PLAVIX 75MG PILLS
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Plavix / Plavix
The safety of clopidogrel has been investigated in more than 44,000 patients, incl. more than 12,000 patients who received treatment for a year or more. In general, the tolerability of clopidogrel at a dose of 75 mg / day in the CAPRIE study was consistent with the tolerability of acetylsalicylic acid (ASA) at a dose of 325 mg / day, regardless of age, gender, and race of patients. The following are clinically significant adverse effects observed in five large clinical studies: CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A.
Bleeding and hemorrhage
Comparison of monotherapy with clopidogrel and ASA
In a clinical study of CAPRIE, 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.
In general, the incidence of Gastrointestinal bleeding in patients taking clopidogrel and in patients taking ASA was 2% and 2.7%, respectively, incl. the incidence of gastrointestinal bleeding requiring hospitalization was 0.7% and 1.1%, respectively.
The overall frequency of bleeding at another site when clopidogrel was taken was higher compared with taking ASA (7.3% versus 6.5%, respectively).However, the frequency of severe bleeding when using clopidogrel and ASA was comparable (0.6% or 0.4%, respectively). The most commonly reported on the development of the following bleeding: purpura / bruising, nosebleeds. Rarely, hematomas, hematuria and ocular hemorrhages (mainly conjunctival) were reported.
The frequency of intracranial hemorrhage when using clopidogrel and ASA was comparable (0.4% or 0.5%, respectively).
Comparison of combination therapy with clopidogrel + ASA and placebo + ASA
In a clinical study of CURE, patients treated with clopidogrel + ASA, compared with patients taking placebo + ASA, showed an increase in the incidence of large bleeding (3.7% vs. 2.7%) and small bleeding (5.1% vs. 2.4%). The main sources of major bleeding were the gastrointestinal tract and artery puncture sites.
The incidence of life-threatening bleeding in patients treated with clopidogrel + ASK 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 treated with 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 therapy).
The incidence of major bleeding in the clopidogrel + ASK group depended on the ASK dose (<100 mg — 2.6%; 100–200 mg — 3.5%;> 200 mg — 4.9%), as did the incidence of major bleeding in the placebo + ASA group (< 100 mg - 2.0%; 100-200 mg - 2.3%;> 200 mg - 4%).
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 + ASK group and 5.3% in the placebo + ASC group). In patients who continued antiplatelet therapy during the last 5 days before coronary artery bypass surgery, the incidence of these events after the intervention was 9.6% (in the clopidogrel + ASK group) and 6.3% (in the placebo + ASK group).
In the CLARITY clinical trial, the incidence of major bleeding (defined as intracranial bleeding or bleeding with a decrease in hemoglobin of> 5 g / dL) in both groups (clopidogrel + ASA and placebo + ASA) was comparable (1.3% vs. 1.1% in the clopidogrel + ASA and placebo + ASC, respectively). She was the same in subgroups of patients, separated by baseline characteristics and types of fibrinolytic therapy or Heparin therapy.
The incidence of fatal bleeding (0.8% versus 0.6%) and intracranial hemorrhage (0.5% versus 0.7%) in the treatment of clopidogrel + ASA and placebo + ASA, respectively, was low and comparable in both treatment groups.
In the clinical study COMMIT, the overall incidence of non-cerebral major bleeding or cerebral bleeding was low and equal (0.6% in the clopidogrel + ASK group and 0.5% in the placebo + ASK group).
In the ACTIVE-A clinical trial, the incidence of major bleeding in the clopidogrel + ASK group was higher than in the placebo + ASK group (6.7% versus 4.3%, respectively). Large bleedings were mainly extracranial in both groups (5.3% versus 3.5%), mainly from the gastrointestinal tract (3.5% versus 1.8%). In the clopidogrel + ASK group, intracranial hemorrhage was higher compared with the placebo + ASK 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% versus 0.7%) and hemorrhagic stroke (0.8% versus 0.6%).
From the hemopoietic system
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.
In 2 of 9599 patients taking clopidogrel, there was 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 when taking clopidogrel is low enough, if a patient taking clopidogrel has a fever or other signs of infection, the patient should be examined for possible neutropenia.
In the treatment of clopidogrel in one case, the development of aplastic anemia was observed.
