CLOPIDOGREL-SANOFI

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLOPIDOGREL-SANOFI

Composition:

Active substance: clopidogrel;

1 tablet contains 75 mg of clopidogrel hydrogen sulfate (expressed as base);

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, slightly biconvex, film-coated tablets of pink color with "75" engraved on one side and "1171" on the other side.

Pharmacotherapeutic group. Platelet aggregation inhibitors, excluding heparin.

ATC code B01AC04.

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 that inhibits platelet aggregation, clopidogrel must be biotransformed by cytochrome CYP450 enzymes. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its P2Y12 receptors on the platelet surface and subsequent ADP-induced activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. Since the binding is irreversible, platelets that interact with clopidogrel remain altered throughout their lifespan (approximately 7–10 days), and normal platelet function is restored at a rate corresponding to the rate of platelet turnover. Platelet aggregation induced by other agonists besides ADP is also inhibited, as the drug blocks platelet activation by released ADP.

Since the active metabolite is formed under the influence of cytochrome CYP450 enzymes, some of which are polymorphic or inhibited by other medicinal products, sufficient inhibition of platelet aggregation does not occur in all patients.

Pharmacodynamic effects. Significant slowing of ADP-induced platelet aggregation is observed from the first day of repeated daily doses of 75 mg of the drug. This effect progressively increases and stabilizes between days 3 and 7. At steady state, the average level of inhibition of aggregation with a daily dose of 75 mg ranges from 40% to 60%. Platelet aggregation and bleeding time return to baseline levels on average within 5 days after discontinuation of treatment.

Pharmacokinetics.

Absorption

After oral administration of single and multiple daily doses of 75 mg clopidogrel, the drug is rapidly absorbed. Mean maximum plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) were reached about 45 minutes after dosing. Absorption is at least 50%, as indicated by urinary excretion of clopidogrel metabolites.

Distribution

Clopidogrel and the main (inactive) circulating metabolite in blood reversibly bind 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 involves esterases and leads to hydrolysis, forming an inactive carboxylic acid derivative (which accounts for 85% of all metabolites circulating in plasma), and the other involves cytochrome P450 enzymes. Initially, clopidogrel is converted into the intermediate metabolite 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to the formation of a thiol derivative – the active metabolite. This active metabolite is formed predominantly by the CYP2C19 enzyme, with the involvement of several other CYP system enzymes such as CYP1A2, CYP2B6, and CYP3A4. The active metabolite of clopidogrel (thiol derivative), isolated in vitro, rapidly and irreversibly binds to receptors on platelets, thereby preventing platelet aggregation.

The Cmax value for the active metabolite is twice as high after administration of a single 300 mg loading dose of clopidogrel compared to that observed after 4 days of maintenance therapy with 75 mg. Cmax is reached approximately 30–60 minutes after drug intake.

Excretion

Within 120 hours after administration of radiolabeled 14C-clopidogrel to humans, approximately 50% of the radiolabel was excreted in urine and about 46% in feces. After oral administration of a single 75 mg 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 both single and multiple doses.

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 antiplatelet effects, as measured by platelet aggregation ex vivo, vary depending on the CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional metabolism, whereas the CYP2C19*2 and CYP2C19*3 alleles correspond to 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 reduced metabolism are less common and include CYP2C19*4, *5, *6, *7, and *8. A patient with reduced metabolism has two non-functional alleles, as indicated above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasian individuals, 4% of African-American patients, and 14% of Chinese patients. Tests are currently available to determine CYP2C19 genotype.

In a crossover study involving 40 healthy volunteers, 10 in each of four groups corresponding to a specific CYP2C19 metabolic phenotype (ultrarapid, extensive, intermediate, and poor), the pharmacokinetics and antiplatelet effects were evaluated after administration of a 300 mg dose followed by 75 mg daily, and a 600 mg dose followed by 150 mg daily. Each treatment regimen was administered for a total of 5 days (to reach steady state). No significant differences in blood concentrations of the active metabolite or mean platelet aggregation inhibition (PAI) were observed between individuals with ultrarapid, extensive, and intermediate metabolism. In individuals with poor metabolism, the concentration of the active metabolite in blood was reduced by 63–71% compared to those with extensive metabolism. After administration of the 300 mg/75 mg regimen, antiplatelet effects in individuals with poor metabolism were less pronounced, with mean PAI (5 µM ADP) values of 24% (24 hours) and 37% (day 5), compared to PAI values of 39% (24 hours) and 58% (day 5) in individuals with extensive metabolism and 37% (24 hours) and 60% (day 5) in those with intermediate metabolism. When individuals with poor metabolism received the 600 mg/150 mg regimen, the concentration of the active metabolite in blood was higher than with the 300 mg/75 mg regimen. Furthermore, PAI values were 32% (24 hours) and 61% (day 5), which were higher than in poor metabolizers receiving 300 mg/75 mg and similar to values obtained in other metabolic phenotype groups receiving the 300 mg/75 mg regimen. Based on clinical effect studies, the appropriate dosing regimen for this patient group has not been established.

