Pharmacological properties of the drug Plagril
Clopidogrel (methyl-(+)-(S)-b-(o-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)acetate) is an antiplatelet agent. Clopidogrel selectively inhibits the binding of ADP to its receptors on the platelet surface and the activation of the GP IIb/IIIa complex by ADP, thereby inhibiting platelet aggregation. For this effect to occur, the biotransformation of clopidogrel is necessary. Clopidogrel acts by irreversibly altering the ADP receptor on the platelet; platelets that interact with it remain damaged throughout their entire life; normal platelet function is restored at a rate that corresponds to the rate at which new platelets appear. Repeated use of the drug at a dose of 75 mg/day leads to a significant slowdown in platelet aggregation caused by ADP. The inhibitory effect progressively increases, an equilibrium state is achieved after 3–7 days of treatment. With a course of use, the average level of inhibition of platelet aggregation is 40–60%. Platelet aggregation and bleeding duration return to baseline levels on average 5 days after cessation of treatment. When repeated orally at a dose of 75 mg/day, clopidogrel is rapidly absorbed, but the concentration of the parent compound in the blood plasma is low and 2 hours after administration does not reach the measurement limit (0.00 025 mg/l). At least 50% of the active substance is absorbed. Clopidogrel is rapidly metabolized in the liver. The main metabolite, a carboxyl derivative, is pharmacologically inactive and accounts for 85% of the original compound circulating in the blood. The maximum concentration of this metabolite in the blood plasma is reached 1 hour after administration and is about 3 mg/l. The active metabolite, a thiol derivative, quickly and irreversibly binds to platelet receptors, thus inhibiting platelet aggregation. This metabolite is not detected in blood plasma. The kinetics of the main metabolite shows a linear relationship (increased plasma concentrations in vitro - 98 and 94%, respectively). This bond remains unsaturated in vitro over a wide range of concentrations. About 50% of clopidogrel is excreted from the body in the urine, about 46% in feces over 120 hours. The half-life of the main circulating metabolite is 8 hours. The drug is well tolerated by patients with cirrhosis of the liver.
Plagril®
Data obtained from clinical studies
The safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more. Overall, the tolerability of clopidogrel 75 mg/day in the CAPRIE study was similar to that of ASA 325 mg/day. regardless of the age, gender and race of patients. The following are clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A.
Bleeding and hemorrhage
Comparison of monotherapy with clopidogrel and ASA
In the CAPRIE clinical trial, the overall incidence of all bleeding in patients taking clopidogrel and in patients taking ASA was 9.3%. The incidence of severe bleeding with clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.
Overall, the incidence of gastrointestinal bleeding in patients taking clopidogrel and in patients taking ASA was 2.0% and 2.7%, respectively, including the incidence of gastrointestinal bleeding requiring hospitalization was 0. 7% and 1.1%, respectively.
The overall incidence of bleeding from other sites was higher when taking clopidogrel compared to taking ASA (7.3% versus 6.5%, respectively).
However, the incidence of severe bleeding with clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most commonly reported bleeding events were purpura/bruising, epistaxis. Less commonly reported were the development of hematomas, hematuria and ocular hemorrhages (mainly conjunctival).
The incidence of intracranial hemorrhage with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).
Comparison of combination therapy clopidogrel + ASA and placebo + ASA
In the CURE clinical trial, patients taking clopidogrel + ASA compared with patients taking placebo + ASA had an increased incidence of major bleeding (3.7% vs. 2.7%) and minor bleeding (5.1% vs. 2.7%). 4%). Mainly, the sources of major bleeding were the gastrointestinal tract and arterial puncture sites.
The incidence of life-threatening bleeding in patients taking clopidogrel + ASA, compared with patients taking placebo + ASA, was not significantly different (2.2% and 1.8%, respectively), the incidence of fatal bleeding was the same (0.2% for both types of therapy).
The incidence of non-life-threatening major bleeding was significantly higher in patients taking clopidogrel + ASA compared with patients taking placebo + ASA (1.6% and 1%, respectively), but the incidence of intracranial hemorrhage was the same (0.1% in both types of therapy).
The incidence of major bleeding in the clopidogrel + ASA group depended on the dose of ASA (<100 mg: 2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%), as did the incidence of major bleeding in placebo + ASA group (<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).
