — vasculitis, decreased blood pressure.
Respiratory, thoracic and mediastinal disorders:Â unknown frequency-bronchospasm, interstitial pneumonia, eosinophilic pneumonia.
From the gastrointestinal tract: 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, lichen planus.
Musculoskeletal and connective tissue disorders:Â unknown frequency-arthralgia (joint pain), arthritis, myalgia.
From the side of the kidneys and urinary tract: unknown frequency — glomerulopathy (including glomerulonephritis).
General disorders and disorders at the injection site:Â unknown frequency-fever.
Laboratory and instrumental data: unknown frequency — deviation from the norm of laboratory parameters of the functional state of the liver, an increase in the concentration of creatinine in the blood.
Interaction
Warfarin: although taking clopidogrel at a dose of 75 mg / day did not change the pharmacokinetics of warfarin (a substrate of the CYP2C9 isoenzyme) or INR in patients receiving long-term warfarin treatment, concomitant use of clopidogrel increases the risk of bleeding due to its independent additional effect on blood clotting. Therefore, caution should be exercised when taking warfarin and clopidogrel at the same time.
IIb/IIIa receptor blockers:Â the use of IIb/IIIa receptor blockers in combination with clopidogrel requires caution in patients who have an increased risk of bleeding (due to injuries and surgical interventions or other pathological conditions) (see “Special Instructions”).
ASA does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant use of ASA 500 mg twice daily for 1 day with clopidogrel did not cause an additional increase in bleeding time due to clopidogrel use. There may be a pharmacodynamic interaction between clopidogrel and ASA, which leads to an increased risk of bleeding. Therefore, caution should be exercised when they are used simultaneously, although in clinical studies patients received combination therapy with clopidogrel and ASA for up to one year.
Heparin: according to a clinical trial conducted with healthy subjects, clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. Concomitant use of heparin did not alter the antiplatelet effect of clopidogrel. There may be a pharmacodynamic interaction between Plavix® and heparin, which may increase the risk of bleeding, so the simultaneous use of these drugs requires caution.
Thrombolytics:Â The safety of co-use of clopidogrel, fibrin-specific or fibrin-specific thrombolytic drugs, and heparin was studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of combined use of thrombolytics and heparin with ASA.
NSAIDs:Â in a clinical study conducted in healthy volunteers, the combined use of clopidogrel and naproxen increased hidden blood loss through the gastrointestinal 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 together with other NSAIDs. Therefore, the use of NSAIDs, including COX-2 inhibitors, in combination with clopidogrel should be carried out with caution (see “Special instructions”).
Other drug interactions. Since clopidogrel is partially metabolized to its active metabolite by the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme may lead to a decrease in the level of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established.
Concomitant use with clopidogrel of strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole or esomeprazole — see “Pharmacokinetics”, subsection, “Pharmacogenetics”; “Special instructions”) should be avoided. If proton pump inhibitors are to be taken concomitantly with clopidogrel, proton pump inhibitors with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole, should be used.
A number of clinical studies were conducted with clopidogrel and other concomitantly used drugs to investigate possible pharmacodynamic and pharmacokinetic interactions, which showed that:
– the use of clopidogrel in conjunction with atenolol, nifedipine, or a combination of clinically significant pharmacodynamic interactions were observed;
– concurrent use of phenobarbital, cimetidine and estrogen had no significant effect on the pharmacodynamics of clopidogrel;
– the pharmacokinetic parameters of digoxin or theophylline was not altered in their joint application with clopidogrel;
– antacids did not reduce the absorption of clopidogrel;
– phenytoin and tolbutamide can be safely administered concomitantly with clopidogrel (study CAPRIE). It is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide, as well as NSAIDs that are metabolized by the CYP2C9 isoenzyme of the cytochrome P 450 family.
– ACE inhibitors, diuretics, beta-blockers, BCC, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement therapies, and GPIIb/IIIa receptor blockers: no clinically significant adverse interactions were identified in clinical studies.
How to take, course of use and dosage
Inside, regardless of food intake.
Adults and the elderly with normal activity of the CYP2C19 isoenzyme
Myocardial infarction, ischemic stroke and diagnosed occlusive disease of peripheral arteries. The drug is taken at 75 mg 1 time a day.
Acute coronary syndrome without ST-segment elevation (unstable angina, non-Q-wave myocardial infarction). Treatment with clopidogrel should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg once a day (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 is not officially defined. Data from clinical studies support taking the drug for up to 12 months, and the maximum beneficial effect was observed by the 3rd month of treatment.
Acute ST-segment elevation coronary syndrome (acute ST-segment elevation myocardial infarction). Clopidogrel should be taken once a day 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 of age, treatment with clopidogrel should begin without taking its loading dose. Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least 4 weeks. The effectiveness of using a combination of clopidogrel and ASA for this indication for more than 4 weeks has not been studied.