The incidence of severe thrombocytopenia (<80–10%) was 0.2% in patients taking clopidogrel and 0.1% in patients taking ASA, very rare cases of a decrease in platelet count <30–10% were reported.
In the CURE and CLARITY studies, a comparable number of patients with thrombocytopenia or neutropenia were observed in both treatment groups.
Other clinically significant adverse reactions observed during clinical studies of CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A
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%), infrequently (≥0.1% and <1%), rarely (≥0.01% and <0.1%), very rarely (<0.01%), unknown frequency (it is not possible to determine the frequency of occurrence of side effects from the available data).
From the nervous system: infrequently - headache, dizziness, paresthesia; rarely - vertigo.
From the digestive system: often - dyspepsia , abdominal pain, diarrhea; infrequently - nausea, gastritis, bloating, constipation, vomiting, gastric ulcer, duodenal ulcer.
Dermatological reactions: infrequently - rash, itching.
From the hemopoietic system: infrequently - a decrease in the number of platelets in peripheral blood, leukopenia, a decrease in the number of neutrophils in peripheral blood, eosinophilia.
From the blood coagulation system: infrequently - an increase in bleeding time.
Post-marketing experience with the drug
Hemorrhagic disorders: unknown frequency - cases of serious bleeding, mainly subcutaneous, musculoskeletal, eye hemorrhages (conjunctival, in the tissue and retina), respiratory bleeding (hemoptysis, pulmonary hemorrhage),nasal bleeding, hematuria and bleeding from postoperative wounds and cases of fatal bleeding (especially intracranial hemorrhage, gastrointestinal bleeding and retroperitoneal hemorrhage).
From the hemopoietic system: unknown frequency - agranulocytosis, granulocytopenia, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.
Allergic reactions: unknown frequency - anaphylactoid reactions, serum sickness; allergic and hematological cross-reactions with other thienopyridines (such as ticlopidine, prasagrel).
Mental disorders: unknown frequency - confusion, hallucinations.
From the nervous system: unknown frequency - taste disturbances.
Since the cardiovascular system: unknown frequency - vasculitis, lowering blood pressure.
On the part of the respiratory system: unknown frequency - bronchospasm, interstitial pneumonia, eosinophilic pneumonia.
From the digestive system: unknown frequency - colitis (including ulcerative colitis or lymphocytic colitis), pancreatitis, stomatitis, hepatitis (non-infectious), acute hepatic failure.
Dermatological reactions: unknown frequency - makulo-papular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome,toxic epidermal necrolysis), drug hypersensitivity syndrome, drug rash with eosinophilia and systemic (DRESS syndrome), eczema, lichen planus.
From the musculoskeletal system: unknown frequency - arthralgia, arthritis, myalgia.
From the urinary system: unknown frequency - glomerulonephritis.
Common disorders: unknown frequency - fever.
Laboratory and instrumental data: unknown frequency - deviation from the norm of laboratory parameters of the functional state of the liver, increasing the concentration of creatinine in the blood.
- severe liver failure;
- acute bleeding, for example, bleeding from a peptic ulcer or intracranial hemorrhage;
- rare hereditary intolerance to galactose, lactase deficiency and glucose-galactose malabsorption syndrome;
- lactation period (breastfeeding);
- children and adolescents under 18 years of age (safety and efficacy have not been established);
- hypersensitivity to clopidogrel or any of the auxiliary components of the drug.
WITH caution prescribe the drug for moderate liver failure, in which there is a predisposition to bleeding (limited clinical experience); renal failure (limited clinical experience); for diseasesin which there is a predisposition to the development of bleeding (in particular gastrointestinal or intraocular), and especially with the simultaneous use of drugs that can cause damage to the mucous membrane of the gastrointestinal tract (such as ASA and NSAIDs); in patients who have an increased risk of bleeding (due to trauma, surgery or other pathological conditions), as well as in patients receiving ASA, heparin, Warfarin , glycoprotein IIb / IIIa inhibitors, NSAIDs , including selective COX-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs); in patients with low activity of isoenzyme CYP2C19; with indications of a history of allergic and hematological reactions to other thienopyridines, such as ticlopidine, prasugrel (the possibility of cross-allergic and hematological reactions); after a recent transient cerebral circulation or ischemic stroke.
