Acetylsalicylic acid + Clopidogrel - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antiaggregants

Included in the formulation

Clopigrant® A

capsules inwards

Micro Labs Limited India

Coplavix®

pills inwards

Sanofi Pharma Bristol-Myers Squibb EsenSi France

АТХ:

B.01.A.C Inhibitors of platelet aggregation (excluding heparin)

Pharmacodynamics:

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. Its active metabolite irreversibly binds to the platelet receptors of adenosine diphosphate and selectively inhibits the binding of adenosine diphosphate to platelet adenosine diphosphate receptors and the subsequent activation of the GPIIb / IIIa complex by adenosine diphosphate, thereby inhibiting the adenosine diphosphate-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation caused by other agonists by blocking the activation of platelets by the released adenosine diphosphate. Due to the irreversibility of clopidogrel binding to platelet adenosine diphosphate receptors, platelets remain immune to adenosine diphosphate stimulation for the remainder of their life span (about 7-10 days), and the restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Due to the fact that the formation of the active metabolite occurs with the isoenzymes of the cytochrome P450 system, some of which may differ in polymorphism or inhibited by other drugs, not all patients may have sufficient inhibition of platelet aggregation.

With daily administration of clopidogrel at a dose of 75 mg, a significant suppression of platelet aggregation induced by adenosine diphosphate is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (when the equilibrium state is reached). In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time gradually return to the baseline level on average for 5 days.

Acetylsalicylic acid suppresses platelet aggregation due to irreversible inhibition of cyclooxygenase-1, resulting in a decrease in the formation of thromboxane A2, which is an inducer of platelet aggregation and vasoconstriction. This effect persists throughout the life span of platelets.

Acetylsalicylic acid does not change the inhibitory effect of clopidogrel on adenosine diphosphate-induced platelet aggregation, while clopidogrel enhances the effect of acetylsalicylic acid on collagen-induced platelet aggregation.

Both active substances in monotherapy and with simultaneous application are able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in the lesions of the cerebral, coronary or peripheral arteries.

The advantage of taking clopidogrel in combination with acetylsalicylic acid compared with the use of acetylsalicylic acid in combination with placebo was detected early and persisted throughout the study period (up to 5 years). Reduction of the risk of major vascular complications in the group of patients taking clopidogrel in combination with acetylsalicylic acid, was mainly due to a greater decrease in the incidence of strokes.

The risk of stroke of any severity with the use of clopidogrel in combination with acetylsalicylic acid was reduced, and there was a tendency to decrease the incidence of myocardial infarction in the group of patients taking clopidogrel in combination with acetylsalicylic acid, but there was no difference in the frequency of thromboembolism outside the vessels of the central nervous system or death from vascular causes. In addition, the use of clopidogrel in combination with acetylsalicylic acid reduced the total number of days of hospitalization for cardiovascular disease.

Pharmacokinetics:

Clopidogrel

Clopidogrel. With a single and course administration in a dose of 75 mg per day clopidogrel quickly absorbed in the intestine. Medium C_max unchanged clopidogrel in blood plasma (approximately 2.2-2.5 ng / ml after ingestion of a single dose of 75 mg) are achieved approximately 45 minutes after its single administration. According to the excretion of metabolites of clopidogrel with kidneys, its absorption is approximately 50%.

In vitro clopidogrel and its main circulating inactive non-active metabolite binds reversibly to blood plasma proteins (by 98 and 94%, respectively), and this linkage in vitro is unsaturated up to a concentration of 100 mg / l. Clopidogrel intensively metabolized in the liver. In vitro and in vivo clopidogrel metabolized along two metabolic pathways. The first way - metabolism is carried out with the help of enzymes (esterases),which leads to hydrolysis with the formation of an inactive metabolite - a derivative of carboxylic acid (accounting for 85% of circulating metabolites in the systemic circulation); the second way: metabolism with several isoenzymes of the cytochrome P450 system. At the same time, in the beginning clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite.

Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of an active metabolite of clopidogrel-thiol clopidogrel derivative. In vitro this pathway of metabolism occurs with the help of isoenzymes CYP2C19, CYP1A2, CYP3A4 and CYP2B6. The active thiol clopidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, inhibiting platelet aggregation.

