Plagril, 75 mg 30 pcs.
€12.17 €10.14
Pharmacodynamics
Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor of platelets and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, leading to suppression of platelet aggregation.
Due to irreversible binding, platelets remain immune to ADP stimulation for the remainder of their lives (approximately 7-10 days), and recovery of normal platelet function occurs at a rate consistent with the rate of platelet renewal.
Platelet aggregation caused by agonists other than ADP is also inhibited by blocking enhanced platelet activation by the released ADP.
Since the formation of the active metabolite occurs via isoenzymes of the P450 system, some of which may be polymorphic or may be inhibited by other drugs, adequate inhibition of platelet aggregation is not possible in all patients.
When clopidogrel is taken daily at a dose of 75 mg, significant suppression of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases over 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed by an average of 40-60 %. After stopping clopidogrel administration platelet aggregation and bleeding time gradually return to the initial level, on average within 5 days
Clopidogrel is able to prevent atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in lesions of the cerebral, coronary or peripheral arteries.
The ACTIVE-A clinical trial showed that patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel combined with acetylsalicylic acid (compared with taking acetylsalicylic acid alone) reduced the incidence of stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS), or vascular death combined, more by reducing the risk of stroke.
The efficacy of clopidogrel in combination with acetylsalicylic acid was detected early and persisted for up to 5 years. The reduction in the risk of major vascular complications, in the group of patients who took clopidogrel in combination with acetylsalicylic acid, was mainly due to a greater reduction in the incidence of strokes.
Indications
Prevention of thrombosis, Prevention of heart attacks and strokes Secondary prevention of atherothrombotic complications
In adult patients with myocardial infarction (from several days to 35 days), ischemic stroke (from 7 days to 6 months) or with diagnosed peripheral artery occlusive disease.
In adult patients with acute coronary syndrome:
– Without ST-segment elevation (unstable angina or myocardial infarction without Q-wave), including patients who have had stenting for percutaneous coronary intervention (in combination with acetylsalicylic acid);
– with ST-segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis (in combination with acetylsalicylic acid).
Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation).
In patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications, cannot take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).
Active ingredient
Clopidogrel
Composition
Each film-coated tablet contains:
The active ingredient:
clopidogrel hydrosulfate (form-I) 97.875 mg,
equivalent to 75 mg clopidogrel.
Auxiliary substances:
microcrystalline cellulose (Avicel PH 112) 211.125 mg,
mannitol 58.0 mg,
croscarmellose sodium 12.0 mg,
opadray pink 03B54202 (hypromellose 62.50%, titanium dioxide 30.60%, macrogol 400 6.25%, iron oxide red dye 0.65%) 13.475 mg.
How to take, the dosage
Clopidogrel should be taken orally, regardless of meals.
Secondary prevention of atherothrombotic complications in adult patients with myocardial infarction (from several days to 35 days), ischemic stroke (from 7 days to 6 months) or with diagnosed peripheral artery occlusive disease
The drug should be taken 75 mg once daily.
Secondary prevention of atherothrombotic complications in adult patients with acute coronary syndrome without ST-segment elevation (unstable angina or myocardial infarction without Q-wave), including patients who underwent stenting during percutaneous coronary intervention (in combination with acetylsalicylic acid)
Treatment with clopidogrel should be started with a single loading dose of 300 mg and then continued with a maintenance dose of 75 mg once daily (in combination with ASA in doses of 75-325 mg daily). Since higher doses of ASA are associated with an increased risk of bleeding, the recommended ASA dose for this indication should not exceed 100 mg. The optimal duration of treatment has not been officially determined. Data from clinical trials support use of the drug for up to 12 months, and the maximum favorable effect was observed by the third month of treatment.
Secondary prevention of atherothrombotic complications in adult patients with acute coronary syndrome with ST-segment elevation (acute myocardial infarction) with drug treatment and thrombolysis (in combination with acetylsalicylic acid)
br>
Clopidogrel should be taken once daily at a dose of 75 mg with an initial single loading dose of clopidogrel 300 mg in combination with ASA in combination with thrombolytics or without combination with thrombolytics. In patients over 75 years old, treatment with clopidogrel should be started without its loading dose. Combination therapy should be started as soon as possible after the onset of symptoms and continued for at least four weeks. The effectiveness of the combination of clopidogrel and ASA for this indication beyond 4 weeks has not been studied.