Use during pregnancy and lactation
AT experimental studies no direct or indirect adverse effects on the course of pregnancy, fetal development, childbirth and postnatal development were found. Since not always, according to the results of animal studies, it is possible to predict the reaction in humans, and due to the lack of data from controlled clinical studies on the use of clopidogrel in pregnant women,As a precautionary measure, it is not recommended to take clopidogrel during pregnancy, unless, in the opinion of the doctor, the use of the drug is urgently needed.
Lactation period (breastfeeding)
Studies in rats have shown that clopidogrel and / or its metabolites are excreted into breast milk. Whether clopidogrel penetrates into breast milk of a nursing woman is unknown. Since many drugs can be excreted in breast milk and have an adverse effect on the infant, the attending physician, based on the importance of the use of the drug Plavix® for the mother, should recommend her or stop using the drug, or take the drug, but refuse to breastfeed.
Application for violations of the liver
WITH caution prescribe the drug for moderate liver failure, in which there is a predisposition to bleeding (limited clinical experience).
Contraindicated use in severe liver failure.
Application for violations of kidney function
WITH caution prescribe a drug for renal failure (limited clinical experience).
Use in children
Contraindicated: children and adolescents under 18 years of age (safety and efficacy have not been established).
Use in elderly patients
In patients over the age of 75, Plavix treatment should be started without taking a loading dose.
When treating clopidogrel, especially during the first weeks of therapy and / or after invasive cardiac procedures / surgery, it is necessary to carefully monitor patients for signs of bleeding, including and hidden.
In connection with the risk of bleeding and hematological side effects, if clinical symptoms that are suspicious of bleeding occur during the treatment, a blood test should be urgently performed, the APTT, platelet count, indicators of functional platelet activity and other necessary studies should be determined.
Clopidogrel, as well as other antiplatelet agents, should be used with caution in patients who have an increased risk of bleeding associated with injuries, surgical interventions or other pathological conditions, as well as in patients taking ASA, NSAIDs (including COX inhibitors -2), heparin or glycoprotein IIb / IIIa inhibitors.
The combined use of clopidogrel with warfarin can increase the risk of bleeding, therefore, caution should be exercised when using clopidogrel and warfarin together.
With planned surgical interventions and in the absence of the need for an anti-platelet effect, treatment with clopidogrel should be stopped 5-7 days before the operation.
Clopidogrel prolongs bleeding time, so the drug should be used with caution in patients with diseases that predispose to the development of bleeding (especially gastrointestinal and intraocular).Drugs that can cause damage to the gastrointestinal mucosa (such as ASA, NSAIDs) in patients receiving clopidogrel should be used with caution.
Patients should be warned that when taking clopidogrel (alone or in combination with ASA), it may take longer to stop the bleeding, and that if they have unusual (localization or duration) bleeding, they should be reported this to your doctor. Before any upcoming surgery and before taking any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.
Very rarely after taking clopidogrel (sometimes even short) were there have been cases of thrombotic thrombocytopenic purpura (TTP), which is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with either neurological symptoms, impaired renal function or fever. TTP is a potentially life-threatening condition that requires urgent action, including plasmapheresis.
It has been shown that in patients with a recent transient cerebral circulation disorder or stroke with a high risk of recurring ischemic complications, the combination of ASA and clopidogrel increases the incidence of major bleeding. Therefore, such a combination therapy should be carried out with caution and only in the case of proven clinical benefit from its use.
It was reported about the development of acquired hemophilia while taking clopidogrel.With a confirmed isolated increase in APTT, accompanied or not accompanied by the development of bleeding, the possibility of developing acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should discontinue clopidogrel and be monitored and treated by specialists for the disease.
In patients with low activity of the CYP2C19 isoenzyme when using clopidogrel in recommended doses, less active metabolite of clopidogrel is formed and its antiaggregant effect is less pronounced, therefore, when receiving clopidogrel in usually recommended doses for acute coronary syndrome or percutaneous coronary intervention, it would be possible to use clopidogrel in the recommended doses for acute coronary syndrome or percutaneous coronary intervention. -vascular complications than in patients with normal activity of the isoenzyme CYP2C19. There are tests for determining the genotype of CYP2C19, which can be used to help select a therapeutic strategy. Consideration is being given to the use of clopidogrel in higher doses in patients with low CYP2C19 activity.