Similarly, in a meta-analysis of 6 studies assessing steady-state data from 335 patients receiving clopidogrel, it was demonstrated that the concentration of the active metabolite in blood was reduced by 28% in individuals with intermediate metabolism and by 72% in those with poor metabolism; inhibition of platelet aggregation (5 µM ADP) was also reduced, with PAI differences of 5.9% and 21.4%, respectively, compared to individuals with extensive metabolism.

The impact of CYP2C19 genotype on clinical outcomes in patients receiving clopidogrel has not been studied in prospective randomized controlled trials. However, several retrospective analyses have been conducted to evaluate this effect in patients receiving clopidogrel who had genotyping results available: CURE (n = 2721), CHARISMA (N = 2428), CLARITY-TIMI 28 (n = 227), TRITON-TIMI 38 (n = 1477), and ACTIVE-A (n = 601). Additionally, results from several published cohort studies are available.

In the analysis of TRITON-TIMI 38 and three cohort studies (Collet, Sibbing, Giusti), the combined group of individuals with intermediate and poor metabolism had a significantly higher incidence of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to those with extensive metabolism.

In the analysis of CHARISMA and one cohort study (Simon), individuals with poor metabolism showed a higher incidence of events compared to those with extensive metabolism.

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

None of these analyses included a sufficient number of patients to detect differences in clinical outcomes in patients with poor metabolism.

Special patient categories

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

Renal impairment

After regular administration of 75 mg clopidogrel daily, patients with severe renal impairment (creatinine clearance 5–15 mL/min) showed less pronounced inhibition of ADP-induced platelet aggregation (25%) compared to healthy volunteers, and bleeding time was prolonged almost to the same extent as in healthy volunteers receiving 75 mg clopidogrel daily. 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 causing intermediate and poor metabolic activity of CYP2C19 varies by racial/ethnic background (see section "Pharmacogenetics"). Limited data are available for Mongoloid race patients to assess the clinical significance of genotyping for this CYP.

Preclinical safety data

The most frequently observed adverse effects in preclinical animal studies were liver-related changes. These occurred at doses nearly 25 times higher than the therapeutic dose of 75 mg clopidogrel daily in humans and were due to the drug's effect on enzymes involved in hepatic metabolism. No effect on enzymes involved in hepatic metabolism was observed in humans receiving therapeutic doses of clopidogrel.

Poor gastrointestinal tolerability of the drug (gastritis, erosive gastric lesions, and/or vomiting) was observed in animals receiving high doses of clopidogrel.

Administration of clopidogrel to mice for 78 weeks and to rats for 104 weeks at doses up to 77 mg/kg daily (approximately 25 times the therapeutic dose of 75 mg clopidogrel daily in humans) provided no evidence of carcinogenic potential.

A number of genotoxicity studies of clopidogrel were conducted in vitro and in vivo, but none revealed genotoxic effects of the drug.

Clopidogrel did not affect reproductive function in male and female rats, nor did it show teratogenic effects in rats or rabbits. Administration to lactating female rats resulted in slight developmental delay in offspring. Specific pharmacokinetic studies with radiolabeled clopidogrel demonstrated that the parent compound and its metabolites penetrate into breast milk. Therefore, both direct (slight toxic effect) and indirect (due to deterioration of milk palatability) effects on offspring cannot be excluded.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• in patients who have suffered myocardial infarction (treatment initiation – within a few days, but no later than 35 days after onset), ischaemic stroke (treatment initiation – within 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease;
• in patients with acute coronary syndrome:
  • with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who have undergone percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);
  • with acute ST-segment elevation myocardial infarction in combination with acetylsalicylic acid (in patients receiving standard medical therapy and for whom thrombolytic therapy is indicated).

Transient ischaemic attack (TIA) of moderate or high risk, or minor ischaemic stroke (MIS)

Clopidogrel in combination with ASA is indicated in adult patients with TIA of moderate or high risk (ABCD2 score ≥ 4) or minor ischaemic stroke (NIHSS score ≤ 3) within 24 hours of the TIA or MIS event.