Prevention of atherothrombotic and thromboembolic complications, including stroke, in patients with atrial fibrillation (atrial fibrillation) who have at least one risk factor for vascular complications, cannot take indirect anticoagulants and have low risk of bleeding (in combination with acetylsalicylic acid)
Clopidogrel should be taken once daily in a dose of 75 mg. In combination with clopidogrel, ASA (75-100 mg/day) should be started and then continued.
Missing the next dose
– If less than 12 hours have passed since the next dose was missed, the missed dose of the drug should be taken immediately and then the next doses taken at the usual time.
– If more than 12 hours have passed since the next dose was missed, the patient should take the next dose at the usual time (do not take a double dose).
Special patient groups
Patients with genetically determined reduced CYP2C19 isoenzyme activity
Low CYP2C19 isoenzyme activity is associated with decreased antiaggregant effect of clopidogrel. A regimen of higher doses (600 mg – loading dose, then 150 mg once daily) in patients with low CYP2C19 isoenzyme activity increases the antiplatelet effect of clopidogrel (see section “Pharmacokinetics”). However, at the moment in clinical studies that take into account clinical outcomes, the optimal dosing regimen of clopidogrel for patients with its reduced metabolism due to genetically determined low activity of CYP2C19 isoenzyme has not been established.
Elderly persons
No differences in platelet aggregation and bleeding time were observed in elderly volunteers (over 75 years) when compared to younger volunteers. Dose adjustment for the elderly is not required.
Children
There is no experience of using the drug in children.
Patients with impaired renal function
. After repeated administration of clopidogrel at dose 75 mg/day in patients with severe renal impairment (creatinine clearance from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation (25%) was lower compared to that in healthy volunteers, but prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel at dose 75 mg/day. In addition, all patients had good tolerability of the drug.
Patients with impaired liver function
After 10 days of daily administration of clopidogrel at a daily dose of 75 mg in patients with severe liver damage inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups.
Patients of different ethnicity
The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and reduced metabolism of clopidogrel to its active metabolite differs among representatives of different ethnic groups (see section “Pharmacogenetics”). Only limited data are available for mongoloid races to assess the effect of CYP2C19 isoenzyme genotype on clinical outcome events.
Female and male patients
In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women showed less inhibition of ADP-induced platelet aggregation, but no difference in prolongation of bleeding time. In the large controlled CAPRIE trial (clopidogrel versus acetylsalicylic acid in patients at risk for ischemic complications), the incidence of clinical outcomes, other adverse events, and abnormal clinical and laboratory parameters was similar in both men and women.
Interaction
The concomitant use of drugs with clopidogrel that are associated with a risk of bleeding should be used with caution (with warfarin, with IIb/IIIa-receptor blockers, with acetylsalicylic acid, with heparin, with thrombolytics, in NSAIDs, with SSRIs).
Special Instructions
When treating with clopidogrel, especially during the first weeks of treatment and/or after invasive cardiac procedures/surgery, patients should be closely monitored for signs of bleeding, including hidden bleeding.
Due to the risk of bleeding and adverse effects on the blood (see section “Side effects”). In case of occurrence of clinical symptoms during the treatment that are suspicious for bleeding, a general clinical blood test should be performed urgently, the activated partial thromboplastin time (APT), platelet count, platelet functional activity parameters and other necessary studies should be determined.
Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients with increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients taking ASA, NSAIDs, including COX-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors.
Co-administration of clopidogrel with warfarin may increase the risk of bleeding (see section “Interaction with other medicinal products”), so caution should be exercised when coadministering clopidogrel and warfarin.
If a patient is to undergo elective surgery and there is no need for antiplatelet effect, clopidogrel should be discontinued 5-7 days before surgery.
Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases that predispose to bleeding (especially gastrointestinal and intraocular). Drugs that may cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) in patients taking clopidogrel should be used with caution.
Patients should be warned that it may take longer to stop bleeding when taking clopidogrel (alone or in combination with ASA), and that if they have unusual (in location or duration) bleeding, they should inform their attending physician. Patients should inform their physician (including their dentist) about clopidogrel intake before any upcoming surgery and before starting any new medication.
Very rare cases of TTP, characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, impaired renal function and fever have been reported after clopidogrel use (sometimes even short-term). TTP is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.
In patients with recent transient cerebral haemorrhage or stroke with a high risk of recurrent ischemic complications, the combination of ASA and clopidogrel has been shown to increase the risk of major bleeding. Therefore, such combination therapy should be used with caution and only in case of clinical evidence of benefit from its use.
Cases of development of acquired hemophilia while taking clopidogrel have been reported. If there is a confirmed isolated increase in the ACEF with or without bleeding, the possibility of acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease and discontinue clopidogrel.
In patients with low CYP2C19 isoenzyme activity, the use of clopidogrel in recommended doses produces less of the active metabolite clopidogrel and its antiaggregant effect is less pronounced; therefore, a higher incidence of cardiovascular complications may occur when using normally recommended doses of clopidogrel for acute coronary syndrome or percutaneous coronary intervention than in patients with normal CYP2C19 isoenzyme activity. Tests are available to determine the CYP2C19 genotype. These tests can be used to assist in the choice of therapeutic strategy. The use of higher doses of clopidogrel in patients with low CYP2C19 activity is being considered (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, sections “Caution”, “Dosage and administration”).
Patients should have a history of previous allergic and/or hematologic reactions to other thienopyridines (such as ticlopidine, prasugrel), since cross-allergic and/or hematologic reactions between thienopyridines have been reported (see
Thienopyridines may cause moderate to severe allergic reactions (such as rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia). Patients who have previously had allergic and/or hematological reactions to one of the drugs of thienopyridine group may have an increased risk of developing similar reactions to another drug of thienopyridine group. It is recommended to monitor cross-allergic and/or hematologic reactions.
During the treatment it is necessary to monitor the liver function state. In case of severe liver lesions it is necessary to remember about the risk of hemorrhagic diathesis. Administration of clopidogrel is not recommended in acute stroke with duration of less than 7 days (because there are no data on its use in this condition).
The drug Plagril® has no significant effect on the ability to drive a car or engage in other potentially dangerous activities.
Contraindications
- High sensitivity to clopidogrel or any of the excipients of the drug
- Severe hepatic impairment.
- Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.
- Rare hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption. Pregnancy and Breastfeeding
- Children under 18 years of age (safety and efficacy not established).
With caution:
In moderate hepatic insufficiency with possible susceptibility to bleeding (limited clinical experience of use).
In renal insufficiency (limited clinical experience of use).
In diseases with a predisposition to bleeding (in particular gastrointestinal or intraocular), and especially with the simultaneous use of drugs that may cause damage to the mucosa of the gastrointestinal tract (such as acetylsalicylic acid [ASA] and nonsteroidal anti-inflammatory drugs [NSAIDs]).
In patients who have an increased risk of bleeding: Because of trauma, surgery, or other pathological conditions, and in patients treated with ASA, heparin, warfarin, glycoprotein IIb/IIIa inhibitors, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, and other medications whose use is associated with a risk of bleeding, selective serotonin reuptake inhibitors (SSRIs) (see
When concomitant use with drugs that are substrates of CYP2C8 isoenzyme (repaglinide, paclitaxel) (see sections “Interaction with other medicinal products”, “Cautions”).
In patients with low activity of CYP2C19 isoenzyme (see section “Pharmacokinetics”, subsection “Pharmacogenetics”, section “Dosage and administration”, “Caution”).
If the anamnesis indicates allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) (possibility of cross-allergic and hematological reactions, see section “Special Indications.
In recently suffered transient cerebral haemorrhage or ischemic stroke (when combined with ASA, see section “Special Indications”).