Within 120 hours after ingestion by a human 14C-labeled clopidogrel about 50% of the radioactivity is excreted by the kidneys and approximately 46% through the intestine. After a single oral dose of 75 mg, the half-elimination (half-life) of clopidogrel is approximately 6 hours. After a single and course administration of clopidogrel, the half-elimination (half-life) of the inactive metabolite circulating in the blood is 8 hours.

Acetylsalicylic acid

After suction acetylsalicylic acid is hydrolyzed to form salicylic acid, C_maxwhich in the blood plasma is achieved in 1 hour after taking acetylsalicylic acid. Due to rapid hydrolysis, 1.5-3 hours after ingestion acetylsalicylic acid in blood plasma is practically not determined.

Acetylsalicylic acid weakly binds to blood plasma proteins and has a small V_d (10 L). Its metabolite - salicylic acid - binds well to blood plasma proteins, but its relationship to blood plasma proteins depends on its concentration in the blood plasma (nonlinear connection). At low concentrations (<100 μg / ml), about 90% of salicylic acid binds to plasma albumin. Salicylic acid is well distributed in tissues and body fluids, including the central nervous system, breast milk and fetal tissues.

Acetylsalicylic acid when taken in combination with clopidogrel quickly undergoes hydrolysis in the blood plasma to salicylic acid with a half-elimination (half-life) period of 0.3-0.4 hours for doses of acetylsalicylic acid 75-100 mg. Salicylic acid mainly subjected to conjugation in the liver with the formation of salicyluric acid, phenolic glucuronide and acyl glucuronide, as well as a large number of secondary metabolites.

Acetylsalicylic acid. When taking the drug salicylic acid has a half-elimination (half-life) period from the blood plasma, approximately 2 hours. The metabolism of salicylate is saturable, and the overall clearance decreases at higher serum concentrations due to the limited ability of the liver to form salicyluric acid and phenolic glucuronide. After taking toxic doses of acetylsalicylic acid (10-20 g), the plasma half-elimination period (half-life) can be increased to 20 hours. At high doses of acetylsalicylic acid, the elimination of salicylic acid corresponds to kinetics of zero order (ie, the elimination rate depends on the concentration in the blood plasma) with a half-elimination (half-life) period of 6 hours or more. Renal excretion of the unchanged active substance depends on the pH of the urine.With an increase in the hydrogen index of more than 6.5, the renal clearance of free salicylate increases from <5 to> 80%. After taking therapeutic doses in urine, approximately 10% of the dose in the form of salicylic acid is detected, 75% of the dose taken in the form of salicylicuric acid, 10% of the dose taken is in the form of phenolic glucuronides and 5% of the accepted dose in the form of acyl glucuronides.

Indications:

This combined preparation is indicated for use in patients who are already receiving concomitantly clopidogrel and acetylsalicylic acid.

Prevention of atherothrombotic complications (adult patients with acute coronary syndrome):

- without ST segment elevation (unstable angina or myocardial infarction without Q wave), including patients who underwent stenting in percutaneous coronary intervention;

- c elevation of the ST segment (acute myocardial infarction) with medical treatment and the possibility of carrying out thrombolysis.

Prevention of atherothrombotic and thromboembolic complications, including stroke, in atrial fibrillation (atrial fibrillation):

- adult patients with atrial fibrillation (atrial fibrillation),which have at least one risk factor for vascular complications, can not take indirect anticoagulants and have a low risk of bleeding.

ICD-10

IX.I20-I25.I20.0 Unstable angina

IX.I20-I25.I21 Acute myocardial infarction

IX.I20-I25.I24.9 Acute ischemic heart disease, unspecified

IX.I20-I25.I25.2 Postponed myocardial infarction

IX.I30-I52.I48 Atrial fibrillation and flutter

IX.I30-I52.I49.8 Other specified disorders of heart rhythm

IX.I60-I69.I64 Stroke not specified as a hemorrhage or infarction

IX.I70-I79.I74 Embolism and thrombosis of the arteries

Contraindications:

Severe hepatic failure (more than 9 on the Child-Pugh scale).