Patients should have a history of previous allergic and / or hematological reactions to other thienopyridines (such as ticlopidine, prasgrel), because Allergic and / or hematological reactions between thienopyridines have been reported. Thienopyridines can cause mild and severe allergic reactions (such as a rash, angioedema) or hematological reactions (such as thrombocytopenia and neutropenia).Patients who have previously experienced allergic and / or hematological reactions to one of the drugs of the thienopyridine group may have an increased risk of developing similar reactions to another drug from this group. Monitoring of cross-allergic and / or hematological reactions is recommended.
During the period of treatment it is necessary to control the functional activity of the liver. In severe liver damage, the risk of hemorrhagic diathesis should be considered.
The use of clopidogrel is not recommended for acute stroke with a prescription of less than 7 days (since there are no data on its use in this state).
Influence on ability to drive motor transport and control mechanisms
Drug Plavix® does not have a significant impact on the ability to drive vehicles or engage in other potentially hazardous activities.
Symptoms: prolongation of bleeding time and subsequent complications in the form of bleeding.
Treatment: if bleeding occurs, appropriate therapy should be performed. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended. There is no specific antidote.
Although the use of clopidogrel at a dose of 75 mg / day did not alter the pharmacokinetics of warfarin (CYP2C9 isoenzyme substrate) or MHO in patients who received long-term treatment with warfarin, the simultaneous use of clopidogrel increases the risk of bleeding in due to its independent additional effects on blood clotting.Therefore, care must be taken while taking warfarin and clopidogrel.
The use of GPIIb / IIIa receptor blockers in conjunction with clopidogrel requires caution in patients who have an increased risk of bleeding (for injuries and surgical interventions or other pathological conditions).
ASK does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. However, simultaneous administration of ASK with 500 mg 2 times / day for 1 day with clopidogrel did not cause a significant increase in bleeding time caused by taking clopidogrel. Between clopidogrel and ASA possible pharmacodynamic interaction, which leads to an increased risk of bleeding. Therefore, with their simultaneous use, caution should be exercised, although in clinical studies, patients received combination therapy with clopidogrel and ASA up to 1 year.
According to a clinical study conducted with the participation of healthy volunteers, taking clopidogrel did not require a change in the dose of heparin and its anticoagulant effect did not change. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between the drug Plavix® and heparin may have a pharmacodynamic interaction, which may increase the risk of bleeding (this combination requires caution).
The safety of the combined use of clopidogrel, fibrin-specific or fibrin-nonspecific thrombolytic drugs and heparin has been studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of the joint use of thrombolytic agents and heparin with ASA.
In a clinical study conducted with healthy volunteers, the combined use of clopidogrel and Naproxen increased hidden blood loss through the gastrointestinal tract. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel along with other NSAIDs (the prescription of NSAIDs, including inhibitors of COX-2, together with clopidogrel requires caution).
Since SSRIs disrupt platelet activation and increase the risk of bleeding, the simultaneous use of SSRIs with clopidogrel should be carried out with caution.
Other Drug Interactions
Since Clopidogrel is metabolized to form an active metabolite, partly with the participation of the CYP2C19 isoenzyme, the use of drugs that inhibit this isoenzyme, can lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction has not been established. As a precautionary measure, the use of strong or moderate inhibitors of the CYP2C19 isoenzyme with clopidogrel should be avoided.The potent and mild CYP2C19 isoenzyme inhibitors are Omeprazole , esomeprazole, fluvoxamine, Fluoxetine , moclobemide, voriconazole, Fluconazole , ticlopidine, Ciprofloxacin , cimetidine, Carbamazepine , oxcarbazepine, chloramphenicol.
Simultaneous use of proton pump inhibitors, which are strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole), with clopidogrel should be avoided. If proton pump inhibitors should be taken simultaneously with clopidogrel, a proton pump inhibitor should be used with the least inhibition of the CYP2C19 isoenzyme, such as pantoprazole and lansoprazole.
A number of clinical studies have been conducted with clopidogrel and other concomitantly prescribed drugs in order to study possible pharmacodynamic and pharmacokinetic interactions.