Platogrill®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PLATOGREL®

Composition:

Active substance: clopidogrel;

1 tablet contains clopidogrel bisulfate equivalent to 75 mg of clopidogrel;

Excipients: povidone K-30, mannitol (E 421), microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydrogenated castor oil, iron oxide red (E 172); coating Opadry Y-1-7000 white: hypromellose, polyethylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties: pink, round, biconvex, smooth film-coated tablets on both sides.

Pharmacotherapeutic group. Antiplatelet agents, excluding heparin.

ATC code B01AC04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Clopidogrel is a prodrug. One of its metabolites is an inhibitor of platelet aggregation. To form the active metabolite that inhibits platelet aggregation, clopidogrel must undergo biotransformation 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 binding is irreversible, platelets exposed to clopidogrel remain altered throughout their lifespan (approximately 7–10 days), and normal platelet function recovers at a rate consistent with platelet turnover. Platelet aggregation induced by other agonists (except ADP) is also inhibited, as the drug blocks platelet activation by released ADP.

Since the active metabolite is formed via cytochrome CYP450 enzymes, some of which are polymorphic or inhibited by other drugs, not all patients achieve adequate platelet aggregation inhibition.

Pharmacodynamic effects

Significant inhibition of ADP-induced platelet aggregation is observed from the first day of repeated daily doses of 75 mg. 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 is rapidly absorbed. The mean peak plasma concentration of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) is reached about 45 minutes after administration. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution

Clopidogrel and its main (inactive) circulating metabolite 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, two major metabolic pathways exist: one involving esterases, leading to hydrolysis and formation of an inactive carboxylic acid derivative (accounting for 85% of circulating metabolites in plasma), and another involving cytochrome P450 enzymes. Initially, clopidogrel is converted to an 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 contributions from other CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4. The active metabolite of clopidogrel (thiol derivative), isolated in vitro, rapidly and irreversibly binds to platelet receptors, thereby preventing platelet aggregation. The Cmax of the active metabolite is approximately twice higher after a single 300 mg loading dose of clopidogrel compared to that observed after 4 days of 75 mg maintenance dosing. Cmax is reached approximately 30–60 minutes after drug administration.

Elimination

Within 120 hours after administration of radiolabeled 14C-clopidogrel in humans, approximately 50% of the dose was excreted in urine and about 46% in 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 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, measured by ex vivo platelet aggregation, 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. 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 described above. According to published data, CYP2C19 genotypes associated with reduced metabolism occur in 2% of Caucasians, 4% of African descent patients, and 14% of Chinese patients. Tests are currently available to determine CYP2C19 genotype.

In a crossover study involving healthy volunteers with specific CYP2C19 metabolic phenotypes (ultrarapid, extensive, intermediate, and reduced), the pharmacokinetics and antiplatelet effects were evaluated after a 300 mg dose followed by 75 mg daily, and after 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 reduced metabolism, the blood concentration of the active metabolite was reduced by 63–71% compared to those with extensive metabolism. After the 300 mg/75 mg dosing regimen, antiplatelet effects in individuals with reduced metabolism were less pronounced, with mean PAI (5 µM ADP) values of 24% (24 hours) and 37% (day 5), compared to 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 reduced metabolism received the 600 mg/150 mg regimen, the blood concentration of the active metabolite 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 those with reduced metabolism receiving 300 mg/75 mg and similar to values observed in other CYP2C19 metabolic phenotype groups receiving 300 mg/75 mg. Based on clinical effect studies, the appropriate dosing regimen for this patient group has not been established.

Consistent with the above results, data show that the blood concentration of the active metabolite decreased by 28% in individuals with intermediate metabolism and by 72% in those with reduced metabolism; platelet aggregation inhibition (5 µM ADP) was also reduced, with PAI differences of 5.9% and 21.4%, respectively, compared to individuals with extensive metabolism.

There are data indicating that individuals with intermediate and reduced metabolism have a higher incidence of cardiovascular events (death, myocardial infarction, stroke) or stent thrombosis compared to those with extensive metabolism.

However, other data show no significant difference in cardiovascular event rates depending on metabolic characteristics.

Therefore, it can be concluded that none of the known analyses included a sufficient number of patients to detect differences in clinical outcomes among patients with reduced metabolism.