Side effects
Data from clinical trials
Safety of clopidogrel has been studied in more than 44,000 patients, including more than 12,000 patients treated for a year or more. In general, the tolerability of clopidogrel at a dose of 75 mg/day in the CAPRIE study corresponded to the tolerability of ASA at a dose of 325 mg/day, regardless of age, sex and race of patients. Listed below are the clinically significant adverse effects observed in five large clinical trials: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A.
Bleeding and hemorrhage
Comparison of clopidogrel and ASA monotherapy
In the CAPRIE clinical trial, the overall incidence of all bleeding in patients taking clopidogrel and patients taking ASA was 9.3%. The incidence of severe bleeding when using clopidogrel and ASA was comparable: 1.4% and 1.6%, respectively.
In general, 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 other localized bleeding during clopidogrel administration compared with ASA administration was higher (7.3% versus 6.5%, respectively).
However, the incidence of major bleeding during clopidogrel and ASA administration was comparable (0.6% or 0.4%, respectively). The following bleeding events were most frequently reported: purpura/bleeding, nasal bleeding. Hematomas, hematuria and ocular hemorrhages (mainly conjunctival) were less frequently reported.
The incidence of intracranial hemorrhages with clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).
Comparison of clopidogrel + ASA and placebo + ASA combination therapy
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.
2.4%). Mainly, the sources of major bleeding were gastrointestinal tract and arterial puncture sites.
The frequency of life-threatening bleeding in patients receiving clopidogrel + ASA, compared with patients taking placebo + ASA, did not differ significantly (2.2% and 1.8%, respectively), the frequency 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% for both types of therapy).
The incidence of major bleeding in the clopidogrel + ASA group depended on the ASA dose (< 100 mg: 2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%), as did the rate of major bleeding in the 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 grafting, 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 for the last 5 days before coronary artery bypass grafting, the incidence of these events after intervention was 9.6% (clopidogrel + ASA) and 6.3% (placebo + ASA).
In the CLARITY clinical trial, the incidence of major bleeding events (defined as intracranial bleeding or bleeding with decreased hemoglobin> 5 g/dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable in both treatment groups
(1.3% versus 1.1% in the clopidogrel + ASA and placebo + ASA groups, respectively).
It was similar in patient subgroups separated by baseline characteristics and by type of fibrinolytic therapy or heparin therapy.
The incidence of fatal bleeding (0.8% versus 0.6%) and intracranial hemorrhage (0.5% versus 0.7%) was low and comparable in both treatment groups when treated with clopidogrel + ASA and placebo + ASA, respectively.
In the COMMIT clinical trial, the overall incidence of non-cerebral 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 in the clopidogrel + ASA group was higher than in the placebo + ASA group (6.7% vs 4.3%, respectively). Major bleeding was mainly extracranial in both groups (5.3% vs. 3.5%), mainly from the gastrointestinal tract (3.5% vs. 1.8%). The clopidogrel + ASA group had more intracranial hemorrhages compared to the placebo + ASA group (1.4% vs. 0.8%, respectively). There were no statistically significant differences between these treatment groups in the incidence of fatal bleeding (1.1% versus 0.7%) and hemorrhagic stroke (0.8% versus 0.6%).
Blood disorders
In the CAPRIE study, severe neutropenia (< 0.45×109/L) was observed in 4 patients
(0.04%) taking clopidogrel and in 2 patients (0.02%) taking ASA.
Two of the 9,599 patients taking clopidogrel had a complete absence of neutrophils in the peripheral blood, which was not observed in any of the 9,586 patients taking ASA. Despite the fact that the risk of myelotoxic effects while taking clopidogrel is quite low, if a patient taking clopidogrel has fever or other signs of infection, the patient should be examined for possible neutropenia.
During treatment with clopidogrel, the development of aplastic anemia was observed in one case.
The incidence of severe thrombocytopenia (< 80×109/l) was 0.2% in patients treated with clopidogrel and 0.1% in patients treated with ASA; very rare cases of platelet count reduction ≤ 30×109/l were reported.
In the CURE and CLARITY studies, comparable numbers of patients with thrombocytopenia or neutropenia were observed in both treatment groups.
