Coplavix
The following are clinically significant adverse effects observed in five large clinical studies and post-marketing use of the combination of clopidogrel + ASA, clopidogrel as monotherapy and ASA as monotherapy.
The incidence of side effects was determined according to the WHO classification: very often (≥10%), often (≥1% and
Legend
1 Adverse effects that were observed when using a combination of clopidogrel and ASA.
2 Adverse effects that were observed with the use of clopidogrel.
3 Adverse effects that were observed with the use of ASA.
Hematological disorders (purpura/bruising; nosebleeds; hematuria; hemorrhages in skin tissue, bones and muscles; hematomas; hemorrhages in the joint cavity [hemarthrosis], in the conjunctiva, in the internal media and retina of the eye; bleeding from the respiratory tract, hemoptysis; bleeding from a surgical wound; intracranial hemorrhages (hemorrhagic strokes); bleeding from the gastrointestinal tract, retroperitoneal hemorrhages, etc.)
Bleeding and hemorrhage were the most frequently observed adverse events in clinical studies and post-marketing use of the drug, mainly occurring during the first month of treatment.
Often - major bleeding1: life-threatening bleeding requiring transfusion of 4 or more units of blood; other major bleeding requiring 2-3 units of blood transfusion; non-life-threatening major bleeding (in the COMMIT study, the incidence of major non-cerebral bleeding and intracranial hemorrhage was “infrequent”)1; minor bleeding (according to the ACTIVE-A study, the incidence of minor bleeding was “very common”)1; bleeding at the site of vascular puncture1,2; bruising2; hematomas2.
The incidence of major bleeding when using the combination of clopidogrel + ASA depended on the dose of ASA, as well as their frequency when using ASA alone.
Patients who stopped treatment more than 5 days before coronary artery bypass grafting did not experience an increase in major bleeding within 7 days after this procedure. In patients who remained on antiplatelet therapy in the last 5 days before coronary artery bypass surgery, the incidence of these bleedings after surgery was 9.6% (clopidogrel + ASA) and 6.3% (ASA alone).
Uncommon - fatal bleeding1: life-threatening bleeding: bleeding with a decrease in blood hemoglobin by more than 5 g/dl (according to the CLARITY clinical trial, the frequency of their development was “common”)1; bleeding requiring surgery1; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical trial, the incidence of their development was “common”)1; bleeding requiring the administration of inotropic drugs1; severe bleeding: purpura and nosebleeds were most often observed; Hematuria and intraocular hemorrhages, mainly conjunctival, were less common2.
Rarely - intraocular hemorrhages with significant visual impairment1, retroperitoneal hemorrhages1.
Unknown frequency (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 media and retina of the eye)2, bleeding from respiratory tract2, hemoptysis2, nosebleeds2, hematuria2, bleeding from the surgical wound2; intracranial hemorrhage3, including fatal cases3, especially in elderly patients; other cases of fatal bleeding (in particular, bleeding from the gastrointestinal tract and retroperitoneal hemorrhage)2.
From the hematopoietic system: infrequently - a decrease in the number of platelets in the peripheral blood1, severe thrombocytopenia with a platelet count in the peripheral blood of 80,000/μl, but >30,000/μl1, leukopenia1, a decrease in the number of neutrophils in the peripheral blood1, eosinophilia1, prolongation of bleeding time1; rarely - neutropenia1, including severe neutropenia (
From the central and peripheral system: infrequently - headache1, dizziness1 and paresthesia1; rarely - vertigo1; unknown frequency (post-marketing experience of use) - change in taste sensations2.
From the digestive system: often - gastrointestinal bleeding1, dyspepsia1, abdominal pain1, diarrhea1; uncommon - nausea1, gastritis1, flatulence1, constipation1, vomiting1, gastric ulcer1 and duodenal ulcer1; unknown frequency (post-marketing experience) - colitis (including ulcerative or lymphocytic colitis)2, pancreatitis2, stomatitis2, esophagitis3, ulceration, esophageal perforation3, erosive gastritis3, erosive duodenitis3, ulcer or ulcerative perforation of the stomach and/or duodenum3, symptoms of upper tract lesions gastrointestinal tract, such as gastralgia3, ulcers of the small intestine (jejunum and ileum)3 and large intestine (colon and rectum)3, colitis and intestinal perforation3 (these reactions may or may not be accompanied by bleeding, and can occur with any dose of ASA, as well as in patients with and without warning symptoms and a history of serious gastrointestinal complications).