Special patient populations

The pharmacokinetics of the active metabolite of clopidogrel have not been studied in the special patient populations listed below.

Renal impairment

After repeated administration of 75 mg clopidogrel daily in patients with severe renal impairment (creatinine clearance 5–15 mL/min), inhibition of ADP-induced platelet aggregation was less pronounced (25%) compared to healthy volunteers, while bleeding time was prolonged to a similar extent as in healthy volunteers receiving 75 mg clopidogrel daily. Clinical tolerability was good in all patients.

Hepatic impairment

After repeated 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. Mean prolongation of bleeding time was also comparable between both groups.

Racial origin

The prevalence of CYP2C19 alleles associated with intermediate and poor metabolic activity varies depending on racial/ethnic background (see section "Pharmacogenetics"). Limited data are available in Mongoloid race patients to assess the clinical significance of genotyping for this CYP.

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adult patients:

• who have had myocardial infarction (treatment initiation – several days, but no later than 35 days after onset), ischaemic stroke (treatment initiation – after 7 days, but no later than 6 months after onset), or who have been diagnosed with peripheral arterial disease;
• with acute coronary syndrome:
  • 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);
  • acute ST-elevation myocardial infarction, in combination with acetylsalicylic acid (ASA) (patients undergoing percutaneous coronary intervention, including those receiving stents, and patients receiving medical therapy eligible for thrombolytic/fibrinolytic therapy).

Transient ischaemic attack (TIA) of moderate to high risk or minor ischaemic stroke (IS).

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

1 Age, blood pressure, clinical features, duration of symptoms, and diabetes diagnosis.

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, in whom vitamin K antagonists (VKA) are contraindicated and who have a low risk of bleeding, for prevention of atherothrombotic and thromboembolic events, including stroke.

For additional information, see 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 these medicinal products with clopidogrel requires caution (see section "Special warnings and precautions for use").

Oral anticoagulants.

Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this combination may increase the risk and severity of bleeding (see section "Special warnings and precautions for use"). Although administration of clopidogrel at a dose of 75 mg once daily does not alter the pharmacokinetics of S-warfarin or the international normalized ratio (INR) in patients receiving long-term warfarin therapy, concomitant use of clopidogrel and warfarin increases the risk of bleeding due to their 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).

ASA does not affect the inhibitory action 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 significantly increase the bleeding time prolonged by clopidogrel. Nevertheless, 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"). Despite this, clopidogrel and ASA have been co-administered for up to 1 year (see section "Pharmacological properties").

Heparin.

Available data indicate that clopidogrel does not require dose adjustment of heparin and does not alter the effect of heparin on coagulation. Concomitant administration of heparin does not alter the inhibitory effect of clopidogrel on platelet aggregation. However, 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 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 with ASA (see section "Undesirable effects").

Non-steroidal anti-inflammatory drugs (NSAIDs).

Concomitant use of clopidogrel and naproxen increased the number of occult gastrointestinal bleeding events. However, due to the lack of studies on the interaction of the drug 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).

Concomitant use of SSRIs with clopidogrel should be done with caution, as SSRIs affect platelet activation and increase the risk of bleeding.

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 enhanced platelet inhibition, which may particularly increase the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers with clopidogrel 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 drugs 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 CYP2C19 inhibitors should be avoided (see sections "Pharmacokinetics" and "Special warnings and precautions for use").

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 taken within 12 hours of each other, reduced the plasma concentration of the active metabolite by 45% (loading dose) and by 40% (maintenance dose). This reduction was associated with a decrease in platelet aggregation inhibition by 39% (loading dose) and by 21% (maintenance dose). A similar interaction with clopidogrel is expected with esomeprazole.

Data on the clinical consequences of these pharmacokinetic and pharmacodynamic interactions regarding the occurrence of major cardiovascular events are conflicting. 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 concentrations in blood 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 by 14% (maintenance dose). This reduction was associated with a decrease in the mean platelet aggregation inhibition by 15% and 11%, respectively. These results suggest that pantoprazole may be used concomitantly with clopidogrel.

There is no evidence that other medicinal products that reduce gastric acid production, such as H2-receptor antagonists 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 ritonavir-boosted ART who experienced recurrent occlusive events after revascularization or thrombotic events despite high-dose clopidogrel therapy. Concomitant use of clopidogrel and ritonavir may reduce the 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 drugs to investigate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. Furthermore, the pharmacodynamic activity of clopidogrel remained practically unchanged when administered concomitantly with phenobarbital and estrogen.