Other clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY COMMIT and ACTIVE- A
The frequency of adverse reactions observed during the above clinical trials is presented according to the WHO classification:
- very frequently (≥10%); frequently (≥1% and < 10%);
- very rare (< 0.01%);
- frequency is unknown – it is not possible to determine the incidence of side effects from the available data.
Nervous system disorders
- Infrequent: headache, dizziness, paresthesia.
- Rarely: vertigo.
- Gastrointestinal disorders
- Often: dyspepsia, abdominal pain, diarrhea.
- Infrequent: nausea, gastritis, bloating, constipation, vomiting, peptic ulcer, duodenal ulcer.
Skin and subcutaneous tissue disorders
- Infrequent: rash, itching.
- Blood and lymphatic system disorders
- Infrequent: increased bleeding time, decreased number of platelets in peripheral blood; leukopenia, decreased number of neutrophils in peripheral blood, eosinophilia.
Postmarketing experience with the drug
.Blood and lymphatic system disorders
- Frequency unknown: Cases of severe bleeding, primarily subcutaneous, skeletal-muscular, ocular hemorrhages (conjunctival, tissue and retina), respiratory bleeding (hemoptysis, pulmonary bleeding), nasal bleeding, Hematuria and bleeding from postoperative wounds and cases of fatal bleeding (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage), agranulocytosis, granulocytopenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.
Cardiac disorders
- Frequency unknown: Coneys 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 hematologic reactions with other thienopyridines (such as ticlopidine, prasugrel) [see Special Indications].
Mental disorders
- Frequency unknown: confusion, hallucinations.
Nervous system disorders
- Frequency unknown: taste disorders.
- Vascular disorders
- Frequency unknown: vasculitis, decreased blood pressure.
Hepatic and biliary tract disorders
- Frequency unknown: hepatitis (non-infectious), acute liver failure.
Skin and subcutaneous tissue disorders
- Frequency unknown: Maculopapular erythematous or exfoliative rash, urticaria, pruritus, angioneurotic edema, 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, flat tetter.
Muscular and connective tissue disorders
- Frequency unknown: arthralgia (joint pain), arthritis, myalgia.
- Renal and urinary tract disorders
- Frequency unknown: glomerulonephritis.
Gender and mammary gland disorders
- Frequency unknown: gynecomastia.
General disorders and disorders at the site of administration
- Frequency unknown: fever.
Laboratory and instrumental data
- Frequency unknown: abnormal laboratory indicators of liver function, increased blood creatinine concentration.
.
Overdose
Clopidogrel overdose may lead to increased bleeding time with subsequent complications in the form of bleeding development. If bleeding occurs, appropriate treatment measures are required.
The antidote for clopidogrel has not been established. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.
Pregnancy use
Pregnancy
Animal studies have shown no direct or indirect adverse effects on pregnancy, fetal development, labor and postnatal development. Because it is not always possible to predict response in humans based on animal studies, and because there are no controlled clinical trial data on clopidogrel administration in pregnant women, clopidogrel administration during pregnancy is not recommended as a precautionary measure unless the physician determines its use is imperative.
Breastfeeding
In studies in rats, clopidogrel and/or its metabolites have been shown to be excreted into breast milk. Whether clopidogrel passes into human breast milk is unknown. Since many drugs may be excreted into the breast milk and have adverse effects on the infant, the attending physician, based on the importance of taking Plagril® for the mother, should recommend her either to stop taking the drug, or to take the drug, but to stop breastfeeding.
Similarities
Clopidogrel, Zilt, Egithromb, Lopirel, Clopidex, Clopidogrel-SZ
Weight | 0.024 kg |
---|---|
Shelf life | 1 year |
Conditions of storage | In the original package at a temperature not exceeding 25 ° C. Keep out of reach of children! |
Manufacturer | Dr. Reddy's, India |
Medication form | pills |
Brand | Dr. Reddy's |
Related products
Buy Plagril, 75 mg 30 pcs. with delivery to USA, UK, Europe and over 120 other countries.