Renal failure of a serious degree (creatinine clearance <30 ml per minute) because of the content of the drug acetylsalicylic acid.

Acute bleeding, such as bleeding from a peptic ulcer or intracranial hemorrhage.

Bronchial asthma, induced by the intake of salicylates and other non-steroidal anti-inflammatory drugs, bronchial asthma, rhinitis and recurrent polyposis of the nose and paranasal sinuses, hypersensitivity to non-steroidal anti-inflammatory drugs (due to the content of the drug acetylsalicylic acid).

Mastocytosis, in which the use of acetylsalicylic acid can cause severe allergic reactions, including the development of shock with skin flushing, a decrease in blood pressure, tachycardia and vomiting (due to the content of the drug acetylsalicylic acid).

Rare hereditary conditions, such as galactose intolerance, lactose intolerance due to lactase deficiency, glucose-galactose malabsorption syndrome (due to the content of lactose in the formulation).

Pregnancy.

Lactation period (breastfeeding).

Children and adolescents under 18 years of age (safety and efficacy not established).

Hypersensitivity to any of the active or auxiliary substances of the drug.

Carefully:

With moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), which can predispose to bleeding (limited clinical experience of use).

With renal insufficiency of mild and moderate severity with the clearance of creatinine 30-60 ml per minute (limited clinical experience of use).

In trauma, surgical interventions, including invasive cardiac procedures or surgical interventions.

In diseases in which there is a predisposition to the development of bleeding, especially intraocular or gastrointestinal (with gastric ulcer and duodenal ulcer or gastrointestinal hemorrhage in anamnesis, with symptoms of violations from the upper parts of the gastrointestinal tract).

With a recent transient impairment of cerebral circulation or ischemic stroke.

With the simultaneous use of non-steroidal anti-inflammatory drugs, incl. and selective inhibitors of cyclooxygenase-2.

With the simultaneous use of warfarin, heparin, glycoprotein IIb / IIIa inhibitors, selective serotonin reuptake inhibitors and thrombolytic agents.

With bronchial asthma and allergies in history (increased risk of allergic reactions to acetylsalicylic acid).

With gout, hyperuricemia (acetylsalicylic acid, incl. and in low doses, increases the concentration of uric acid in the blood).

In patients with a genetically determined decrease in the activity of the isoenzyme CYP2C19.

With the simultaneous use of methotrexate in a dose of more than 20 mg per week.

With history of allergic and hematologic reactions to other thienopyridine (such as ticlopidine, prasugrel) because of the possibility of cross-allergic and hematological reactions.

Pregnancy and lactation:

Recommendations Food and Drug Administration (US Food and Drug Administration) - C.

As a precaution, the drug should not be taken during the first two trimesters of pregnancy, except when the woman's clinical condition requires treatment with clopidogrel in combination with acetylsalicylic acid. Due to the presence of acetylsalicylic acid in the composition, it is contraindicated in the third trimester of pregnancy.

Studies in animals showed no direct or indirect adverse effects in pregnancy, fetal development, childbirth, and postnatal development in clopidogrel. However, sufficient in volume and controlled studies in pregnant women were not conducted. Acetylsalicylic acid has been shown to have a teratogenic effect, although it has been established in clinical studies that,that doses of acetylsalicylic acid up to 100 mg per day, limitedly used in obstetrics and requiring specialized monitoring, proved to be safe.

Breastfeeding should be discontinued in case of drug treatment; determined that acetylsalicylic acid is excreted in breast milk, and studies in rats have shown that clopidogrel and / or its metabolites are also excreted into the milk of lactating rats. Penetrates or not clopidogrel in human breast milk is unknown.

Dosing and Administration:

Inside, regardless of food intake, one tablet containing clopidogrel - 97, 875 mg, aspirin - 100 mg, once a day.