[1] Age, blood pressure, clinical features, duration, and diagnosis of diabetes mellitus.

2 National Institutes of Health Stroke Scale.

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 vitamin K antagonist (VKA) therapy is contraindicated and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke (see also section "Pharmacological properties").

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product. Severe hepatic impairment. Active bleeding (e.g., peptic ulcer or intracranial haemorrhage).

Interaction with other medicinal products and other forms of interaction.

Medicinal products associated with increased risk of bleeding. Due to the potential additive effect, there is an increased risk of haemorrhagic complications; therefore, concomitant use of such medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

Oral anticoagulants. Concomitant use of the medicinal product with oral anticoagulants is not recommended, as this combination may increase the intensity of bleeding (see section "Special warnings and precautions for use"). Although administration of clopidogrel 75 mg once daily does not alter the pharmacokinetic profile of S-warfarin or the international normalized ratio (INR) in patients on long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to independent effects on haemostasis.

Glycoprotein IIb/IIIa inhibitors. Clopidogrel should be used with caution in patients receiving glycoprotein IIb/IIIa inhibitors (see section "Special warnings and precautions for use").

Acetylsalicylic acid (ASA). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg ASA twice daily for one day did not cause a significant increase in bleeding time prolonged by clopidogrel. Since a pharmacodynamic interaction between clopidogrel and ASA with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special warnings and precautions for use"). Nevertheless, clopidogrel and ASA have been used together for up to one year (see section "Pharmacodynamic properties").

Heparin. In a clinical study conducted in healthy volunteers, clopidogrel did not require dose adjustment of heparin and did not alter the effect of heparin on coagulation. Concomitant administration of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. Since a pharmacodynamic interaction between clopidogrel and heparin with an increased risk of bleeding is possible, concomitant use of these agents requires caution (see section "Special warnings and precautions for use").

Thrombolytic agents. The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents, and heparin was 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 with ASA (see section "Undesirable effects").

Non-steroidal anti-inflammatory drugs (NSAIDs). In a clinical study conducted in healthy volunteers, concomitant use of clopidogrel and naproxen increased the number of occult gastrointestinal bleeding episodes. However, due to the lack of studies on the interaction of the medicinal product with other NSAIDs, it is not yet established whether the risk of gastrointestinal bleeding increases with all NSAIDs. Therefore, caution is required when using NSAIDs, particularly COX-2 inhibitors, concomitantly with clopidogrel (see section "Special warnings and precautions for use").

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

Concomitant use with other medicinal products.

Inducers of CYP2C19

Since clopidogrel is metabolized to its active metabolite partly via CYP2C19, the use of medicinal products that induce the activity of this enzyme is expected to increase the level 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 precaution, concomitant use of strong inducers of CYP2C19 should be avoided (see section "Special warnings and precautions for use").

Inhibitors of CYP2C19

Since clopidogrel is converted to its active metabolite partly by CYP2C19, the use of medicinal products that reduce the activity of this enzyme will most likely lead to decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. Therefore, as a precaution, concomitant use of strong and moderate inhibitors of CYP2C19 should be avoided (see sections "Special warnings and precautions for use" and "Pharmacokinetics").

Medicinal products 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 doses of these two medicinal products, reduced the plasma concentration of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was accompanied by a decrease in platelet aggregation inhibition by 39% (loading dose) and 21% (maintenance dose). The interaction between esomeprazole and clopidogrel is expected to be similar.

Observational and clinical trials have yielded conflicting data regarding the clinical consequences of these pharmacokinetic (PK) and pharmacodynamic (PD) interactions in terms of the development of major cardiovascular events. As a precaution, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section "Special warnings and precautions for use").

A less pronounced reduction in metabolite plasma concentrations was observed with pantoprazole or lansoprazole.

When pantoprazole 80 mg once daily was co-administered, plasma concentrations of the active metabolite decreased by 20% (loading dose) and 14% (maintenance dose). This reduction was accompanied by a decrease in the mean platelet aggregation inhibition by 15% and 11%, respectively. These results suggest that concomitant use of clopidogrel and pantoprazole is possible.

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

Booster antiretroviral therapy. In HIV-infected patients receiving boosted antiretroviral therapy (ART), there is a high risk of vascular events.