In patients who stopped antiplatelet therapy more than 5 days before coronary artery bypass surgery, there was no increase in the incidence of major bleeding within 7 days after the intervention (4.4% in the clopidogrel + ASA group and 5.3% in the placebo + ASA group). In patients who continued antiplatelet therapy during the last five days before coronary artery bypass surgery, the incidence of these events after surgery was 9.6% (clopidogrel + ASA) and 6.3% (placebo + ASA).
In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in hemoglobin >5 g/dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups (1.3% vs. 1% in the clopidogrel + ASA group and the placebo + ASA group, respectively).
It was similar in subgroups of patients divided by baseline characteristics and by type of fibrinolytic therapy or heparin therapy.
The incidence of fatal bleeding (0.8% vs. 0.6%) and intracranial hemorrhage (0.5% vs. 0.7%) with clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.
In the COMMIT clinical trial, the overall incidence of noncerebral major bleeding or cerebral bleeding was low and similar (0.6% in the clopidogrel + ASA group and 0.5% in the placebo + ASA group).
In the ACTIVE-A clinical trial, the incidence of major bleeding was higher in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%, respectively). Major bleeding was mostly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There were more intracranial hemorrhages in the clopidogrel + ASA group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% vs. 0.7%) and hemorrhagic stroke (0.8% vs. 0.6%).
Blood disorders
In the CAPRIE study, severe neutropenia (<0.45 x 109/L) was observed in 4 patients (0.04%) taking clopidogrel and 2 patients (0.02%) taking ASA.
Two of the 9599 patients taking clopidogrel had a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9586 patients taking ASA. Although the risk of myelotoxicity with clopidogrel is low, if a patient taking clopidogrel develops a fever or other signs of infection, the patient should be monitored for possible neutropenia.
During treatment with clopidogrel, the development of aplastic anemia was observed in one case. The incidence of severe thrombocytopenia (<80x109/L) was 0.2% in patients taking clopidogrel and 0.1% in patients taking ASA, and very rare cases of platelet counts <30x109/L have been reported.
The CURB and CLARITY studies observed comparable numbers of patients with thrombocytopenia or neutropenia in both treatment groups.
A clinical studies
The frequency of adverse reactions that were observed during the above clinical studies is presented in accordance with the WHO classification: very often (≥ 10%); often (≥ 1% and < 10%); uncommon (≥ 0.1% and <1%); rare (≥ 0.01% and <0.1%); very rare (<0.01%); frequency unknown - it is not possible to determine the frequency of side effects from the available data.
Nervous system disorders
Uncommon: headache, dizziness, paresthesia.
Rarely: vertigo.
Gastrointestinal disorders
Common: dyspepsia, abdominal pain, diarrhea.
Uncommon: nausea, gastritis, bloating, constipation, vomiting, gastric ulcer, duodenal ulcer.
Skin and subcutaneous tissue disorders
Uncommon: rash, itching.
Blood and lymphatic system disorders
Uncommon: increased bleeding time, decreased platelet count in peripheral blood; leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.
Post-marketing experience with the drug
Blood and lymphatic system disorders
Frequency is unknown: cases of serious bleeding, mainly subcutaneous, musculoskeletal, ocular hemorrhages (conjunctival, tissue and retinal), bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), nosebleeds, hematuria and bleeding from postoperative wounds and cases of bleeding from fatal outcome (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.
Heart disorders
Not known: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) due to a hypersensitivity reaction to clopidogrel.
Immune system disorders
Frequency unknown: anaphylactoid reactions, serum sickness; cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine, prasugrel) [see. Section "Special Instructions"].
Mental disorders
Frequency unknown: confusion, hallucinations.
Nervous system disorders
Frequency unknown: taste disturbances.
Vascular disorders
Frequency unknown: vasculitis, decreased blood pressure.
Respiratory, thoracic and mediastinal disorders
Frequency unknown: bronchospasm, interstitial pneumonia, eosinophilic pneumonia.
Gastrointestinal disorders
Not known: colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis.
Disorders of the liver and biliary tract
Frequency unknown: hepatitis (non-infectious), acute liver failure.
Skin and subcutaneous tissue disorders
Not known: maculopapular erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized eczematous pustulosis, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome), eczema, lichen planus.
Musculoskeletal and connective tissue disorders
Frequency unknown: arthralgia (joint pain), arthritis, myalgia.
Renal and urinary tract disorders
Frequency unknown: glomerulonephritis.
Genital and breast disorders
Frequency unknown: gynecomastia.
General and administration site disorders
Frequency unknown: fever.