Side effects:

Clopidogrel

On the part of the blood and lymphatic system: cases of severe bleeding, mainly hemorrhages in the subcutaneous tissue, in the muscles and joints, in the eye tissue (conjunctival, in the internal environment and the retina), bleeding from the respiratory tract, nosebleeds, hematuria, bleeding from operating wound; cases of bleeding with a fatal outcome (in particular, intracranial hemorrhages,bleeding from the gastrointestinal tract and retroperitoneal hemorrhage); agranulocytosis, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A.

On the part of the immune system: anaphylactoid reactions, serum sickness, cross-allergy with other thienopyridines (such as ticlopidine, prasugrel).

Disorders of the psyche: confusion, hallucinations.

From the side of the nervous system: changes in taste.

From the vessels: vasculitis, lowering blood pressure.

On the part of the respiratory system, chest and mediastinal organs: bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

From the gastrointestinal tract: colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.

From the liver and biliary tract: hepatitis (non-infectious nature), acute liver failure.

From the skin and subcutaneous tissues: maculopapular or erythematous skin rash, hives, itching, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis),drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome), eczema and lichen.

From the musculoskeletal and connective tissue: arthralgia, arthritis, myalgia.

From the side of the kidneys and urinary tract: glomerulopathy (including glomerulonephritis).

General disorders and disorders at the injection site: fever.

Laboratory and instrumental data: a deviation from the norm of biochemical indicators of the functional state of the liver, an increase in the concentration of creatinine in the blood.

Acetylsalicylic acid

From the immune system: anaphylactic shock, increased symptoms of food allergies.

From the nervous system: intracranial hemorrhage.

From the side of metabolism and nutrition: hypoglycemia, exacerbation of gout.

From the side of the hearing organ and labyrinthine disorders: loss of hearing, tinnitus.

On the part of the respiratory system, chest and mediastinum: noncardiogenic pulmonary edema in chronic drug administration associated with a hypersensitivity reaction (refers to acetylsalicylic acid).

From the gastrointestinal tract: esophagitis,ulceration, perforation of the esophagus, erosive gastritis, erosive duodenitis, ulcer or peptic ulcer perforation of the stomach and / or duodenum, symptoms of upper gastrointestinal tract damage, such as gastralgia. Ulcers of the small intestine (lean and ileum) and large intestine (colon and rectum), colitis and perforation of the intestine. These reactions may or may not be accompanied by bleeding and occur when any dose of acetylsalicylic acid is used, as well as in patients who have warning signs and anamnesis of serious gastrointestinal complications and those who do not.

On the part of the liver and bile ducts: increased activity of liver enzymes, a violation of liver function, mainly associated with cellulose liver damage.

On the part of the kidneys and urinary tract: acute renal failure (especially in patients with pre-existing renal failure, decompensation of heart failure, nephritic syndrome, or in patients taking diuretics simultaneously).

Overdose:

Clopidogrel

Symptoms: an overdose of clopidogrel may lead to an increase in bleeding time with subsequent complications in the form of development of bleeding.

Treatment: when bleeding occurs, appropriate treatment is required. The antidote of clopidogrel is not established. If rapid correction of prolonged bleeding time is necessary, transfusion of platelet mass is recommended.

Acetylsalicylic acid

Symptoms: a moderate degree of overdose - dizziness, ringing in the ears, headaches, confusion and symptoms of the gastrointestinal tract (nausea, vomiting and pain in the stomach).

When there are signs of severe intoxication, severe acid-base disturbances 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, metabolic acidosis develops in the blood. In addition, the following symptoms appear: hyperthermia and profuse sweating, leading to dehydration, motor anxiety, convulsions, hallucinations and the development of hypoglycemia.Oppression of the nervous system can lead to the development of coma, collapse and stopping breathing.

The lethal dose of acetylsalicylic acid is 25-30 g. The plasma concentration of salicylate exceeds 300 mg / l (1.67 mmol / l) confirms the presence of intoxication.

Treatment: with acute and chronic overdose of acetylsalicylic acid, non-cardiogenic pulmonary edema can develop. When identifying the symptoms of severe overdose, hospitalization is required. With moderate intoxication, one can try to induce vomiting, in case of failure, gastric lavage is indicated. After this, take in (if the patient can swallow) or enter the stomach through a probe Activated carbon (adsorbent) and salt laxative. For the purpose of forced urine alkalinization, intravenous drip injection of 250 mmol of sodium bicarbonate for 3 hours under the control of the hydrogen index of urine and acid-base state was shown to accelerate the elimination of salicylates. The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is used.

