Instructions for use Clopidogrel-Teva film-coated tablets 75 mg No. 30
Composition
active ingredient: clopidogrel;
1 tablet contains clopidogrel bisulfate 97.86 mg, equivalent to clopidogrel 75 mg;
excipients: anhydrous lactose, microcrystalline cellulose, crospovidone, glycerol dibehenate, talc;
shell: Opadry II 85G34669 pink (polyvinyl alcohol, talc, macrogol 3350, lecithin, titanium dioxide (E 171), iron oxide red (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties: pink, round, biconvex, film-coated tablets, engraved with "I" on one side.
Pharmacotherapeutic group
Platelet aggregation inhibitors, except heparin.
ATX code B01A C04.
Pharmacological properties
Pharmacodynamics
Mechanism of action. Clopidogrel is a prodrug, one of the metabolites of which is an inhibitor of platelet aggregation. Clopidogrel is metabolized by CYP450 enzymes to form an active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor P2Y12 and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to irreversible binding, the effect is felt on platelets throughout their lifespan (approximately 7–10 days), and the restoration of normal platelet function corresponds to the rate of their renewal. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by ADP release.
Since the active metabolite is formed with the participation of CYP450 enzymes, among which there are polymorphic or those that are inhibited by other drugs, adequate inhibition of platelet aggregation may not be achieved in all patients.
Pharmacodynamic effects. From the first day of use of the drug in repeated daily doses of 75 mg, a significant slowdown in ADP-induced platelet aggregation is observed. This effect progressively increases and stabilizes between the third and seventh days. In a stable state, the average level of inhibition of aggregation under the influence of a daily dose of 75 mg is from 40% to 60%. Platelet aggregation and bleeding time return to baseline on average 5 days after discontinuation of treatment.
Clopidogrel is known to significantly reduce the incidence of new ischemic events (a composite endpoint of myocardial infarction, ischemic stroke, and vascular death) compared with acetylsalicylic acid (ASA); the efficacy of clopidogrel is independent of the use of concomitant therapy (e.g., heparin, platelet GPIIb/IIIa antagonists, fibrinolytics, lipid-lowering agents, beta-blockers, ACE inhibitors), ASA dose (75–325 mg once daily), and age and gender.
Pharmacokinetics
Absorption: Clopidogrel is rapidly absorbed after single and multiple oral doses of 75 mg/day. Mean peak plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) were achieved approximately 45 minutes after dosing. Absorption is at least 50% based on urinary excretion of clopidogrel metabolites.
Distribution: Clopidogrel and the major (inactive) circulating metabolite are reversibly bound to human plasma proteins in vitro (98% and 94%, respectively). This binding remains unsaturated in vitro over a wide concentration range.
Metabolism. Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, there are two main pathways of its metabolism: one occurs with the participation of esterases and leads to hydrolysis with the formation of an inactive carboxylic acid derivative (which constitutes 85% of all metabolites circulating in blood plasma), and the other involves enzymes of the cytochrome P450 system. First, clopidogrel is converted to an intermediate metabolite 2-oxo-clopidogrel. As a result of further metabolism of 2-oxo-clopidogrel, a thiol derivative of clopidogrel is formed - the active metabolite. This active metabolite is formed mainly with the help of the enzyme CYP2C19, with the participation of several other enzymes of the CYP system - CYP1A2, CYP2B6 and CYP3A4. The active metabolite of clopidogrel (a thiol derivative), which was isolated in vitro, binds rapidly and irreversibly to receptors on platelets, thereby inhibiting platelet aggregation.
The Cmax of the active metabolite is twice as high after a single 300 mg loading dose than after 4 days of a 75 mg maintenance dose.
Cmax is reached approximately 30 to 60 minutes after administration.
Pharmacogenetics. CYP2C19 is involved in the formation of both the active metabolite and the intermediate metabolite 2-oxo-clopidogrel. The pharmacokinetics of the active metabolite of clopidogrel and the antiplatelet effects, as measured by ex vivo platelet aggregation, differ depending on the CYP2C19 genotype.