Atrial fibrillation (atrial fibrillation). Clopidogrel should be taken once a day at a dose of 75 mg. In combination with clopidogrel, you should start and then continue taking ASA (75-100 mg / day).
Skipping the next dose
1. If less than 12 hours have passed since you missed the next dose, then you should immediately take the missed dose of the drug, and then take the next dose at the usual time.
2. If more than 12 hours have passed since the next dose was missed, then the patient should take the next dose at the usual time (do not take a double dose).
Patients with genetically determined reduced activity of the CYP2C19 isoenzyme
Low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of clopidogrel. A higher dose regimen (600 mg as a loading dose, followed by 150 mg once daily) in patients with low CYP2C19 activity increases the antiplatelet effect of clopidogrel (see Pharmacokinetics). However, currently, clinical studies that take into account clinical outcomes have not established the optimal dosage regimen of clopidogrel for patients with its reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.
Special patient groups
Elderly people. No differences in platelet aggregation and bleeding time were found in elderly volunteers (over 75 years of age) when compared with young 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 at a dose of 75 mg / day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml / min), the inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, but the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel at a dose of 75 mg/day. In addition, all patients had good drug tolerance.
Patients with impaired liver function. After taking clopidogrel daily for 10 days at a daily dose of 75 mg in patients with severe liver damage, the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.
Patients of different ethnic backgrounds. The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and reduced metabolism of clopidogrel to its active metabolite differs among representatives of different ethnic groups (see”Pharmacogenetics”). There are only limited data available for the Mongoloid race to assess the effect of the 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, women showed less inhibition of ADP-induced platelet aggregation, but there were no differences in prolongation of bleeding time. In a large controlled trial of CAPRIE (clopidogrel versus ASA in patients at risk of developing ischemic complications), the incidence of clinical outcomes, other side effects, and abnormal clinical and laboratory parameters was similar in both men and women.
Overdose
Symptoms:Â overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of the development of bleeding.
Treatment:Â if bleeding occurs, appropriate treatment measures are required. If a rapid correction of prolonged bleeding time is required, platelet transfusion is recommended. The antidote of clopidogrel has not been established.
Special instructions
During treatment with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be carefully monitored for signs of bleeding, including latent bleeding.
Due to the risk of developing bleeding and hematological undesirable effects (see “Side effects”), if clinical symptoms appear during treatment that are suspicious of the occurrence of bleeding, a clinical blood test should be performed urgently, APTT, platelet count, platelet functional activity indicators should be determined, and other necessary studies should be carried out.
Clopidogrel, as well as other antiplatelet drugs, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgery or other pathological conditions, as well as in patients receiving ASA, other NSAIDs, including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors.
Concomitant use of clopidogrel with warfarin may increase the intensity of bleeding (see “Interaction”), so caution should be exercised when using clopidogrel and warfarin together.
If the patient is going to undergo elective surgery, and there is no need for an antiplatelet effect, then 5-7 days before the operation, clopidogrel should be discontinued.
Clopidogrel prolongs the bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially gastrointestinal and intraocular). Drugs that may cause damage to the gastrointestinal mucosa (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 if they experience unusual (by location or duration) bleeding, they should inform their doctor about this. Patients should inform their doctor (including their dentist) about the use of clopidogrel before any upcoming surgery and before starting any new medication.
Very rarely, after the use of clopidogrel (sometimes even for a short time), cases of TTP have been observed, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever. TTP is a potentially life-threatening condition that requires immediate treatment, including plasmapheresis.
The combination of ASA and clopidogrel has been shown to increase the risk of major bleeding in patients with a recent transient cerebrovascular accident or stroke who are at high risk for recurrent ischemic events. Therefore, such combination therapy should be carried out with caution and only if there is clinical evidence of benefits from its use.
Cases of acquired hemophilia have been reported with clopidogrel. When isolated zoom is confirmed APTT, whether or not accompanied by the development of bleeding, should be considered the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists for this condition and stop taking clopidogrel.
Patients should be interviewed for a history of allergy to thienopyridines (such as ticlopidine, prasugrel), as cross-allergy between thienopyridines and clopidogrel has been reported.
During treatment, it is necessary to monitor the functional state of the liver. With severe liver damage, you should be aware of the risk of developing hemorrhagic diathesis.Taking clopidogrel is not recommended for acute stroke with a duration of less than 7 days (since there are no data on its use in this condition).
Influence on the ability to drive a car and work with mechanisms. Plavix® does not significantly affect the abilities required for driving a car or working with mechanisms.
Composition
Tablet Form of production
Storage conditions
At a temperature not exceeding 30 °C
Shelf life
3 years
Active ingredient
Clopidogrel
Conditions of release from pharmacies
By prescription
Dosage form
Tablets
Purpose
For adults as directed by your doctor
Indications
Prevention of thrombosis, Prevention of heart attacks and strokes
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