Interaction:

Thrombolytics

The safety of the joint use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic drugs and heparin was analyzed in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents and heparin with acetylsalicylic acid. Due to the lack of clinical data on the joint use of the drug and thrombolytic agents in their simultaneous use, exercise caution.

Ilb / IIIa glycoprotein inhibitors

The use of Ilb / IIIa glycoprotein inhibitors together with the drug requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions).

Heparin

According to a clinical study conducted with the participation of healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation.Between the drug and heparin pharmacodynamic interaction is possible, which may increase the risk of bleeding, and therefore the joint use of these drugs requires caution.

Indirect anticoagulants

The simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding, and therefore the use of this combination is not recommended. Clopidogrel at a dose of 75 mg does not affect the pharmacokinetics of warfarin and does not change the values of MHO in patients taking long-term warfarin. However, simultaneous use of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

Non-steroidal anti-inflammatory drugs

In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent blood loss through the gastrointestinal tract. Therefore, the use of non-steroidal anti-inflammatory drugs, incl. inhibitors of cyclooxygenase-2, in combination with the drug is not recommended. Experimental evidence suggests that ibuprofen (taken at a dose of 400 mg 8 hours before or 30 minutes after the immediate administration of 81 mg immediate-release acetylsalicylic acid) may inhibit the effect of low doses of acetylsalicylic acid on platelet aggregation. However, with irregular intake of ibuprofen, no clinically significant effects of it on the antiplatelet effect of acetylsalicylic acid are expected.

Selective serotonin reuptake inhibitors

Since selective serotonin reuptake inhibitors disrupt platelet activation and increase the risk of bleeding, simultaneous use of selective serotonin reuptake inhibitors with clopidogrel should be carried out with caution.

Strong and moderate inhibitors of the isoenzyme CYP2C9

Because clopidogrel is metabolized to its active metabolite in part by the CYP2C19 isoenzyme, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown.As a precaution, simultaneous use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided. Strong and moderate inhibitors of the isoenzyme CYP2C9 are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

The simultaneous use of proton pump inhibitors with clopidogrel, which are strong or moderate inhibitors of the CYP2C19 isoenzyme (eg, omeprazole, esomeprazole), is not recommended. If the patient still needs the use of proton pump inhibitors while taking the drug, then a proton pump inhibitor with a slight effect on CYP2C19 activity should be used, such as pantoprazole or lansoprazole.

It was reported on the interaction of acetylsalicylic acid with the following drugs:

- uricosuric medicines (drugs that promote the excretion of uric acid) (benzbromarone, probenecid, sulfinpyrazone) - acetylsalicylic acid can suppress their uricosuric effect due to competition with uric acid at the elimination level;

- methotrexate, taken in doses of more than 20 mg per week, should be used with caution when combined with the drug (due to the presence in the composition of acetylsalicylic acid), t. acetylsalicylic acid can reduce the renal clearance of methotrexate, which, in turn, can increase its myelotoxic effect;

- inhibitors of angiotensin-converting enzyme, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta-adrenoblockers, diuretics and oral hypoglycemic agents - the interaction of these drugs with acetylsalicylic acid, used in high (anti-inflammatory) doses.

Other interactions with clopidogrel and acetylsalicylic acid

ACE inhibitors, diuretics, beta adrenoblockers, slow calcium channel blockers, lipid-lowering agents, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptics, hormone replacement therapy and GPIIb / IIIa receptors blockers in clinicalstudies on the use of clopidogrel in combination with acetylsalicylic acid in maintenance doses ≤ 325 mg, conducted with the participation of more than 30 000 patients, there were no clinically significant adverse interactions.

Special instructions:

In connection with the risk of bleeding and blood disorders in the event of clinical symptoms appearing during treatment, suspicious for bleeding, it is urgent to make a general clinical blood test, determine activated partial thromboplastin time, platelet count, platelet function and perform other necessary research.