The CYP2C19*1 allele corresponds to a fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to a non-functional metabolism. The CYP2C19*2 and CYP2C19*3 alleles are responsible for the majority of alleles that impair function in patients of the Caucasian (85%) and Mongoloid (99%) races with reduced metabolism. Other alleles associated with absent or reduced metabolism are much less common. These include CYP2C19*4, *5, *6, *7 and *8. A patient with a reduced metabolism has two non-functional alleles, as mentioned above. According to published data, CYP2C19 genotypes that correspond to reduced metabolism are present in 2% of patients of the Caucasian race, 4% of patients of the Negroid race and 14% of patients of the Mongoloid race. There are now tests that allow you to determine the CYP2C19 genotype.
According to data on the use of clopidogrel at a dose of 300 mg followed by a dose of 75 mg/day, as well as a dose of 600 mg followed by a dose of 150 mg/day for 5 days (until a stable state is achieved) in patients with different types of CYP2C19 metabolism (ultra-rapid, extensive, intermediate and poor), no significant differences were found in the concentration of the active metabolite in the blood and the mean inhibition of platelet aggregation (PAT) between individuals with ultra-rapid, extensive and intermediate metabolism. In individuals with poor metabolism, the concentration of the active metabolite in the blood decreased by 63–71% compared with individuals with extensive metabolism. After the 300 mg/75 mg regimen, the antiplatelet effects in poor metabolizers were less pronounced, with mean PAP (5 μM ADP) of 24% (24 hours) and 37% (day 5), compared with PAP of 39% (24 hours) and 58% (day 5) in extensive metabolizers and 37% (24 hours) and 60% (day 5) in intermediate metabolizers. When poor metabolizers were given the 600 mg/150 mg regimen, the blood concentration of the active metabolite was higher than with the 300 mg/75 mg regimen. In addition, the PBMC values were 32% (24 hours) and 61% (day 5), which were higher than those in poor metabolizers receiving the 300 mg/75 mg dose and similar to those obtained in other CYP2C19 metabolizer groups using the 300 mg/75 mg dose regimen. Based on the available data, an appropriate dose regimen for this patient population has not been determined.
Similar to the results above, there is additional evidence that the concentration of the active metabolite in the blood was reduced by 28% in intermediate metabolizers and by 72% in poor metabolizers; inhibition of platelet aggregation (5 μM ADP) was also reduced, with a difference in PTA of 5.9% and 21.4%, respectively, compared with extensive metabolizers.
There is evidence that when using clopidogrel, the incidence of cardiovascular events (fatal outcome, myocardial infarction and stroke) or stent thrombosis was significantly higher in individuals with intermediate and poor metabolizers than in individuals with extensive metabolizers. According to other data, the incidence of cardiovascular events did not significantly differ depending on the characteristics of metabolism.
Therefore, it can be concluded that none of the known analyses included a sufficient number of patients to detect a difference in clinical outcomes in patients with reduced metabolism.
Special patient populations: The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the following special patient populations.
Renal impairment: After regular administration of 75 mg clopidogrel per day to patients with severe renal impairment (creatinine clearance 5–15 ml/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared with the same effect in healthy volunteers, and bleeding time was prolonged almost as much as in healthy volunteers receiving 75 mg clopidogrel per day. Clinical tolerability was good in all patients.
Hepatic impairment: After regular administration of 75 mg clopidogrel daily for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean prolongation of bleeding time was also similar in both groups.
Race: The prevalence of CYP2C19 alleles that confer intermediate and poor CYP2C19 metabolic activity varies by race/ethnicity (see Pharmacogenetics). There are limited data in patients of Mongoloid race to assess the clinical relevance of genotyping this CYP in terms of clinical outcomes.
When high doses of clopidogrel were administered to rats and baboons, poor gastric tolerability of the drug was observed (gastritis, gastric erosive lesions and/or vomiting occurred).
When clopidogrel was administered to mice for 78 weeks and rats for 104 weeks at doses up to 77 mg/kg/day (which was almost 25 times the therapeutic dose of 75 mg/day of clopidogrel in humans), no evidence of carcinogenic effects of the drug was obtained.
