Plagril®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PLAGRIL® (PLAGRIL)

Composition:

Active substance: clopidogrel;

One film-coated tablet contains clopidogrel bisulfate equivalent to clopidogrel 75 mg;

Excipients: microcrystalline cellulose, mannitol (E 421), sodium croscarmellose, hydrogenated castor oil, Opadry pink 03B54202 (hypromellose, polyethylene glycol, titanium dioxide (E 171), iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, pink film-coated tablets with the inscription "CD" on one side and "75" on the other side.

Pharmacological properties.

Pharmacodynamics.

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor on the platelet surface and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby suppressing platelet aggregation. A biotransformation of clopidogrel is required to form the active inhibitory metabolite. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation caused by released ADP. Clopidogrel irreversibly modifies platelet ADP receptors. Therefore, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Normal platelet function recovers at a rate consistent with platelet turnover.

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 within an average of 5 days after discontinuation of therapy.

Pharmacokinetics.

Absorption. After oral administration of single and repeated 75 mg daily doses, clopidogrel is rapidly absorbed. Mean peak plasma concentrations of unchanged clopidogrel (approximately 2.2–2.5 ng/mL after a single 75 mg oral dose) are reached about 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution. Clopidogrel and its main circulating (inactive) 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, two major metabolic pathways exist: one involves esterases leading to hydrolysis and formation of an inactive carboxylic acid derivative (which accounts for 85% of circulating metabolites in plasma), and the other involves cytochrome P450 enzyme system. Initially, clopidogrel is converted into an intermediate metabolite, 2-oxo-clopidogrel. Further metabolism of 2-oxo-clopidogrel leads to the formation of a thiol derivative – the active metabolite. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2, and CYP2B6 enzymes. The active thiol metabolite of clopidogrel, isolated in vitro, rapidly and irreversibly binds to platelet receptors, thereby preventing platelet aggregation.

Elimination. Within 120 hours after administration of radiolabeled 14C-clopidogrel orally to humans, approximately 50% of the dose 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 repeated dosing.

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 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 account for the majority of loss-of-function alleles in Caucasian (85%) and Mongoloid (99%) patients with reduced metabolism. Other alleles associated with absent or reduced metabolism occur less frequently, including 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 Caucasian patients, 4% of Black patients, and 14% of Chinese patients. Tests are currently available to determine CYP2C19 genotype.

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

Renal impairment. With 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, while the prolongation of bleeding time was nearly the same 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, patients with severe hepatic impairment showed inhibition of ADP-induced platelet aggregation similar to that observed in healthy volunteers. The mean prolongation of bleeding time was also similar in both groups.

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

Clinical characteristics.

Indications.

Secondary prevention of atherothrombotic events in adults:

• in patients who have had a myocardial infarction (treatment initiation – within a few days, but no later than 35 days after the event), ischemic stroke (treatment initiation – within 7 days, but no later than 6 months after the event), or diagnosed peripheral arterial disease (arterial disease and atherothrombosis of lower limb vessels);
• in patients with acute coronary syndrome:
  • acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction), including patients who underwent percutaneous coronary intervention with stent placement, in combination with acetylsalicylic acid (ASA);
  • acute myocardial infarction with ST-segment elevation, in combination with acetylsalicylic acid (in patients receiving standard medical therapy 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, in whom vitamin K antagonists (VKA) are contraindicated and who have a low risk of bleeding, for the prevention of atherothrombotic and thromboembolic events, including stroke.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment. Active bleeding (e.g., peptic ulcer or intracranial hemorrhage).

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this combination may increase the risk of bleeding (see section "Special precautions for use"). Although administration of clopidogrel at a dose of 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 their independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors. Clopidogrel should be used with caution in patients receiving glycoprotein IIb/IIIa inhibitors (see section "Special 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. 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 precautions for use"). Nevertheless, clopidogrel and ASA have been co-administered for up to 1 year (see section "Pharmacological properties").

Heparin. Clinical study data in healthy volunteers indicate that clopidogrel does not require dose adjustment of heparin and does not alter heparin's effect on coagulation. Concomitant administration of heparin did not affect 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.

Thrombolytic agents. The safety of concomitant administration 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 "Adverse reactions").

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 interaction studies with other NSAIDs, it is not yet established whether the risk of gastrointestinal bleeding increases with all NSAIDs. Therefore, caution is required when co-administering NSAIDs, particularly COX-2 inhibitors, with clopidogrel (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs). SSRIs should be used concomitantly with clopidogrel with caution, as SSRIs affect platelet activation and increase the risk of bleeding.

Concomitant use of other medicinal products. Since clopidogrel is partially converted into its active metabolite via CYP2C19, concomitant use of drugs that reduce the activity of this enzyme is likely to result in decreased plasma concentrations of the active metabolite of clopidogrel. The clinical significance of this interaction is not established. Therefore, as a precautionary measure, concomitant use of strong and moderate CYP2C19 inhibitors should be avoided (see sections "Pharmacokinetics" and "Special precautions for use").

Medicinal products that inhibit CYP2C19 activity include omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol, 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 drugs, reduced the plasma concentration of the active metabolite by 45% (loading dose) and 40% (maintenance dose). This reduction was associated with a 39% (loading dose) and 21% (maintenance dose) decrease in platelet aggregation inhibition. A similar interaction with clopidogrel is expected for esomeprazole.