Markedly reduced platelet inhibition was observed in HIV patients receiving ART boosted with ritonavir or cobicistat. Although the clinical significance of these data is not established, spontaneous reports have been received of HIV-infected patients receiving ART boosted with ritonavir who experienced recurrent occlusive events after revascularization or thrombotic events despite high-dose clopidogrel therapy. Concomitant use of clopidogrel and ritonavir may result in reduced mean platelet inhibition. Therefore, concomitant use of clopidogrel with boosted ART should be avoided.

Combination with other medicinal products. Several clinical studies have been conducted with clopidogrel and other medicinal products to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was used concomitantly with atenolol, nifedipine, or both. In addition, the pharmacodynamic activity of clopidogrel remained essentially unchanged when used concomitantly with phenobarbital and estrogen.

The pharmacokinetic properties of digoxin or theophylline were not altered by concomitant administration with clopidogrel.

Antacid agents did not affect the absorption of clopidogrel.

Results from 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 exposure to repaglinide in healthy volunteers. In vitro studies demonstrated that this increased exposure to repaglinide 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 with medicinal products that are primarily eliminated via metabolism mediated by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution (see section "Special warnings and precautions for use").

Except for the information on interactions with specific medicinal products provided above, interaction studies between clopidogrel and medicinal products commonly prescribed to patients with atherothrombosis have not been conducted. However, patients participating in clinical trials of clopidogrel were concomitantly using other medicinal products, 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 signs of clinically significant adverse effects.

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

Rosuvastatin. Following administration of clopidogrel 300 mg, exposure to rosuvastatin was found to increase 2-fold (AUC) and 1.3-fold (Cmax). After repeated administration of clopidogrel 75 mg, rosuvastatin exposure increased 1.4-fold (AUC) without affecting Cmax.

Special precautions for use.

Bleeding and hematological disorders

Due to the risk of bleeding and hematological adverse reactions, a complete blood count and/or other appropriate tests should be performed immediately if symptoms suggesting possible bleeding occur during treatment (see section "Adverse reactions"). As with other antiplatelet agents, clopidogrel should be used with caution in patients with an increased risk of bleeding due to trauma, surgical procedures, or other pathological conditions, and also when patients are receiving acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, selective serotonin reuptake inhibitors (SSRIs), potent inducers of CYP2C19, or other medicinal products associated with an increased risk of hemorrhagic events, such as pentoxifylline (see section "Interaction with other medicinal products and other forms of interaction"). Triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended due to increased risk of bleeding for secondary prevention of stroke in patients with acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA) (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Patients should be carefully monitored for signs of bleeding, including occult bleeding, especially during the first weeks of treatment and/or following invasive cardiac procedures and surgical interventions. 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 forms of interaction").

For planned surgical procedures when antiplatelet effect is temporarily undesirable, clopidogrel treatment should be discontinued 7 days prior to surgery. Patients should inform physicians (including dentists) that they are taking clopidogrel before any surgery or before starting any new medication. Clopidogrel prolongs bleeding time; therefore, it should be used with caution in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular bleeding).

Patients should be advised that when treated with clopidogrel (alone or in combination with ASA), bleeding may take longer than usual to stop, and they should report any unusual bleeding (in site or duration) to their physician.

The use of a 600 mg loading dose of clopidogrel is not recommended in patients with non-ST-segment elevation acute coronary syndrome aged ≥ 75 years due to increased risk of bleeding in this population.

Thrombotic thrombocytopenic purpura (TTP)

Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported following clopidogrel use, sometimes even after short-term treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, with neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Acquired hemophilia

Cases of acquired hemophilia have been reported after clopidogrel use. In cases of confirmed isolated prolongation of activated partial thromboplastin time (aPTT), with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with confirmed diagnosis of acquired hemophilia should be managed by a specialist and receive appropriate treatment; clopidogrel therapy should be discontinued.

Recent ischemic stroke

Initiation of treatment

• In patients with acute minor ischemic stroke or moderate- to high-risk TIA, dual antiplatelet therapy (clopidogrel and ASA) should be initiated within 24 hours of symptom onset.
• There are no data on the benefit-risk ratio of short-term dual antiplatelet therapy in patients with acute minor ischemic stroke or moderate- to high-risk TIA who have a history of (non-traumatic) intracranial hemorrhage.
• In patients with non-minor ischemic stroke, clopidogrel monotherapy should only be initiated 7 days after symptom onset.

Patients with non-minor ischemic stroke (NIHSS score > 4)

Due to lack of data, dual antiplatelet therapy is not recommended (see section "Indications").