From the liver and biliary tract: unknown frequency (post-marketing experience of use) - hepatitis (infectious etiology)2, acute liver failure2, increased activity of liver enzymes3, deviations from the norm in indicators of the functional state of the liver2, liver damage, mainly hepatocellular3.
Dermatological reactions: uncommon - skin rash1, itching1; unknown frequency (post-marketing experience with use) - maculopapular, erythematous or exfoliative rash2, urticaria2, pruritus2, angioedema2, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)2, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome)2, eczema2, lichen planus2.
Allergic reactions: unknown frequency (post-marketing experience) - anaphylactoid reactions2, serum sickness2, cross-hypersensitivity reactions with other thienopyridines (such as ticlopidine, prasugrel)2, anaphylactic shock3, increased symptoms of food allergy3.
Mental disorders: unknown frequency (post-marketing experience) - confusion2, hallucinations2.
From the cardiovascular system: unknown frequency (post-marketing experience) - vasculitis2, decreased blood pressure2.
From the respiratory system: unknown frequency (post-marketing experience of use) - bronchospasm2, interstitial pneumonitis2, eosinophilic pneumonia2, non-cardiogenic pulmonary edema with constant use of the drug associated with a hypersensitivity reaction3.
From the musculoskeletal system: unknown frequency (post-marketing experience) - arthralgia2, arthritis2, myalgia2.
From the urinary system: unknown frequency (post-marketing experience of use) - glomerulopathy, including glomerulonephritis2, acute renal dysfunction (especially in patients with pre-existing renal failure, decompensated chronic heart failure, nephritic syndrome or in patients simultaneously taking diuretics)3.
General disorders: unknown frequency (post-marketing experience) - fever2.
Laboratory and instrumental data: unknown frequency (post-marketing experience of use) - deviation from the norm in indicators of the functional state of the liver2, increased concentration of creatinine in the blood2.
From the metabolic side: unknown frequency (post-marketing experience of use) - hypoglycemia3, gout3.
On the part of the hearing organ: unknown frequency (post-marketing experience of use) - hearing loss3, tinnitus3.
There are no data regarding overdose.
An overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of bleeding. If bleeding occurs, appropriate treatment is required. No antidote for clopidogrel has been established. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.
Symptoms of a moderate overdose of ASA: dizziness, ringing in the ears, headache, confusion and gastrointestinal symptoms (nausea, vomiting and stomach pain).
Severe overdose of ASA: severe disturbances in acid-base balance occur. Initially, the resulting hyperventilation leads to the development of respiratory alkalosis, then respiratory acidosis develops as a consequence of the inhibitory effect of respiratory alkalosis on the respiratory center. Also, due to the presence of salicylates in the blood, metabolic acidosis develops. In addition, the following symptoms appear: hyperthermia and profuse sweating, leading to dehydration, restlessness, convulsions, hallucinations and the development of hypoglycemia. Suppression of the nervous system can lead to the development of coma, collapse and respiratory arrest. The lethal dose of ASA is 25-30 g. A plasma concentration of salicylate over 300 mg/l (1.67 mmol/l) confirms the presence of intoxication. In acute and chronic overdose of ASA, non-cardiogenic pulmonary edema may develop.
If symptoms of a severe overdose of acetylsalicylic acid are detected, hospitalization is required. In case of moderate intoxication, you can try to artificially induce vomiting; if unsuccessful, gastric lavage is indicated. After this, activated charcoal and a saline laxative should be taken orally (if the patient can swallow) or administered into the stomach through a tube. In order to force the alkalinization of urine to accelerate the excretion of salicylates, intravenous drip administration of 250 mmol of sodium bicarbonate is indicated for 3 hours under the control of urine pH and acid-base balance. The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is used.
Indications for use
- Prevention of atherothrombotic complications.
- In adult patients with acute coronary syndrome:
- without ST segment elevation (unstable angina or non-Q wave myocardial infarction), including patients who underwent stenting for percutaneous coronary intervention;
- with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of thrombolysis.
- Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation)
- Adult 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.