A number of in vitro and in vivo genotoxicity studies of clopidogrel have been conducted, but they have not revealed any genotoxic effects of the drug.
Clopidogrel did not affect the reproductive function of male and female rats, and did not have a teratogenic effect in either rats or rabbits. When administered to lactating female rats, clopidogrel resulted in a slight delay in the development of the offspring. Special pharmacokinetic studies with radiolabeled clopidogrel have shown that the parent compound and its metabolites penetrate into breast milk. Therefore, both a direct effect of the drug on the offspring (slight toxic effect) and an indirect effect (due to a deterioration in the palatability of milk) cannot be excluded.
Indication
Secondary prevention of atherothrombosis in adults:
in patients who have had myocardial infarction (treatment should be started within a few days but no later than 35 days after the onset), ischemic stroke (treatment should be started within 7 days but no later than 6 months after the onset) or who have been diagnosed with peripheral arterial disease (arterial damage and atherothrombosis of the vessels of the lower extremities); in patients with acute coronary syndrome: without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including patients who have had a stent placed during percutaneous coronary angioplasty, in combination with acetylsalicylic acid (ASA); with acute myocardial infarction with ST segment elevation, in combination with acetylsalicylic acid (in patients receiving standard medical treatment and for whom thrombolytic therapy is indicated).
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation. Clopidogrel in combination with ASA is indicated in adult patients with atrial fibrillation who have at least one risk factor for vascular events, who have contraindications to treatment with vitamin K antagonists (VKAs) and who are at low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.
For more information, see the Pharmacodynamics section.
Contraindication
Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment. Acute bleeding (e.g. peptic ulcer or intracranial haemorrhage).
Interaction with other medicinal products and other types of interactions
Interaction with boosted human immunodeficiency virus (HIV) antiviral therapy. Reduced exposure to the active metabolite of clopidogrel and reduced platelet inhibition have been demonstrated in HIV-infected patients receiving antiretroviral therapy (ART) boosted with ritonavir or cobicistat. Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of
HIV-infected patients receiving intensified ART who have experienced recurrent occlusive events after deobstruction or thrombotic events during loading treatment with clopidogrel. Clopidogrel exposure and mean platelet inhibition may be reduced when co-administered with ritonavir. Therefore, clopidogrel should not be co-administered with intensified ART.
Medicinal products associated with an increased risk of bleeding. Due to the potential additive effect, there is an increased risk of haemorrhagic complications, therefore the concomitant use of such medicinal products with clopidogrel requires caution (see section 4.4).
Oral anticoagulants. The concomitant use of Clopidogrel Teva with oral anticoagulants is not recommended as this combination may increase the intensity of bleeding (see section 4.4). Although the use of clopidogrel at a dose of 75 mg/day does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin treatment, the concomitant use of clopidogrel and warfarin increases the risk of bleeding due to the existence of independent effects on haemostasis.
Acetylsalicylic acid (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice daily for one day did not significantly increase the bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and ASA with an increased risk of bleeding is possible, caution should be exercised when these medicinal products are used concomitantly (see section 4.4). However, there is experience with the concomitant use of clopidogrel and ASA for up to 1 year (see section 5.1).
Heparin. Based on available data from a clinical study conducted in healthy volunteers, clopidogrel did not require adjustment of the heparin dose and did not alter the effect of heparin on coagulation. Concomitant use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin is possible, with an increased risk of bleeding, caution should be exercised when these drugs are used concomitantly.
Thrombolytic agents: The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparins has been evaluated in patients with acute myocardial infarction: the incidence of clinically significant bleeding was similar to that observed with concomitant use of thrombolytic agents and heparin in combination with ASA (see section "Adverse reactions").
Nonsteroidal anti-inflammatory drugs (NSAIDs). In a clinical study conducted in healthy volunteers, the concomitant use of clopidogrel and naproxen increased the incidence of occult gastrointestinal bleeding. However, due to the lack of interaction studies with other NSAIDs, it is not yet clear whether the risk of gastrointestinal bleeding is increased with all NSAIDs. Therefore, caution should be exercised when NSAIDs, particularly COX-2 inhibitors, are co-administered with clopidogrel (see section 4.4).