The pharmacokinetic properties of digoxin or theophylline were not altered when administered concomitantly with clopidogrel.

Antacids did not affect the absorption of clopidogrel.

Study results indicate that phenytoin and tolbutamide, which are metabolized via the CYP2C9 enzyme, can be safely used concomitantly with clopidogrel.

Medicinal products that are substrates of the CYP2C8 enzyme.

It has been shown that clopidogrel increases 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 and medicinal products that are primarily eliminated via CYP2C8-mediated metabolism (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, studies on interactions between clopidogrel and drugs commonly prescribed to patients with atherothrombosis have not been conducted. However, in patients who concomitantly used 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, there were no signs 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, 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.

It has been found that after administration of clopidogrel 300 mg, exposure to rosuvastatin increased 2-fold (AUC) and 1.3-fold (Cmax), and after repeated administration of clopidogrel 75 mg, exposure to rosuvastatin 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").

Like 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 such as pentoxifylline, which are associated with an increased risk of hemorrhagic events (see section "Interaction with other medicinal products and other forms of interaction"). Due to the increased risk of bleeding, triple antiplatelet therapy (clopidogrel + ASA + dipyridamole) is not recommended 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 after cardiac invasive procedures and surgery. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as it may increase the severity of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

For planned surgical procedures where the antiplatelet effect is temporarily undesirable, treatment with clopidogrel should be discontinued 7 days before surgery. Patients should inform their physician (including dentist) that they are taking clopidogrel prior to any surgical procedure or before starting a new medicinal product. Clopidogrel prolongs bleeding time; therefore, it should be used cautiously in patients with an increased risk of bleeding (particularly gastrointestinal and intraocular bleeding).

Patients should be warned that when taking clopidogrel (alone or in combination with ASA), bleeding may stop later than usual, and they should report any episodes of unusual bleeding (in location or duration) to their physician.

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

Due to limited clinical data in patients aged ≥75 years with STEMI undergoing PCI, and because of the increased risk of bleeding, administration of a 600 mg loading dose of clopidogrel should only be considered after individual assessment of bleeding risk by the physician.

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 that may lead to death and therefore requires immediate treatment, including plasma exchange.

Acquired hemophilia.

Cases of acquired hemophilia have been reported following clopidogrel use. In the presence of confirmed isolated prolonged aPTT (activated partial thromboplastin time), with or without bleeding, the diagnosis of acquired hemophilia should be considered. Patients with confirmed diagnosis of acquired hemophilia should be managed by a specialist and receive appropriate treatment; clopidogrel should be discontinued in such patients.

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, monotherapy with clopidogrel should be initiated only 7 days after the event.

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

Due to lack of data, the use of 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 undergoing carotid endarterectomy or endovascular thrombectomy, or in patients scheduled for thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.

Cytochrome P450 2C19 (CYP2C19).

Pharmacogenetics: In patients with genetically reduced CYP2C19 function, lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect are observed when standard recommended doses of clopidogrel are administered. Currently available tests can identify the CYP2C19 genotype of a patient.

Since clopidogrel is partially converted to its active metabolite by CYP2C19, concomitant use of medicinal products that reduce the activity of this enzyme will most likely result in reduced plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction has not been established. Therefore, as a precaution, concomitant use of strong and moderate inhibitors of CYP2C19 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 inducers of CYP2C19 with clopidogrel should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Substrates of the CYP2C8 enzyme.

Caution is advised when clopidogrel is used concomitantly with medicinal products that are substrates of the CYP2C8 enzyme (see section "Interaction with other medicinal products and other forms of interaction").

Cross-sensitivity of thienopyridines.

Patients should be evaluated for history of hypersensitivity to other thienopyridines (such as clopidogrel, ticlopidine, prasugrel), as cross-sensitivity among thienopyridines has been reported (see section "Adverse reactions"). Use of thienopyridines may result in 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 developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity is recommended in patients with known allergy to thienopyridines.

Renal function impairment.

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

Hepatic function impairment.

Experience with the use of clopidogrel in patients with moderate to severe liver disease and potential for hemorrhagic diathesis is limited; therefore, clopidogrel should be used with caution in these patients (see section "Dosage and administration").

