Clopidogrel-Sanofi film-coated tablets 75 mg blister No. 90

Instructions Clopidogrel-Sanofi film-coated tablets 75 mg blister No. 90

Composition

active ingredient: clopidogrel;

1 tablet contains clopidogrel hydrosulfate in the form of base 75 mg;

excipients: mannitol (E 421), microcrystalline cellulose, macrogol 6000, low-substituted hydroxypropylcellulose, hydrogenated castor oil, Opadry 32K14834, type II (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, red iron oxide
(E 172)), carnauba wax.

Dosage form

Film-coated tablets.

Main physicochemical properties: round, slightly biconvex, film-coated tablets, pink in color, engraved with "75" on one side and "1171" on the other 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 clopidogrel is an inhibitor of platelet aggregation. To form the active metabolite, which inhibits platelet aggregation, clopidogrel must be biotransformed by cytochrome CYP 450 enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y12 receptors on the platelet surface and the subsequent ADP-induced activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since the binding is irreversible, platelets that have interacted with clopidogrel remain altered throughout their lifespan (which is approximately 7–10 days), and the restoration of normal platelet function occurs at a rate that corresponds to the rate of platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by the drug blocking platelet activation by released ADP.

Since the active metabolite is formed by cytochrome CYP 450 enzymes, some of which are polymorphic or inhibited by other drugs, not all patients experience sufficient inhibition of platelet aggregation.

Pharmacodynamic effects. From the first day of use, repeated daily doses of 75 mg of the drug show a significant inhibition of ADP-induced platelet aggregation. This effect progressively increases and stabilizes between 3 and 7 days. At steady 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 levels on average 5 days after discontinuation of treatment.

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 1 hour after dosing.
45 minutes after dosing. Absorption is at least 50%, as shown by urinary excretion of clopidogrel metabolites.

Distribution

Clopidogrel and the main (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 accounts for 85% of all metabolites circulating in blood plasma), and the other involves enzymes of the cytochrome P450 system. Clopidogrel is first converted to the intermediate metabolite 2-oxo-clopidogrel. As a result of further metabolism of 2-oxo-clopidogrel, a thiol derivative 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, such as 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 for the active metabolite is twice as high after a single 300 mg loading dose of clopidogrel compared to that observed after 4 days of 75 mg maintenance dose. Cmax is reached approximately 30–60 minutes after administration.

Breeding

After 120 hours of oral administration of 14C-labeled clopidogrel in humans, approximately 50% of the label was excreted in the urine and approximately 46% in the feces. After a single 75 mg oral dose, the elimination half-life of clopidogrel is approximately 6 hours. The elimination half-life of the main (inactive) circulating metabolite is 8 hours after single and multiple doses.

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate. 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 constitute the majority of alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism. Other alleles associated with absent or impaired metabolism are much less common. These include CYP2C19*4, *5, *6, *7, and *8. A poor metabolizer has two nonfunctional alleles, as described above. According to published data, CYP2C19 genotypes corresponding to poor metabolizers are found in 2% of Caucasians, 4% of Negroids, and 14% of Chinese. Tests are now available to determine the CYP2C19 genotype.

In a crossover study involving 40 healthy volunteers, 10 in each of four groups corresponding to a specific CYP2C19 metabolizer type (ultra-rapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects of a 300 mg dose followed by 75 mg daily and a 600 mg dose followed by 150 mg daily were evaluated. Each of these treatments was administered for a total of 5 days (until steady state was achieved). There were no significant differences in blood concentrations of the active metabolite and mean platelet aggregation inhibition (PAI) between ultra-rapid, extensive, and intermediate metabolizers. In poor metabolizers, blood concentrations of the active metabolite were reduced by 63-71% compared with extensive metabolizers. After the 300 mg/75 mg regimen, the antiplatelet effects in poor metabolizers were less pronounced, with mean PAO (5 μM ADP) of 24% (24 hours) and 37% (day 5) compared with PAO 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. The appropriate dose regimen for this patient population has not been determined from clinical efficacy studies.

Similar to the results above, a meta-analysis of 6 studies using steady-state data from 335 patients treated with clopidogrel demonstrated that the concentration of the active metabolite in the blood was reduced by 28% in intermediate metabolisers and 72% in poor metabolisers; inhibition of platelet aggregation (5 μM ADP) was also reduced, with a difference in PTH of 5.9% and 21.4%, respectively, compared with extensive metabolisers.

The effect of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been studied in prospective randomized controlled trials. However, a number of retrospective analyses have been conducted to assess this effect in patients treated with clopidogrel for whom genotyping results are available: CURE (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477), and ACTIVE-A-(n = 601). In addition, there are results from several published cohort studies.

In the analysis of TRITON-TIMI 38 and 3 cohort studies (Collet, Sibbing, Giusti), the combined group of intermediate and poor metabolizers had a significantly higher incidence of cardiovascular events (fatal outcome, myocardial infarction, and stroke) or stent thrombosis than extensive metabolizers.

In the CHARISMA analysis and one cohort study (Simon), poor metabolizers had an increased incidence of events compared with extensive metabolizers.