Selective serotonin reuptake inhibitors (SSRIs) affect platelet activation and increase the risk of bleeding, so caution should be exercised when using them simultaneously with clopidogrel.
Concomitant use of other medicinal products. Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of medicinal products that inhibit this enzyme is likely to result in decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. Therefore, as a precautionary measure, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see sections 5.2 and 5.4).
Moderate or strong inhibitors of CYP2C19 include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol, efavirenz.
Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel (both when given simultaneously and with a 12-hour interval between doses of these two drugs), reduced the concentration of the active metabolite in the blood by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a decrease in the inhibition of platelet aggregation by 39% (loading dose) and 21% (maintenance dose). It is expected that esomeprazole will also interact in a similar way with clopidogrel.
The clinical implications of these pharmacokinetic and pharmacodynamic interactions in terms of major cardiovascular events are conflicting. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section 4.4).
A less pronounced decrease in the metabolite concentrations in the blood was observed with the use of pantoprazole or lansoprazole. With the simultaneous use of pantoprazole at a dose of 80 mg 1 time per day, plasma concentrations of the active metabolite decreased by 20% (loading dose) and by 14% (maintenance dose). This decrease was accompanied by a decrease in the mean platelet aggregation inhibition index by 15% and 11%, respectively. The results obtained indicate the possibility of simultaneous use of clopidogrel and pantoprazole.
There is no evidence that other drugs that reduce stomach acid production, such as H2 blockers (except cimetidine, which is a CYP2C9 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.
Combination with other medicinal products. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel was virtually unchanged when administered concomitantly with phenobarbital and estrogen.
The pharmacokinetic properties of digoxin or theophylline were not altered when co-administered with clopidogrel.
Carboxylic metabolites of clopidogrel may inhibit cytochrome P450 2C9 activity. This could potentially increase plasma levels of drugs such as phenytoin and tolbutamide and NSAIDs that are metabolized by cytochrome P450 2C9. Data from the CAPRIE study showed that phenytoin and tolbutamide, which are metabolized by CYP2C9, can be safely administered with clopidogrel.
Medicinal products that are substrates of CYP2C8. Clopidogrel has been shown to increase the exposure of repaglinide in healthy volunteers. In vitro studies have shown that this increase in repaglinide exposure is due to inhibition of the CYP2C8 enzyme by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant use of clopidogrel and medicinal products that are predominantly eliminated by metabolism mediated by the CYP2C8 enzyme (e.g. repaglinide, paclitaxel) requires caution (see section 4.4).
Except for the information on interactions with specific drugs provided above, no studies have been conducted on the interaction of clopidogrel with drugs commonly prescribed for patients with atherothrombosis. However, it is known that in patients taking clopidogrel concomitantly with other drugs, including diuretics, beta-blockers, ACE inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists, no clinically significant adverse effects have been observed.
Application features
Bleeding and haematological disorders: Due to the risk of bleeding and haematological adverse reactions, complete blood count and/or other appropriate tests should be performed promptly if symptoms suggestive of bleeding occur during treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding from trauma, surgery or other pathological conditions, and in patients receiving ASA, heparin, glycoprotein IIb/IIIa inhibitors or NSAIDs including COX-2 inhibitors or SSRIs and other medicinal products that may increase the risk of bleeding (e.g. pentoxifylline). Patients should be closely monitored for signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures and surgery. The concomitant use of clopidogrel with oral anticoagulants is not recommended as it may increase the intensity of bleeding (see section “Interaction with other medicinal products and other types of interactions”).
In the case of elective surgery, when the antiplatelet effect is temporarily undesirable, treatment with clopidogrel should be discontinued 7 days before surgery. Patients should inform their doctor (including dentists) that they are taking clopidogrel before any surgery or before starting a new drug. Clopidogrel prolongs bleeding time and should be used with caution in patients at increased risk of bleeding (especially gastrointestinal and intraocular).