Contraindications
- severe liver failure (more than 9 points on the Child-Pugh scale);
- severe renal failure (creatinine clearance <30 ml/min) due to the content of acetylsalicylic acid (ASA) in the drug;
- acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage;
- bronchial asthma induced by taking salicylates and other NSAIDs, syndrome of bronchial asthma, rhinitis and recurrent polyposis of the nose and paranasal sinuses, hypersensitivity to NSAIDs (due to the content of ASA in the drug);
- mastocytosis, in which the use of ASA can cause severe allergic reactions, including the development of shock with skin hyperemia, decreased blood pressure, tachycardia and vomiting (due to the content of ASA in the drug);
- rare hereditary conditions such as galactose intolerance, lactose intolerance due to lactase deficiency, glucose-galactose malabsorption syndrome (due to the lactose content of the drug);
- pregnancy;
- lactation period (breastfeeding);
- children and adolescents under 18 years of age (safety and effectiveness of use have not been established);
- hypersensitivity to any of the active or excipients of the drug.
Carefully
- with moderate liver failure (7-9 points on the Child-Pugh scale), in which there may be a predisposition to bleeding (limited clinical experience);
- for mild to moderate renal failure with CC 30-60 ml/min (limited clinical experience);
- for trauma, surgery, including invasive cardiac procedures or surgery;
- for diseases in which there is a predisposition to the development of bleeding, especially intraocular or gastrointestinal (with peptic ulcer of the stomach and duodenum or a history of gastrointestinal bleeding, with symptoms of disorders of the upper gastrointestinal tract);
- with a recent transient cerebrovascular accident or ischemic stroke;
- with simultaneous use of NSAIDs, incl. and selective COX-2 inhibitors;
- with simultaneous use of warfarin, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors and thrombolytic agents;
- with a history of bronchial asthma and allergies (increased risk of developing allergic reactions to ASA);
- for gout, hyperuricemia (ASA, including in low doses, increases the concentration of uric acid in the blood);
- in patients with a genetically determined decrease in the activity of the CYP2C19 isoenzyme;
- with simultaneous use of methotrexate at a dose of more than 20 mg per week;
- when there is a history of allergic and hematological reactions to other thienopyridines (such as ticlopidine, prasugrel) due to the possibility of cross-allergic and hematological reactions.
Directions for use and doses
Coplavix® should be taken 1 time/day, regardless of meals.
Adults and elderly patients with normal CYP2C19 isoenzyme activity
Acute coronary syndrome (ACS). Treatment begins as soon as possible after symptoms appear. Taking the drug Coplavix® begins after taking a single loading dose of clopidogrel in combination with ASA in the form of separate drugs, namely clopidogrel at a dose of 300 mg and ASA at doses of 75-325 mg/day, and in acute myocardial infarction with ST-segment elevation - in combination with or without thrombolytics. Since the use of higher doses of ASA is associated with an increased risk of bleeding, the recommended dose of ASA for this indication should not exceed 100 mg. In acute myocardial infarction with ST segment elevation in patients over 75 years of age, treatment with clopidogrel should begin without taking a loading dose.
In patients with non-ST segment elevation ACS (unstable angina or non-Q wave myocardial infarction), the maximum beneficial effect is observed by the 3rd month of treatment. The optimal duration of treatment has not been officially determined. Data from clinical studies support taking the drug for up to 12 months.
In patients with acute ST-segment elevation myocardial infarction, treatment should be continued for at least 4 weeks.
Atrial fibrillation. The drug Coplavix® should be taken 1 time / day, after starting treatment with clopidogrel 75 mg and ASA 100 mg in the form of separate drugs.
Patients with genetically determined reduced activity of the CYP2C19 isoenzyme. Low activity of the CYP2C19 isoenzyme is associated with a decrease in the antiplatelet effect of clopidogrel. The use of higher doses of clopidogrel (600 mg loading dose, then 150 mg once a day) in patients with low activity of the CYP2C19 isoenzyme increases the antiplatelet effect of clopidogrel. However, at the moment, in clinical studies that take into account clinical outcomes, the optimal dosage regimen of clopidogrel for patients with its reduced metabolism due to genetically determined low activity of the CYP2C19 isoenzyme has not been established.
Special groups of patients: Safety and effectiveness in children have not yet been established.
In elderly patients, no dosage adjustment is required.
Therapeutic experience with the drug is limited to use in patients with moderately severe liver diseases, who may be prone to the development of hemorrhagic diathesis. Therefore, caution should be used when using Coplavix® in such patients.
There is limited therapeutic experience with the drug in patients with mild to moderate renal failure. Therefore, caution should be used when using Coplavix® in such patients.