In the analyses of CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), the incidence of cardiovascular events was not significantly dependent on metabolic characteristics.

None of these analyses included sufficient numbers of patients to detect a difference in clinical outcomes in patients with reduced metabolism.

Special categories of patients

The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the following special categories of patients.

Kidney failure

After regular administration of 75 mg of clopidogrel per day to patients with severe renal insufficiency (creatinine clearance 5-15 ml per minute), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared with this effect in healthy volunteers, and bleeding time was prolonged almost as much as in healthy volunteers receiving 75 mg of clopidogrel per day. Clinical tolerability was good in all patients.

After regular administration of 75 mg of 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.

Racial affiliation

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 for this CYP.

Preclinical safety data

The most common adverse reactions observed in preclinical animal studies were liver changes. These occurred at doses approximately 25 times the human therapeutic dose of 75 mg clopidogrel per day and were due to the drug's effect on hepatic metabolism enzymes. No effects on hepatic metabolism enzymes were observed at therapeutic doses of clopidogrel in humans.

When high doses of clopidogrel were administered to animals, poor gastric tolerability of the drug was observed (gastritis, erosive gastric 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 clopidogrel per day 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 a 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:

with acute coronary syndrome without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including in patients who have had a stent inserted 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, for whom treatment with vitamin K antagonists (VKAs) is contraindicated and who are at low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke (see also section 5.1).

Contraindication

Hypersensitivity to the active substance or to any component of the drug. Severe hepatic insufficiency. Acute bleeding (e.g. peptic ulcer or intracranial hemorrhage).

Interaction with other medicinal products and other types of interactions

Medicinal products associated with an increased risk of bleeding. Due to a 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: Concomitant use of the drug with oral anticoagulants is not recommended, as this combination may increase the intensity of bleeding (see section "Special instructions"). Although the use of clopidogrel at a dose of 75 mg per day does not change the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin treatment, the simultaneous use of clopidogrel and warfarin increases the risk of bleeding due to the existence of independent effects on hemostasis.

Glycoprotein IIb/IIIa receptor inhibitors: Clopidogrel should be administered with caution to patients receiving glycoprotein IIb/IIIa receptor inhibitors (see section 4.4).

Heparin. In 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 (see section 4.4).

Thrombolytic agents: The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparin has been studied 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 with ASA (see section 4.8).

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 the use of all NSAIDs. Therefore, caution is required when NSAIDs, in particular COX-2 inhibitors, are used concomitantly with clopidogrel (see section 4.4).

Selective serotonin reuptake inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, concomitant use of clopidogrel and SSRIs should be undertaken with caution.

Concomitant use of other drugs.

CYP2C19 inducers

Since clopidogrel is metabolized to its active metabolite in part by CYP2C19, the use of medicinal products that induce the activity of this enzyme is expected to lead to increased levels of the active metabolite of clopidogrel.

Rifampicin strongly induces CYP2C19, leading to both increased levels of the active metabolite of clopidogrel and platelet inhibition, which may in particular increase the risk of bleeding. As a precautionary measure, concomitant use of strong CYP2C19 inducers should be avoided (see section 4.4).

CYP2C19 inhibitors

Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of drugs 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. 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 "Special instructions" and "Pharmacokinetics").

Drugs that are strong or moderate inhibitors of CYP2C19 include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton pump inhibitors (PPIs). Omeprazole 80 mg once daily, when co-administered with clopidogrel or within 12 hours between the 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 the interaction of esomeprazole with clopidogrel is similar.

Observational and clinical studies have provided conflicting data on the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of major cardiovascular events. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section 4.4).

A less pronounced decrease in metabolite concentrations in the blood was observed with pantoprazole or lansoprazole.

When co-administered with pantoprazole 80 mg once daily, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 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 concomitant use of clopidogrel and pantoprazole.

There is no evidence that other drugs that reduce stomach acid production, such as H2 blockers or antacids, affect the antiplatelet activity of clopidogrel.

Significantly reduced platelet inhibition has been observed in HIV patients receiving ART boosted with ritonavir or cobicistat. Although the clinical significance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients receiving ART boosted with ritonavir who experienced recurrent occlusive events after deobstruction or thrombotic events while receiving a loading dose of clopidogrel. Concomitant use of clopidogrel and ritonavir may result in a reduction in mean platelet inhibition. Therefore, concomitant use of clopidogrel with booster ART should be avoided.

Combination with other drugs. A number of clinical studies have been conducted with clopidogrel and other drugs to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both drugs. 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.

Antacids did not affect the level of absorption of clopidogrel.

The results of the CAPRIE study indicate that phenytoin and tolbutamide, which are metabolized by the CYP2C9 enzyme, can be safely used concomitantly with clopidogrel.

Medicinal products that are substrates of the CYP2C8 enzyme. 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, the concomitant use of clopidogrel and medicinal products that are predominantly eliminated by metabolism mediated by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution (see section 4.4).