Observational and clinical trial results have provided conflicting data on the clinical consequences of these pharmacokinetic and pharmacodynamic interactions regarding the occurrence of major cardiovascular events. As a precautionary measure, omeprazole or esomeprazole should not be used concomitantly with clopidogrel (see section "Special 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 associated with a 15% and 11% decrease in the mean inhibition of platelet aggregation, respectively. These results suggest that co-administration of clopidogrel and pantoprazole is possible.

There is no evidence that other medicinal products that reduce gastric acid secretion, such as H2-receptor antagonists (except cimetidine, which is a CYP2C9 inhibitor) or antacids, affect the antiplatelet activity of clopidogrel.

Combination with other medicinal products. Several clinical studies have been conducted with clopidogrel and other drugs to evaluate potential pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interaction was observed when clopidogrel was administered concomitantly with atenolol, nifedipine, or both. Additionally, the pharmacodynamic activity of clopidogrel remained largely unchanged when co-administered with phenobarbital and estrogen.

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

Antacid agents did not affect the absorption of clopidogrel.

The carboxylic acid metabolites of clopidogrel may inhibit the activity of cytochrome P450 2C9. This could potentially increase plasma levels of medicinal products such as phenytoin, tolbutamide, and NSAIDs, which are metabolized by cytochrome P450 2C9. Nevertheless, results from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

Medicinal products that are substrates of the CYP2C8 enzyme. Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies demonstrated that this increased repaglinide exposure is due to inhibition of the CYP2C8 enzyme by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant use of clopidogrel with medicinal products primarily eliminated via metabolism mediated by the CYP2C8 enzyme (such as repaglinide, paclitaxel) requires caution (see section "Special precautions for use").

Except for the information on interactions with specific medicinal products provided above, interaction studies between clopidogrel and drugs commonly prescribed to patients with atherothrombosis have not been conducted. However, patients participating in clinical trials of clopidogrel concurrently used other medications, including diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, lipid-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists, without signs of clinically significant adverse effects.

Special precautions for use.

Hemorrhage and hematological disorders. Due to the risk of hemorrhage and hematological adverse effects, a full blood count and/or other appropriate tests should be performed immediately if symptoms suggesting possible bleeding occur during treatment with the drug (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 used concomitantly with acetylsalicylic acid (ASA), heparin, glycoprotein IIb/IIIa inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors. Close monitoring for signs of bleeding, including occult bleeding, is required, especially during the first weeks of treatment and/or after cardiac invasive procedures or surgery. Concomitant use of clopidogrel with oral anticoagulants is not recommended, as this may increase the risk and severity of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

In the case of planned surgical procedures where antiplatelet effect is undesirable, clopidogrel therapy should be discontinued 7 days prior to surgery. Patients should inform their physician (including dentist) that they are taking clopidogrel before any surgical procedure 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 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.

Thrombotic thrombocytopenic purpura (TTP). TTP has been reported very rarely following clopidogrel use, sometimes even after short-term treatment. TTP is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological symptoms, renal dysfunction, or fever. TTP is a potentially life-threatening condition that may lead to death and requires immediate treatment, including plasma exchange.

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

Recent ischemic stroke. Due to insufficient data, clopidogrel is not recommended within the first 7 days after acute ischemic stroke.

Cytochrome P450 2C19 (CYP2C19). Pharmacogenetics: Patients with genetically reduced CYP2C19 enzyme function have lower plasma concentrations of the active metabolite of clopidogrel and a less pronounced antiplatelet effect. Tests are available to identify the CYP2C19 genotype in patients.

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 reduced plasma concentrations of the active metabolite of clopidogrel. However, the clinical significance of this interaction is not fully established. Therefore, 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 the "Pharmacokinetics" section).

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

Cross-reactivity among thienopyridines. Patients should be evaluated for 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, angioedema (Quincke's edema), or hematological 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 impairment. Experience with clopidogrel use in patients with renal impairment is limited; therefore, the drug should be administered with caution in such patients (see section "Dosage and method of administration").

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

Excipients. Plavix® 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.

Due to lack of clinical data on clopidogrel use during pregnancy, the drug is not recommended for use in pregnant women (precautionary measure).

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

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 this drug.

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

Ability to affect reaction rate 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.

Adults and Elderly Patients.

The drug is administered at 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, followed by a maintenance dose of 75 mg once daily (in combination with ASA at 75–325 mg daily). Since higher doses of ASA increase the risk of bleeding, ASA doses exceeding 100 mg are not recommended. The optimal duration of treatment has not been formally established. Study results support treatment for up to 12 months, with maximum benefit observed after 3 months of therapy.

In patients with acute ST-segment elevation myocardial infarction, 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, 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 in this condition has not been studied.

Patients with atrial fibrillation should receive clopidogrel 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 a missed dose:

• If less than 12 hours have passed since the scheduled dose: 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.

Children.

Clopidogrel should not be used in children due to lack of efficacy data.

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 due to lack of efficacy data.

Overdose.

Prolonged bleeding time with subsequent complications may occur in cases of clopidogrel overdose. If bleeding occurs, symptomatic treatment is recommended.

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

Side effects.

Side effects are categorized by organ system, and their frequency is defined as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known. For each organ system class, adverse effects are listed in order of decreasing severity.

* Information on clopidogrel with the frequency of "frequency unknown".

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product by regulatory authorities is an important procedure. It allows continuous monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare professionals are requested to report all suspected adverse reactions through national reporting systems.

Shelf life. 2 years.

Storage conditions. Store in the original packaging, out of the reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister. 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Ltd, FTO – 3

Manufacturer’s address and location of operations.

Survey Nos. 41, 42R, 45R and 46R, Bachupally Village and Mandal, Medchal-Malkajgiri District – 500090, Telangana, India