Laboratory and instrumental data
Frequency unknown: deviation from normal laboratory parameters of the functional state of the liver, increased concentration of creatinine in the blood.
Special instructions for the use of the drug Plagril
Plagril should not be prescribed during the first few weeks after acute myocardial infarction. Due to the lack of clinical data, Plagril is not recommended for use in unstable angina, after percutaneous transluminal coronary angioplasty, coronary artery bypass grafting and acute ischemic stroke (≤7 days). Plagril should be administered with caution to patients with an increased risk of bleeding due to trauma, surgery, or pathological conditions. In case of surgical interventions in which the antiplatelet effect is undesirable, Plagril should be discontinued 7 days before surgery. Plagril increases bleeding time, so it should be used with caution in patients at risk of bleeding (especially gastrointestinal and intraocular). Patients should tell their doctor about any unusual bleeding. Patients should also inform the doctor about taking the drug if they are planning surgery or if the doctor prescribes a new drug for the patient. The drug should be used with caution in patients with impaired renal function, moderately severe liver dysfunction (the development of hemorrhages is possible).
Interactions of the drug Plagril
The simultaneous use of Plagril with warfarin is not recommended, since this combination may increase the intensity of bleeding. Acetylsalicylic acid does not change the inhibitory effect of Plagril on ADP-induced platelet aggregation, however, Plagril potentiates the effect of acetylsalicylic acid on platelet aggregation induced by collagen. However, the simultaneous use of acetylsalicylic acid at a dose of 500 mg 2 times a day did not cause a significant increase in bleeding time, which was prolonged due to the use of Plagril. The safety of long-term use of Plagril and acetylsalicylic acid has not been established. The simultaneous use of Plagril and heparin does not require dose adjustment of the latter and does not affect the antiplatelet effect of Plagril, however, this combination should be used with caution. During treatment with Plagril, thrombolytic drugs (recombinant tissue plasminogen activator) should be prescribed with caution. The use of a combination of Plagril and NSAIDs requires caution due to the possibility of gastrointestinal bleeding. No clinically significant pharmacodynamic interaction was detected with simultaneous use of Plagril with atenolol or nifedipine. The pharmacodynamic profile of Plagril remains virtually unchanged when used simultaneously with phenobarbital, cimetidine or estrogens. The effect of digoxin or theophylline does not change when used simultaneously with Plagril. Antacids do not affect the absorption of Plagril. Plagril may inhibit the activity of one of the cytochrome P450 enzymes (CYP 2C9), as a result of which the plasma concentration of drugs metabolized by this enzyme (such as phenytoin and tolbutamide) may increase.
Plagril (75mg N30)
INSTRUCTIONS for the use of the medicinal product for medical use Plagril® ( Plagril )
Registration number: LSR-005821/09
Trade name of the drug: Plagril®
International nonproprietary name of the drug: clopidogrel
Dosage form: film-coated tablets.
Composition: each film-coated tablet contains active substance: clopidogrel hydrosulfate - 97.875 mg, equivalent to 75 mg of clopidogrel. Excipients: microcrystalline cellulose (Avicel PH 112) 211.125 mg, mannitol 58.0 mg, croscarmellose sodium 12.0 mg, colloidal silicon dioxide 2.0 mg, magnesium stearate 4.0 mg. Shell: opadry pink 03B54202 (hypromellose 62.5%, titanium dioxide 30.6%, macrogol-400 6.25%, red iron oxide dye 0.65%) 13.475 mg.
Description: Round, biconvex, pink film-coated tablets with “C 127” embossed on one side.
Pharmacotherapeutic group: antiplatelet agent.