Except for the information on interactions with specific drugs provided above, no interaction studies have been conducted with clopidogrel and drugs commonly prescribed for patients with atherothrombosis. However, patients in clinical trials with clopidogrel have been treated concomitantly with other drugs, including diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists, without evidence of clinically significant adverse effects.

As with other oral P2Y12 inhibitors, concomitant use of opioid agonists may potentially delay and reduce the absorption of clopidogrel, possibly due to delayed gastric emptying. The clinical significance of this is unknown. The use of a parenteral antiplatelet agent should be considered in patients with acute coronary syndrome who require concomitant administration of morphine or other opioid agonists.

Application features

Bleeding and hematological disorders

Due to the risk of bleeding and haematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggestive of bleeding occur during treatment with clopidogrel (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 non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors or selective serotonin reuptake inhibitors (SSRIs), or potent CYP2C19 inducers, or other medicinal products such as pentoxifylline, which are associated with an increased risk of haemorrhagic events (see section 4.5). 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 4.5).

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 physicians (including dentists) that they are taking clopidogrel before any surgery or before starting a new medication. Clopidogrel prolongs bleeding time and should be used with caution in patients at increased risk of bleeding (especially gastrointestinal and intraocular).

Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) has been reported very rarely after 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 life-threatening condition that requires immediate treatment, including plasmapheresis.

Acquired hemophilia

Cases of acquired hemophilia have been reported following the use of clopidogrel. In cases of confirmed isolated increases in aPTT (activated partial thromboplastin time), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be placed under specialist supervision and receive appropriate treatment, and clopidogrel should be discontinued.

Recent ischemic stroke

Due to insufficient data, it is not recommended to prescribe clopidogrel in the first 7 days after acute ischemic stroke.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: According to the medical literature, patients with genetically reduced CYP2C19 function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect when using recommended doses of clopidogrel. Tests are now available that can identify the CYP2C19 genotype of the patient.

Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of drugs 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. 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 section "Interaction with other medicinal products and other forms of interaction", a list of CYP2C19 inhibitors is given in the section "Pharmacokinetics").

The use of medicinal products that induce CYP2C19 activity is expected to lead to increased levels of the active metabolite of clopidogrel and may increase the risk of bleeding. As a precautionary measure, concomitant use of strong CYP2C19 inducers should be avoided (see section 4.5).

CYP2C8 substrates

Caution is required in patients concomitantly taking clopidogrel and medicinal products that are substrates of CYP2C8 (see section 4.5).

Cross-reactivity between thienopyridines

Patients should be checked for a history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel) as cross-reactivity between thienopyridines has been reported (see section 4.8). Thienopyridines may be associated with 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 may be at increased risk of developing the same or a different reaction to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Kidney dysfunction

Therapeutic experience with clopidogrel in patients with renal insufficiency is limited, therefore the drug should be prescribed with caution to such patients (see section "Method of administration and dosage").

Liver dysfunction

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-SANOFI contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

CLOPIDOGREL-SANOFI contains hydrogenated castor oil, which may cause stomach upset and diarrhea.

Special precautions for use

Patients should be sure to inform their doctors that they are taking antiretroviral drugs (medicines to treat HIV infections).

Special precautions for disposal and other waste materials: Any unused product or waste material should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding

Pregnancy: Due to the lack of clinical data on the use of clopidogrel during pregnancy, it is not advisable to prescribe the drug to pregnant women (precautionary measure).

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Fertility: Studies in laboratory animals have not shown any adverse effects of clopidogrel on fertility.

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.

Method of administration and doses

Adults and elderly patients: Clopidogrel-SANOFI is prescribed at a dose of 75 mg once daily, regardless of meals.

In patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q wave myocardial infarction on ECG), treatment with clopidogrel should be initiated with a single loading dose of 300 mg, and then continued at a dose of 75 mg once daily (with acetylsalicylic acid (ASA) at a dose of 75-325 mg per day). Since the use of higher doses of ASA increases the risk of bleeding, it is not recommended to exceed a dose of ASA of 100 mg.

The optimal duration of treatment has not been formally established. Clinical trial results suggest that the drug should be used for up to 12 months, with the maximum effect observed after 3 months of treatment.

In patients with acute myocardial infarction with ST-segment elevation, 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 drugs. Treatment of patients aged from
75 years of age should be initiated without a loading dose of clopidogrel. Combination therapy should be initiated as early as possible after symptom onset and continued for at least 4 weeks. The benefit of combining clopidogrel with ASA for longer than 4 weeks in this condition has not been studied.

In patients with atrial fibrillation, clopidogrel should be administered in a single daily dose.
75 mg. ASA (75-100 mg/day) should be initiated and continued in conjunction with clopidogrel (see section 5.1).

In case of missed dose:

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 scheduled 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 (under 18 years of age) 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 may occur with the following complications. 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 (of whom more than 12,000 people received treatment for 1 year or more). In the CAPRIE study, the effect of clopidogrel at a dose of 75 mg per day was generally comparable to the effect of ASA at a dose of 325 mg per day, regardless of age, gender, or race of patients.

In addition to clinical trial data, spontaneous reports of adverse reactions during use of the drug in clinical practice were taken into account.