Due to the presence of two antiplatelet agents in the preparation, it should be used with caution in patients at increased risk of bleeding due to trauma, surgical interventions or other pathological conditions, as well as in patients receiving non-steroidal anti-inflammatory drugs (including inhibitors cyclooxygenase-2), heparin, glycoprotein IIb / IIIa inhibitors and thrombolytics.It is necessary to carefully monitor patients for the exclusion of signs of bleeding, incl. and latent, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgery. Simultaneous use of the drug with warfarin is not recommended, t. this can increase the intensity of bleeding. If the patient is under planned surgical intervention and there is no need for an antithrombotic effect, then 5-7 days before surgery clopidogrel should be canceled. The drug increases the time of bleeding and should be used with caution in patients with diseases and conditions predisposing to the development of bleeding (especially bleeding from the gastrointestinal tract and intraocular hemorrhages).

Patients should be warned that when taking the drug to stop bleeding, they may need more time than usual and that if they have any unusual (localized or prolonged) bleeding, they should inform their doctor about it.

Before any future surgical intervention and before proceeding to receive any new drug, patients should inform the doctor (including the dentist) about the drug treatment.

It has been shown that in patients with recent ischemic transient cerebral infarction or stroke having an increased risk of developing ischemic complications, the combination of acetylsalicylic acid and clopidogrel increases the possibility of developing large bleeding. Therefore, the use of the drug in such patients should be carried out with caution and only in the case of clinical evidence of the benefits of its use.

Very rarely, after the use of clopidogrel (sometimes even a short one), there have been cases of TTP development, which is characterized by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by neurological disorders, renal dysfunction and fever. TTP is potentially life-threatening condition requiring immediate treatment, including plasmapheresis (exchange blood transfusion).

The cases of development of acquired hemophilia with the use of clopidogrel were reported. With confirmed isolated magnification activated partial thromboplastin time, accompanied or not accompanied by the development of bleeding, should consider the possibility of developing acquired hemophilia. Patients with a confirmed diagnosis of acquired hemophilia should be observed and treated by specialists in this disease and stop taking clopidogrel.

Patients should be interviewed for allergies to thienopyridine (such as ticlopidine, prasugrel) in the anamnesis, tk. reported the presence of a cross-allergy between thienopyridine and clopidogrel.

In patients with low metabolic activity of the CYP2C19 isoenzyme, when clopidogrel is used in the recommended doses, less active clopidogrel metabolite is formed and its effect on platelet function is reduced. Therefore, such patients with acute coronary syndrome or patients undergoing percutaneous coronary intervention and taking clopidogrel, may have a higher incidence of cardiovascular events than patients with normal CYP2C19 isoenzyme activity.

The drug should be used with caution in patients with peptic ulcer of the stomach and duodenum or gastrointestinal hemorrhages in the history or patients with even minor symptoms from the upper parts of the gastrointestinal tract, which may be manifestations of ulcerative lesions of the stomach, which can lead to gastric bleeding.

When treating the drug at any time, there may be symptoms from the upper parts of the gastrointestinal tract, such as gastralgia, heartburn, nausea, vomiting and gastrointestinal bleeding. Despite the fact that in the treatment of the drug, minor side effects from the gastrointestinal tract, such as dyspeptic disorders, are often found, the treating doctor always in these cases should exclude ulceration of the mucous membrane of the gastrointestinal tract and bleeding, even in the absence of an anamnesis of pathology with side of the gastrointestinal tract.

Patients should be informed of the symptoms of unwanted reactions from the gastrointestinal tract.

Perhaps the relationship between acetylsalicylic acid and the emergence of a life-threatening Ray syndrome(encephalopathy and acute fatty liver dystrophy with rapid development of liver failure), usually observed in the prodromal period of infections in children.

Due to the presence of acetylsalicylic acid in the formulationAt the time of taking the drug, patients should be warned about the increased risk of bleeding during chronic use of large amounts of alcohol (ethanol).

Instructions

Acetylsalicylic acid + Clopidogrel (Acidum acetylsalicylicum + Clopidogrelum)