ATX code: B01AC04
Pharmacological properties Pharmacodynamics Specific and active inhibitor of platelet aggregation; has a coronary dilating effect. Selectively reduces the binding of adenosine diphosphate (ADP) to platelet receptors and the activation of GPIIb/IIIa receptors by ADP, thereby weakening platelet aggregation. Reduces platelet aggregation caused by other agonists, preventing their activation by released ADP, does not affect phosphodiesterase (PDE) activity. Irreversibly binds to ADP - platelet receptors, which remain unreceptive to ADP stimulation throughout the life cycle (about 7 days). Inhibition of platelet aggregation is observed 2 hours after administration (40% inhibition) of the initial dose of 400 mg. The maximum effect (60% suppression of aggregation) develops after 4–7 days of continuous use at a dose of 50–100 mg/day. The antiplatelet effect persists throughout the life of platelets (7 - 10 days). Platelet aggregation and bleeding time return to baseline levels, on average, 5 days after cessation of treatment. In the presence of atherosclerotic lesions of the vessel, it prevents the development of atherothrombosis, regardless of the localization of the vascular process (cerebrovascular, cardiovascular or peripheral lesions). Pharmacokinetics Absorption and distribution Absorption and bioavailability are high; the plasma concentration is low and 2 hours after administration does not reach the measurement limit (0.025 μg/l). Clopidogrel and the main metabolite are reversibly bound to plasma proteins (98% and 94%, respectively). Metabolism Metabolized in the liver. The main metabolite is an inactive carboxylic acid derivative, accounting for about 85% of the compound circulating in plasma. The time to reach peak concentration (TCmax) of the metabolite after repeated oral doses of clopidogrel 75 mg is achieved within an hour (peak concentration (Cmax) is about 3 mg/l). Clopidogrel is a precursor of the active substance. Its active metabolite, a thiol derivative, is formed by the oxidation of clopidogrel to 2 - oxo - clopidogrel and subsequent hydrolysis. The oxidative process is regulated primarily by cytochrome P450 isoenzymes 2B6 and 3A4, and, to a lesser extent, by 1A1, 1A2 and 1C19. The active thiol metabolite quickly and irreversibly binds to platelet receptors, thereby inhibiting platelet aggregation. This metabolite is not detectable in plasma. Excretion Excretion: kidneys – 50%, intestines – 46% (within 120 hours after administration). The half-life (T1/2) of the main metabolite after a single and repeated dose is 8 hours. The concentration of metabolites excreted by the kidneys is 50%. Pharmacokinetics in special clinical cases The concentration of the main metabolite in plasma after taking clopidogrel at a dose of 75 mg / day is lower in patients with severe kidney disease (creatinine clearance (CC) 5 - 15 ml / min) compared to patients with moderate kidney disease (CC from 30 to 60 ml/min) and healthy individuals. Although the inhibitory effect on ADP - induced platelet aggregation was reduced (25%) compared with the same effect in healthy volunteers, bleeding time was prolonged to the same extent as in healthy volunteers receiving clopidogrel 75 mg/day. In patients with liver cirrhosis, clopidogrel at a daily dose of 75 mg for 10 days was safe and well tolerated. Cmax of clopidogrel, both after a single dose and at steady state, was many times higher in patients with liver cirrhosis than in healthy individuals.
Indications for use Prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusion. In combination with acetylsalicylic acid for the prevention of thrombotic complications in acute coronary syndrome: with ST segment elevation with the possibility of thrombolytic therapy; without ST segment elevation (unstable angina, myocardial infarction without Q wave), including in patients undergoing stenting.
Contraindications Hypersensitivity to the components of the drug; severe liver failure; hemorrhagic syndrome, acute bleeding (including intracranial hemorrhage) and diseases predisposing to its development (peptic ulcer of the stomach and duodenum in the acute stage, nonspecific ulcerative colitis, tuberculosis, lung tumors, hyperfibrinolysis); pregnancy, lactation (breastfeeding); children under 18 years of age (safety and effectiveness of use have not been established).
With caution Moderate hepatic and/or renal failure, trauma, conditions that increase the risk of bleeding (including trauma, surgery), simultaneous use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs (including COX - 2 inhibitors), heparin and glycoprotein IIb/IIIa inhibitors .
Directions for use and dosage : Orally, regardless of food intake. For the prevention of ischemic disorders in patients after myocardial infarction, ischemic stroke, or against the background of diagnosed peripheral arterial diseases, adults (including elderly patients) are prescribed 75 mg 1 time / day. Treatment should begin within 35 days after a Q - forming myocardial infarction and from 7 days to 6 months after an ischemic stroke. In acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave formation), treatment should begin with a single loading dose of 300 mg, then continue using the drug at a dose of 75 mg 1 time / day (with simultaneous administration of acetylsalicylic acid at a dose of 75 - 325 mg/day). Since the use of acetylsalicylic acid in large doses is associated with a greater risk of bleeding, the recommended dose should not exceed 100 mg. The course of treatment is up to 1 year. In acute coronary syndrome with ST segment elevation (acute myocardial infarction), the drug is prescribed at a dose of 75 mg 1 time / day using an initial loading dose in combination with acetylsalicylic acid with or without thrombolytics. For patients over the age of 75 years, treatment with clopidogrel should be carried out without using a loading dose. Combination therapy is started as soon as possible after the onset of symptoms and continued for at least 4 weeks.