Patients with recent minor ischemic stroke or moderate- to high-risk TIA scheduled for or undergoing interventional procedures

There are no data supporting the use of dual antiplatelet therapy in patients scheduled for carotid endarterectomy or endovascular thrombectomy, or in patients undergoing thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: According to 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 receiving recommended doses. Genetic tests are currently available to identify a patient's CYP2C19 genotype.

Since clopidogrel is partially converted to its active metabolite by CYP2C19, concomitant use of drugs that reduce the activity of this enzyme will most likely result in decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not fully established. As a precaution, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see section "Interaction with other medicinal products and other forms of interaction"; list of CYP2C19 inhibitors is provided in section "Pharmacokinetics").

Concomitant use of medicinal products that induce CYP2C19 activity is expected to increase levels of the active metabolite of clopidogrel and may increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Substrates of the CYP2C8 enzyme

Caution is required in patients receiving clopidogrel concomitantly with medicinal products that are CYP2C8 substrates (see section "Interaction with other medicinal products and other forms of interaction").

Cross-reactivity among thienopyridines

Patients should be screened for a history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cross-reactivity among thienopyridines has been reported (see section "Adverse reactions"). Use of thienopyridines may lead to allergic reactions ranging from mild to severe, such as rash, Quincke's edema, or hematological cross-reactions, such as thrombocytopenia and neutropenia. Patients with a history of allergic and/or hematological reactions to one thienopyridine may have an increased risk of similar or other reactions to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal impairment

Experience with clopidogrel use in patients with renal impairment is limited; therefore, the drug should be used with caution in such patients (see section "Posology and method of administration").

Hepatic impairment

Experience with clopidogrel use in patients with moderate liver disease and potential for hemorrhagic diathesis is limited. Therefore, clopidogrel should be used with caution in these patients (see section "Posology and method of administration").

Excipients

CLOPIDOGREL-SANOFI contains lactose. Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

CLOPIDOGREL-SANOFI contains hydrogenated castor oil, which may cause gastrointestinal disturbances and diarrhea.

Special precautions for use

Patients must inform their physicians if they are taking antiretroviral agents (medicinal products for treatment of HIV infection).

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

Use during pregnancy or breastfeeding.

Pregnancy. Due to lack of clinical data on clopidogrel use during pregnancy, the drug should not be administered to pregnant women (as a precautionary measure).

Animal studies have not shown direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development (see section "Preclinical safety data").

Breastfeeding. It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion in milk; therefore, breastfeeding should be discontinued during treatment with CLOPIDOGREL-SANOFI.

Fertility. No adverse effects of clopidogrel on fertility were observed in studies in laboratory animals.

Ability to affect reaction rate while driving or operating machinery.

Clopidogrel has no effect or has a negligible effect on the ability to drive or use machinery.

Method of Administration and Dosage

Adults and elderly patients. CLOPIDOGREL-SANOFI should be administered at a dose of 75 mg once daily, independently of food intake.

In patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), treatment with clopidogrel should be initiated with a single loading dose of 300 mg or 600 mg. A loading dose of 600 mg may be used in patients under 75 years of age when percutaneous coronary intervention (PCI) is planned (see section "Special Instructions"). Clopidogrel treatment should then be continued at a dose of 75 mg once daily (in combination with acetylsalicylic acid (ASA) at a dose of 75–325 mg daily). Since higher ASA doses increase the risk of bleeding, ASA dose should not exceed 100 mg.

The optimal duration of treatment has not been formally established. Clinical trial data support treatment for up to 12 months, with maximum benefit observed after 3 months of therapy.

In patients with acute myocardial infarction with ST-segment elevation, clopidogrel should be administered at a dose of 75 mg once daily, initiated with a single 300 mg loading dose in combination with ASA, with or without thrombolytic agents. In patients aged 75 years and older, treatment should be initiated without a clopidogrel loading dose. Combination therapy should be started as early as possible after symptom onset and continued for at least 4 weeks. The benefit of combining clopidogrel with ASA beyond 4 weeks has not been studied in this condition.

Adult patients with moderate to high-risk TIA or minor ischemic stroke

Adult patients with moderate to high-risk TIA (ABCD2 score ≥ 4) or minor ischemic stroke (NIHSS score ≤ 3) should receive a clopidogrel loading dose of 300 mg, followed by continuation of treatment with 75 mg clopidogrel once daily and ASA 75–100 mg once daily. Treatment with clopidogrel and ASA should be initiated within 24 hours of symptom onset and continued for 21 days, followed by antiplatelet monotherapy.