Excipients

Platogrill® contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Special precautions for disposal of unused medicine and waste

Any unused medicine 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 the use of clopidogrel during pregnancy, the drug should not be used in pregnant women (precautionary measure).

Animal studies did not reveal any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Lactation (breastfeeding).

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion into breast milk; therefore, breastfeeding should be discontinued during treatment with Platogrill®.

Fertility.

No adverse effects of clopidogrel on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Adult and elderly patients

Platogrill® is taken orally 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), clopidogrel therapy should be initiated with a single loading dose of 300 mg or 600 mg. A 600-mg loading dose may be administered to patients under 75 years of age when percutaneous coronary intervention (PCI) is planned (see section "Special Warnings and Precautions for Use"). Clopidogrel therapy should be continued at a dose of 75 mg once daily (in combination with acetylsalicylic acid (ASA) at 75–325 mg daily). Since higher ASA doses increase the risk of bleeding, it is recommended not to exceed an ASA dose of 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 ST-elevation myocardial infarction who are receiving medical therapy and for whom thrombolytic/fibrinolytic therapy is indicated, clopidogrel should be administered at 75 mg once daily, starting with a single 300-mg loading dose in combination with ASA, with or without thrombolytic agents. In patients aged 75 years and older, clopidogrel therapy should be initiated without a loading dose. Combination therapy should be initiated as early as possible after symptom onset and continued for at least 4 weeks. The benefit of using clopidogrel in combination with ASA beyond 4 weeks in this condition has not been studied.

If percutaneous coronary intervention (PCI) is planned:

• In patients undergoing primary PCI and in patients undergoing PCI more than 24 hours after receiving fibrinolytic therapy, clopidogrel therapy should be initiated with a 600-mg loading dose. A 600-mg loading dose should be administered with caution in patients aged 75 years and older (see section "Special Warnings and Precautions for Use");
• In patients undergoing PCI within 24 hours after receiving fibrinolytic therapy, a 300-mg loading dose of clopidogrel should be administered.

Clopidogrel therapy should be continued at 75 mg once daily in combination with ASA. In clinical practice, the prescribed maintenance dose of ASA ranges from 75 mg to 325 mg daily. Since higher ASA doses increase the risk of bleeding, it is recommended not to exceed an ASA dose of 100 mg. Combination therapy should be initiated as early as possible after symptom onset and continued for up to 12 months.

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

Adult patients with moderate to high-risk TIA (ABCD2 score ≥ 4) or minor stroke (NIHSS score ≤ 3) should receive a 300-mg loading dose of clopidogrel, followed by continuation of therapy at 75 mg clopidogrel once daily and ASA at 75–100 mg once daily. Clopidogrel and ASA therapy should be initiated within 24 hours of the event 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 at 75–100 mg daily should be initiated and continued together with clopidogrel (see section "Pharmacological Properties").

In case of a missed dose:

• If less than 12 hours have passed since the scheduled dose time, the patient should take the missed dose immediately, and the next dose should be taken 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 Warnings and Precautions for Use").

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 Warnings and Precautions for Use").

Children

Clopidogrel should not be used in children (under 18 years of age), as there are no data on efficacy of the drug in this patient population.

Overdose

In case of clopidogrel overdose, prolonged bleeding time with subsequent complications may occur. 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, the effect of clopidogrel may be reversed by platelet transfusion.

Adverse reactions

The most commonly reported adverse reaction in clinical and post-marketing studies was bleeding, which most frequently occurred during the first month of treatment.

List of adverse reactions in table form.

Adverse reactions observed during clinical trials or reported during clinical use of the medicinal product based on spontaneous reporting are listed in the table below. Adverse reactions are categorized by System Organ Class, and their frequency is defined as follows: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data). Within each organ system class, adverse reactions are listed in order of decreasing severity.

* Information regarding clopidogrel with an "unknown frequency".

Reporting suspected adverse reactions.

Reporting adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

14 tablets per blister; 2, 4, or 6 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of operations.

40020, Ukraine, Sumy region, Sumy, Skryabina St., 54.

or

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial Area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

or

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's address and location of operations.

40020, Ukraine, Sumy region, Sumy, Davydovskoho Hryhoriia St., 54.