Patients should be warned that during treatment with clopidogrel (alone or in combination with ASA) bleeding may stop later than usual and that they should inform their doctor of any unusual (in terms of location or duration) bleeding.
Thrombotic thrombocytopenic purpura (TTP). Very rare cases of TTP have been reported following the use of clopidogrel, sometimes even after short-term use. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia with neurological manifestations, renal dysfunction, or fever. TTP is a potentially fatal condition and therefore requires immediate treatment, including plasma exchange.
Acquired hemophilia. Cases of acquired hemophilia have been reported following the use of clopidogrel. In cases of confirmed isolated prolongation of the activated partial thromboplastin time (APTT), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated, and clopidogrel should be discontinued.
Recent ischemic stroke: Due to insufficient data, clopidogrel is not recommended for use within 7 days of acute ischemic stroke.
In patients with a recent transient ischemic attack or ischemic stroke and who are at high risk of recurrent ischemic events, the combination of acetylsalicylic acid (ASA) and clopidogrel has been shown to increase the incidence of major bleeding. Therefore, this combination should be used with caution except in clinical situations where this combination has proven beneficial.
Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of medicinal products that reduce the activity of this enzyme is likely to lead to a decrease in the concentration of the active metabolite of clopidogrel in the blood plasma. However, the clinical significance of this interaction is not known. Therefore, as a precautionary measure, the simultaneous use of strong and moderate inhibitors of CYP2C19 should be avoided (see sections "Pharmacokinetics", "Interaction with other medicinal products and other types of interactions").
CYP2C8 substrates: Caution should be exercised when prescribing clopidogrel with medicinal products that are CYP2C8 substrates (see section 4.5).
Cross-reactions between thienopyridines. Patients should be checked for a history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel) as cross-allergy between thienopyridines has been reported (see section 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or haematological reactions to one thienopyridine are at increased risk of developing similar or different reactions to other thienopyridines. Close monitoring of patients with a known allergy to thienopyridines is recommended.
Renal impairment: Therapeutic experience with clopidogrel in patients with renal insufficiency is limited, therefore the drug should be prescribed with caution in such patients (see section "Method of administration and dosage").
Hepatic impairment: Experience in patients with moderate liver disease and a potential for bleeding diathesis is limited, therefore clopidogrel should be administered with caution to such patients (see section 4.2).
Excipients: Clopidogrel-Teva contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Clopidogrel-Teva contains lecithin (soybean oil). Therefore, patients with hypersensitivity to peanut or soya should not use this medicine.
Special precautions for disposal of residues and waste.
Any unused product or waste material should be disposed of in accordance with local requirements.
Ability to influence reaction speed when driving vehicles or other mechanisms
Clopidogrel has no or negligible influence on the reaction rate when driving or operating other mechanisms.
Use during pregnancy or breastfeeding
Pregnancy: As there are no clinical data on the use of clopidogrel during pregnancy, it is not advisable to prescribe the drug to pregnant women (precautionary measure).
Animal studies have not revealed direct or indirect negative effects on the course of pregnancy, embryonal/fetal development, parturition and postnatal development.
Breastfeeding. It is not known whether clopidogrel is excreted in human milk. Animal studies have shown that it is excreted in milk, therefore, breast-feeding should be discontinued during treatment with Clopidogrel-Teva.
Fertility: Animal studies have not shown any adverse effects of clopidogrel on fertility.
Method of administration and doses
Adults, including elderly patients: Clopidogrel-Teva should be taken orally at a dose of 75 mg once daily, regardless of meals.
Clopidogrel treatment of patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q wave myocardial infarction on the ECG) should be initiated with a single loading dose of 300 mg, followed by 75 mg once daily (with ASA 75–325 mg/day). Since higher doses of ASA increase the risk of bleeding, it is recommended that the dose of acetylsalicylic acid not exceed 100 mg. The optimal duration of treatment has not been formally established. The results of clinical studies indicate that the drug should be used for up to 12 months, and the maximum effect was observed after 3 months of treatment.