Side effects Depending on the frequency of occurrence, the following groups of side effects are distinguished: frequent - more than 1%, infrequent - 0.1-1%, rare - 0.01-0.1%, very rare - less than 0.01%. From the blood coagulation system: often – gastrointestinal bleeding; uncommon – hemorrhagic stroke, prolongation of bleeding time, nosebleeds; rarely - hematomas, hematuria and conjunctival bleeding. From the hematopoietic system: infrequently – thrombocytopenia; uncommon – neutropenia, leukopenia, eosinophilia; very rarely - thrombocytopenic purpura; granulocytopenia, agranulocytosis, anemia and aplastic anemia. From the central nervous system and peripheral nervous system: infrequently – headache, dizziness, paresthesia; rarely – vertigo; very rarely - confusion, hallucinations. From the cardiovascular system: very rarely - vasculitis, decreased blood pressure. From the respiratory system: very rarely - bronchospasm, interstitial pneumonitis. From the digestive system: often – dyspepsia, diarrhea, abdominal pain; uncommon – nausea, gastritis, flatulence, constipation, vomiting, ulceration of the gastrointestinal mucosa; exacerbation of peptic ulcer of the stomach and duodenum; very rarely - colitis (including ulcerative or lymphocytic colitis), pancreatitis, changes in taste, stomatitis, hepatitis, acute liver failure, increased activity of liver enzymes. From the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia. From the urinary system: very rarely - glomerulonephritis. Dermatological reactions: infrequently – itching; very rarely - bullous rash (erythema multiforme, Stevens - Johnson syndrome, toxic epidermal necrolysis), erythematous rash, eczema, lichen planus. Allergic reactions: very rarely - angioedema, urticaria, anaphylactoid reactions, serum sickness. Other: very rarely - increased temperature, increased blood creatinine.
Overdose Symptoms: With a single oral dose of 600 mg of clopidogrel (an amount equivalent to 8 standard 75 mg tablets) to healthy people, there were no side effects. Bleeding time was prolonged by 1.7 times, which corresponds to the value recorded after taking a therapeutic dose (75 mg per day). Treatment: platelet transfusion. There is no specific antidote.
Interaction with other drugs and other forms of interaction Enhances the antiplatelet effect of acetylsalicylic acid, heparin, indirect anticoagulants, non-steroidal anti-inflammatory drugs, and when used together increases the risk of bleeding from the gastrointestinal tract. By inhibiting the activity of one of the cytochrome CYP2C9 enzymes, it increases the concentration of drugs metabolized through CYP2C9 (phenytoin, tolbutamide). No clinically significant pharmacodynamic interaction was observed when clopidogrel was used in combination with atenolol, nifedipine, phenobarbital, cimetidine, estrogens, digoxin, theophylline, tolbutamide, or antacids.
Special instructions In case of surgical interventions, if the antiplatelet effect is undesirable, the course of treatment should be discontinued 7 days before surgery. Patients should be warned that since stopping bleeding that occurs while using the drug takes longer, they should report to the doctor any case of unusual bleeding. Patients should also inform the doctor about taking the drug if they are undergoing surgery or if the doctor prescribes a new drug for the patient. During the treatment period, it is necessary to monitor the indicators of the hemostasis system (APTT, platelet count, platelet functional activity tests); regularly examine the functional activity of the liver. In case of severe liver dysfunction, one should remember the risk of developing hemorrhagic diathesis.
Effect on the ability to drive vehicles and operate machinery. There were no signs of deterioration in the ability to drive a car or a decrease in mental performance after taking it.
Release form: Film-coated tablets, 75 mg. 10 tablets in PVC/PVDC/aluminum blister. 3, 10 blisters along with instructions for use in a cardboard pack.
Storage conditions: In a dry place, protected from light, at a temperature not exceeding 25 °C. Keep out of the reach of children!
Shelf life: 3 years. Do not use after the expiration date stated on the packaging.
Conditions for dispensing from pharmacies By prescription.
Manufacturer: Dr. Reddy's Laboratories Ltd., India. Dr. Reddy's Laboratories Ltd., India
Address of production site Survey No. 41, Bachupally Village, Qutbullapur Mandal, Ranga Reddy District, Telangana State, India.
Information about complaints and adverse drug reactions should be sent to the following address: Representative office 115035, Moscow, Ovchinnikovskaya embankment, 20, building 1 Tel Fax