In patients with atrial fibrillation, clopidogrel should be administered at a single daily dose of 75 mg. ASA (75–100 mg daily) should be initiated and continued concomitantly with clopidogrel (see section "Pharmacological Properties").

In case of missed dose:

• If less than 12 hours have passed since the missed 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 should not double the dose to compensate for the missed dose.

Renal impairment. Therapeutic experience with the use of the drug in patients with renal impairment is limited (see section "Special Instructions").

Hepatic impairment. Therapeutic experience with the use of the drug in patients with moderate liver disease and potential risk of hemorrhagic diathesis is limited (see section "Special Instructions").

Children.

Clopidogrel should not be used in children (under 18 years of age) due to lack of data on efficacy in this patient population (see section "Pharmacodynamics").

Overdose.

Prolongation of bleeding time with subsequent complications may occur in case of clopidogrel overdose. Symptomatic treatment is recommended if bleeding occurs.

There is no known antidote for the pharmacological activity of clopidogrel. If immediate correction of prolonged bleeding time is required, clopidogrel's effect may be reversed by platelet transfusion.

Adverse Reactions.

Short description of the safety profile.

The safety of clopidogrel has been evaluated in more than 44,000 patients who participated in clinical studies (including over 12,000 patients treated for 1 year or longer). In the CAPRIE study, the effect of clopidogrel at a dose of 75 mg once daily was generally comparable to that of acetylsalicylic acid (ASA) at a dose of 325 mg once daily, regardless of patient age, gender, or race.

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

Bleeding was the most commonly reported adverse reaction observed both in clinical trials and during the post-marketing period, with most events occurring during the first month of treatment.

In the CAPRIE study, in patients receiving clopidogrel or ASA, the overall incidence of bleeding was 9.3%. The frequency of severe bleeding events was similar for clopidogrel and ASA.

In the CURE study, no increase in the frequency of major bleeding was observed with the combination of clopidogrel + ASA within 7 days following coronary artery bypass graft (CABG) surgery in patients who discontinued treatment more than 5 days prior to surgery. In patients who continued treatment up to 5 days before CABG surgery, the incidence of major bleeding was 9.6% in the clopidogrel + ASA group versus 6.3% in the placebo + ASA group.

In the CLARITY study, an overall increased frequency of bleeding was observed in the group receiving clopidogrel + ASA compared to the placebo + ASA group. However, the rate of major bleeding was similar between both groups. This finding remained consistent across subgroups of patients defined by baseline characteristics and type of fibrinolytic agent or heparin therapy.

In the COMMIT study, the overall frequency of major non-cerebral or cerebral bleeding was low and similar in both treatment groups.

In the ACTIVE-A study, the incidence of major bleeding was higher in the clopidogrel + ASA group compared to the placebo + ASA group (6.7% vs. 4.3%). In both groups, major bleeding events were predominantly extracranial (5.3% in the clopidogrel + ASA group, 3.5% in the placebo + ASA group), mainly gastrointestinal bleeding (3.5% vs. 1.8%). An increased incidence of intracranial bleeding was observed in the clopidogrel + ASA group compared to placebo + ASA (1.4% vs. 0.8%, respectively). There were no statistically significant differences between the groups in the incidence of fatal bleeding (1.1% in the clopidogrel + ASA group vs. 0.7% in the placebo + ASA group) or hemorrhagic stroke (0.8% vs. 0.6%, respectively).

In the TARDIS study, patients with recent ischemic stroke receiving intensive antiplatelet therapy with three agents (ASA + clopidogrel + dipyridamole) experienced excess bleeding and severe bleeding compared to monotherapy with clopidogrel or the combination of ASA and dipyridamole (adjusted overall HR 2.54, 95% CI 2.05–3.16, p < 0.0001).

List of adverse reactions in tabular form.

Adverse effects observed during clinical studies or from spontaneous reports during clinical use are listed in Table 1. Adverse reactions are categorized by system organ class, and their frequency is defined as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each organ system class, adverse effects are listed in order of decreasing severity.

Table 1

* Information regarding clopidogrel with the frequency "frequency not known".

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required.

Keep out of reach and sight of children.

Packaging. No. 14 (14x1): 14 tablets in a blister, 1 blister per cardboard box.

No. 30 (30x1), No. 90 (30x3): 30 tablets in a blister, 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI WINTHROP INDUSTRIE.

Manufacturer's address and place of business. 1 rue de la Vierge Ampère et Lagrave, 33565 CARBON BLANC CEDEX, France.

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine".

Address of the Marketing Authorization Holder.

48-50A Zhylianska Street, Kyiv, 01033, Ukraine.