The safety of clopidogrel in clinical studies has been studied in more than 44,000 patients, including more than 12,000 patients taking it during the year, and more than 30,000 patients taking concomitantly clopidogrel and ASA; by According to one of the clinical studies, the safety of clopidogrel in combination with ASA was evaluated in more than 6,200 patients who took them for 1 year or more. The following are clinically significant adverse effects (AEs) observed in large clinical trials and in the post-marketing application of combination clopidogrel + ASA, clopidogrel in monotherapy and ASA in monotherapy. The incidence of adverse reactions was determined in accordance with the classification of the World Health Organization: Often (≥1/10); often (from ≥1 / 100 to <1/10); infrequently (from ≥1 / 1000 to <1/100); rarely (from ≥1 / 10000 to <1/1000); rarely (<1 /10000), frequency unknown (based on the available data it is impossible to assess).
Legend:
1 AEs that were observed with a combination of clopidogrel and ASA.
2 AE, which were observed with the use of clopidogrel.
3 AEs that were observed with the use of ASA.
Hemorrhagic AE (purpura / bruising, nasal bleeding, hematuria, hemorrhages in skin tissues, bone and muscle, hematomas, hemorrhages in the joint cavity (hemarthrosis), conjunctiva, internal environments and the retina, bleeding from the respiratory tract,hemoptysis; bleeding from the operating wound; intracranial hemorrhages (hemorrhagic strokes); bleeding from the gastrointestinal tract, retroperitoneal hemorrhage, etc.).
Hemorrhages and hemorrhages were the most frequently observed AEs in clinical trials and in post-marketing applications, mainly they occurred during the first month of therapy.
- Often - large bleeding1 (life-threatening hemorrhages requiring transfusion of 4 or more blood units, other large bleeding that require transfusion of 2-3 units of blood, no life-threatening large bleeding (the incidence of major cerebral bleeding and intracranial hemorrhage was "infrequently")1; small bleeding (the incidence of small bleeding was "Often")1, bleeding at the site of vascular puncture1,2; bruising2; hematoma2.
The frequency of major bleeding when applying the combination clopidogrel + ASA depended on the dose of ASA (more than 100 mg - 2.6%, 100-200 mg - 3.5%, more than 200 mg - 4.9%), as well as their frequency with one ASA (more than 100 mg - 2.0%, 100-200 mg - 2.3%, more than 200 mg - 4.0%).
In patients who discontinued treatment more than 5 days before aortocoronary bypass surgery,there was no increase in cases of large bleeding within 7 days after the intervention (4.4% - with the use of clopidogrel + ASA versus 5.3% - with the administration of one ASA). In patients who remained on antiplatelet therapy for the last 5 days before aortocoronary bypass surgery, the incidence of these bleeding after intervention was 9.6% (clopidogrel + ASA) and 6.3% (one ASA).
- Infrequently: bleeding with lethal outcome1; life-threatening bleeding (hemorrhage with a decrease in hemoglobin of more than 5 g / dL (according to one of the clinical studies, the frequency of their development was "often")1; bleeding requiring surgery1; intracranial hemorrhages (hemorrhagic strokes) (according to one of the clinical studies, the frequency of their development was "often")1; bleeding, requiring the introduction of inotropes)1; severe bleeding (most often purpura, nasal bleeding, less common hematuria and intraocular hemorrhages, mainly conjunctival2).
- Rarely: intraocular hemorrhages with significant visual impairment1, retroperitoneal hemorrhage1.
- Frequency is unknown (post-marketing experience): serious cases of bleeding2, mainly, hemorrhage in the skin tissue2, in the bones, muscles and joint cavity (hemarthrosis)2, in the eye tissue (conjunctival, in the internal environment and the retina of the eye)2, bleeding from the respiratory tract2, hemoptysis2, nasal bleeding2, hematuria2, bleeding from an operating wound2, intracranial hemorrhage3, including fatal cases3, especially in elderly patients; Other cases of bleeding with a fatal outcome (in particular bleeding from the gastrointestinal tract and retroperitoneal hemorrhage)2.
Violations of the blood and lymphatic system
- Infrequently: decrease in the number of platelets in peripheral blood1, severe thrombocytopenia with the number of platelets in the peripheral blood ≤80x10;/ l, but more than 30х109/ l1; leukopenia1; decrease in the number of neutrophils in peripheral blood1, eosinophilia1, prolongation of bleeding time1.
- Rarely: neutropenia1, including severe neutropenia (more 0,45x109/ l)1. Although the risk of myelotoxic effects when using clopidogrel is low enough, its potential should be considered when the patient receiving clopidogrel, develops fever and other infectious manifestations.