In patients with acute ST-segment elevation myocardial infarction, clopidogrel should be administered at a dose of 75 mg once daily, starting with a single loading dose of 300 mg in combination with ASA, with or without thrombolytic agents. Treatment of patients over 75 years of age should be initiated without a loading dose of clopidogrel. Combination therapy should be initiated as early as possible after the onset of symptoms and continued for at least 4 weeks. The benefit of the combination of clopidogrel with ASA for more than four weeks in this condition has not been studied.
In patients with atrial fibrillation, clopidogrel should be administered as a single daily dose of 75 mg. ASA (75–100 mg/day) should be initiated and continued in conjunction with clopidogrel (see section 5.1).
If less than 12 hours have passed since the next dose was due, the patient should take the missed dose immediately and take the next dose at the usual time; if more than 12 hours have passed, the patient should take the next dose at the usual time and not double the dose to make up for the missed dose.
Renal insufficiency: Therapeutic experience in patients with renal insufficiency is limited (see section "Special warnings and precautions for use").
Hepatic insufficiency. Therapeutic experience in patients with moderate liver disease and the possibility of hemorrhagic diathesis is limited (see section "Special warnings and precautions for use").
Children
Clopidogrel should not be used in children as there is no data on the efficacy of the drug in this age group of patients (see section "Pharmacodynamics").
Overdose
In case of overdose with clopidogrel, prolonged bleeding time with subsequent complications may occur. In case of bleeding, symptomatic treatment is recommended.
There is no known antidote to the pharmacological activity of clopidogrel. If immediate correction of prolonged bleeding time is required, the effect of clopidogrel can be reversed by platelet transfusion.
Adverse reactions
Brief description of the safety profile.
The safety of clopidogrel has been studied in more than 44,000 patients who participated in clinical trials, including more than 12,000 patients who received treatment for 1 year or more. In the CAPRIE study, the effect of clopidogrel at a dose of 75 mg/day was generally comparable to that of ASA at a dose of 325 mg/day, regardless of the age, gender, or race of the patients.
Clinically significant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are described below.
The most common adverse reaction reported in clinical and post-marketing studies was bleeding, most often occurring in the first month of treatment.
In the CAPRIE study, the overall bleeding rate was 9.3% in patients treated with clopidogrel or ASA. The incidence of major bleeding events was similar for clopidogrel and ASA.
In the CURE study, there was no increase in the incidence of major bleeding with the combination of clopidogrel and ASA within 7 days of coronary artery bypass grafting in patients who discontinued treatment more than 5 days before surgery. In patients who continued treatment for 5 days before coronary artery bypass grafting, the incidence of this event was 9.6% in the clopidogrel plus ASA group and 6.3% in the placebo plus ASA group.
In the CLARITY trial, there was an overall increase in bleeding in the clopidogrel and ASA group compared with the placebo and ASA group. The incidence of major bleeding was similar in both groups. This rate was consistent across subgroups of patients with different baseline characteristics and type of fibrinolytic or heparin therapy.
In the COMMIT trial, the overall incidence of major noncerebral or cerebral bleeding was low and similar in both groups.
In the ACTIVE-A study, the incidence of major bleeding was higher in the clopidogrel and ASA group compared with the placebo and ASA group (6.7% vs. 4.3%). In both groups, major bleeding was predominantly of extracranial origin (5.3% in the clopidogrel and ASA group, 3.5% in the placebo and ASA group), mainly gastrointestinal bleeding (3.5% vs. 1.8%). There was an increase in intracranial bleeding in the clopidogrel and ASA group compared with the placebo and ASA group (1.4% vs. 0.8%, respectively). There was no statistically significant difference between these groups in the incidence of fatal bleeding (1.1% in the clopidogrel and ASA group and 0.7% in the placebo and ASA group) or hemorrhagic stroke (0.8% and 0.6%, respectively).
The following adverse reactions have been observed with clopidogrel, either in clinical trials or spontaneously reported. The frequencies of adverse reactions are classified as follows: very common (≥1/10), common (≥1/100 to <1/10),