- Rarely: aplastic anemia1, severe thrombocytopenia with the number of platelets in the peripheral blood ≤30x109/l1.
- Frequency is unknown (post-marketing experience): thrombocytopenia3, hemolytic anemia in patients with insufficiency of glucose-6-phosphate dehydrogenase3, agranulocytosis2,3; aplastic anemia2,3/ pancytopenia2,3, bicythopenia3, disorders of bone marrow hematopoiesis3, neutropenia3, leukopenia3, granulocytopenia3, anemia1, acquired hemophilia A2, thrombotic thrombocytopenic purpura (TTP)2.
Disorders from the central peripheral nervous system
- Infrequently: headache1, dizziness1 and paresthesia1.
- Rarely: vertigo1.
- Frequency is unknown (post-marketing experience): changes in taste2.
Disorders from the digestive system
- Often: gastrointestinal bleeding1, dyspepsia1, abdominal pain1, diarrhea1.
- Infrequently: nausea1, gastritis1, flatulence1, constipation1, vomiting1, a stomach ulcer1 and duodenal ulcer1.
- Frequency is unknown (post-marketing experience): colitis2,3 (including ulcerative or lymphocytic colitis)2, pancreatitis2, stomatitis2, esophagitis3, ulceration / perforation of the esophagus3, erosive gastritis3, erosive duodenitis3, an ulcer or peptic ulcer perforation of the stomach and / or duodenum3, symptoms of the upper gastrointestinal tract, such as gastralgia3 (see section "Special instructions"), ulcers of the small intestine (lean and ileum)3 and large intestine (colon and rectum)3, intestinal perforation3 (these reactions may or may not be accompanied by bleeding and may occur with any dose of ASA, as well as in patients who have warning signs and anamnesis of serious gastrointestinal complications and who do not); acute pancreatitis, which is a manifestation of the hypersensitivity reaction to ASA3.
Disturbances from the liver and bile ducts
- Frequency is unknown (post-marketing experience): hepatitis (non-infectious nature)2, acute hepatic impairment2, increased activity of "hepatic" enzymes3, liver damage, mainly hepatocellular3, chronic hepatitis3.
Disturbances from the skin and subcutaneous tissues
- Infrequently: skin rash1, itchy skin1.
- Frequency unknown (postmarketing experience of application): maculopapular, erythematous or exfoliative skin rash2, urticaria2, itching2, angioedema edema2, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)2, acute generalized exanthematous pustulosis2, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome)2, eczema2, flat lichen2, a fixed skin rash (single or multiple skin changes, usually in the form of erythematous plaques of round or oval shape, appearing in the same place with the next intake of the drug)3.
Immune system disorders
- Frequency is unknown (post-marketing experience): anaphylactoid reactions2, serum sickness2, cross-reactive hypersensitivity reactions with other thienopyridines (such as ticlopidine, prasugrel)2 (see section "Special instructions"), anaphylactic shock3, increased symptoms of food allergy3.
Disorders of the psyche
- Frequency unknown (post-marketing experience): confusion2, hallucinations2.
Vascular disorders
- Frequency is unknown (post-marketing experience): vasculitis2,3, including the purple Shenlaine-Genocha3, lowering blood pressure2.
Heart Disease
- Frequency is unknown (post-marketing experience): Kunis syndrome (allergic coronary syndrome) due to the hypersensitivity reaction to ASA3.
Disturbances from the respiratory system, chest and mediastinal organs
- Frequency is unknown (post-marketing experience): bronchospasm2, interstitial pneumonitis2, eosinophilic pneumonia2, non-cardiogenic pulmonary edema in chronic drug administration associated with a hypersensitivity reaction3.
Disturbances from musculoskeletal and connective tissue
- Frequency is unknown (post-marketing experience): arthralgia2, arthritis2, myalgia2.
Disorders from the kidneys and urinary tract
- Frequency unknown (post-marketing experience): glomerulopathy, including glomerulonephritis2, kidney failure3, acute renal dysfunction (especially in patients with pre-existing renal failure, decompensation of chronic heart failure, nephrotic syndrome, or in patients taking diuretics simultaneously)3.
Violations of the genitals and mammary gland
- Frequency is unknown (post-marketing experience): gynecomastia2.
General disorders
- Frequency is unknown (post-marketing experience): fever2.
Laboratory and instrumental data
- Frequency is unknown (post-marketing experience): deviation from the norm of biochemical indicators of the functional state of the liver2, an increase in the concentration of creatinine in the blood2.
Disorders from the metabolism and nutrition
- Frequency is unknown (post-marketing experience): hypoglycemia3, gout3.
Hearing disorders and labyrinthine disorders
- Frequency is unknown (post-marketing experience): hearing loss3, noise in ears3.