Clopidogrel, 75 mg 28 pcs

Pharmacotherapeutic group

Antiplatelet drug

ATC code

B01AC04

Pharmacodynamics:

Clopidogrel is a prodrug one of whose active metabolites is a platelet aggregation inhibitor.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor P2Y12 and the subsequent ADP-dependent activation of glycoprotein complex IIb/IIIa, thereby suppressing platelet aggregation. Reduces platelet aggregation caused by other agonists (other than ADP) without affecting phosphodiesterase activity.

Due to the irreversibility of the binding, the exposed platelets are damaged for the rest of their life (approximately 7-10 days) and the restoration of normal platelet function occurs at a rate corresponding to the platelet cycle. Platelet aggregation caused by agonists other than ADP is also inhibited by blocking the enhanced platelet activation that occurs under the influence of the released ADP.

As the active metabolite of clopidogrel is formed with the CYP2C19 isoenzyme, some of which are polymorphic or inhibited by other compound medications, platelet suppression is not sufficient in all patients.

When clopidogrel is taken daily at a dose of 75 mg from the first day there is a significant suppression of ADP-induced platelet aggregation that gradually increases over 3-7 days and then an equilibrium state is reached (reaches a constant level). In the equilibrium state platelet aggregation is suppressed by an average of 40-60%. After stopping clopidogrel administration, platelet aggregation and bleeding time return to the initial level on average within 5 days.

Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, particularly in lesions of the cerebral coronary or peripheral arteries.

In patients with recent myocardial infarction ischemic stroke and/or diagnosed peripheral arterial occlusive disease, administration of clopidogrel at a dose of 75 mg daily significantly reduces the risk of vascular complications (myocardial infarction stroke cardiovascular mortality).

In acute coronary syndrome without ST-segment elevation on ECG (unstable angina pectoris myocardialis infarction) administration of clopidogrel (loading dose of 300 mg once and then 75 mg/day) in combination with acetylsalicylic acid 75-325 mg/day and other standard therapy significantly and independently of other therapy reduces risk of vascular complications.

. In ST-segment elevation myocardial infarction on ECG, administration of clopidogrel (loading dose of 300 mg once during the first 12 hours of illness then 75 mg/day) in combination with acetylsalicylic acid (loading dose of 150-325 mg then 75-162 mg/day) fibrinolytic therapy and, when indicated, heparin reduces the incidence of infarct-related coronary artery occlusion (according to coronary angiography at discharge from hospital) of repeated myocardial infarction and fatal outcomes.

In patients for whom coronary angiography was not performed at discharge, clopidogrel administration according to this regimen reduces the incidence of fatal outcomes and recurrent myocardial infarction until day 8 of illness or until discharge from the hospital.

In general, in myocardial infarction, regardless of ECG changes (ST-segment elevation ST depression or first-ever complete left bundle branch block), clopidogrel at a dose of 75 mg/day in combination with acetylsalicylic acid 162 mg daily leads to a decrease in overall mortality and cumulative incidence of recurrent myocardial infarction ischemic stroke and fatal outcomes.

. Results from a clinical trial showed that in 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 use of acetylsalicylic acid alone) reduced the cumulative incidence of myocardial infarction systemic thromboembolism outside the central nervous system or vascular death by a greater reduction in stroke risk.

Pharmacokinetics:

Intake and distribution: Clopidogrel at a regular oral dose of 75 mg/day is rapidly absorbed.

The maximum concentration (Cmax) of unchanged clopidogrel after a single oral dose of 75 mg is approximately 22-25 ng/mL; the time to maximum concentration (TCmax) of clopidogrel is approximately 45 minutes. Based on the data on excretion of clopidogrel metabolite by the kidneys, the absorption of clopidogrel is at least 50%.

In vitro clopidogrel and its main circulating inactive metabolite are reversibly bound to plasma proteins (98% and 94%, respectively) this bond is unsaturated in a wide range of concentrations.

Metabolism: being a prodrug clopidogrel is extensively metabolized in the liver. In vivo and in vitro clopidogrel is metabolized in two ways: the first – through enzymes and subsequent hydrolysis with the formation of inactive carboxylic acid derivative (85% of circulating metabolites) the second way – through cytochrome P450 isoenzyme system. Initially, clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel – thiol derivative of clopidogrel. In vitro, this metabolic pathway occurs via the CYP3A4 CYP2C19 CYP1A2 and CYP2B6 isoenzymes.

The active thiol metabolite can only be isolated in in vitro studies; under in vivo conditions, it binds rapidly and irreversibly to the P2Y12 receptor of platelets, thereby inhibiting platelet aggregation.

The cmax of active clopidogrel metabolite after administration of its loading dose of 300 mg is 2 times higher than cmax after 4 days of maintenance dose of clopidogrel 75 mg. Moreover, when clopidogrel 300 mg is taken, the Cmax is reached within approximately 30-60 minutes.

After repeated oral administration of clopidogrel at a dose of 75 mg per day, the Cmax of the main inactive metabolite is approximately 3 mg/L. The Cmax of the inactive metabolite is reached after 1 hour.

Elimation: within 120 hours after human oral administration of 14C-labeled clopidogrel about 50% of the dose is excreted by the kidneys and approximately 46% – through the intestine.

After a single oral dose of 75 mg, the elimination half-life (T1/2) is approximately 6 hours. After a single dose and repeated doses, the T1/2 of its main metabolite is 8 hours.

Pharmacogenetics

The active metabolite as well as the intermediate metabolite 2-oxo-clopidogrel are formed using CYP2C19 isoenzyme. Pharmacokinetics and anti-aggregant effect of the active metabolite clopidogrel in platelet aggregation studiesin vivo vary depending on the genotype of CYP2C19 isoenzyme. Allele of CYP2C19*1 gene corresponds to a fully functional metabolism while alleles of CYP2C19*2 and CYP2C19*3 genes cause decreased metabolism in the majority of representatives of Caucasoid (85%) and Mongoloid race (99%). Other alleles associated with absence or reduced metabolism are less common and include, but are not limited to, CYP2C19*4 *5 *6 *7 and *8 alleles. Patients with low CYP2C19 isoenzyme activity should have the two loss-of-function gene alleles listed above. The published frequencies of phenotypes of patients with low CYP2C19 isoenzyme activity are 2% in Caucasoid races, 4% in non-Hispanic races, and 14% in Chinese.

Tests are available to determine a patient’s CYP2C19 genotype these tests can be used as an adjunctive tool in determining treatment tactics.

In a cross-sectional study involving 40 healthy volunteers (10 volunteers each with very fast extensive intermediate and delayed metabolism), the pharmacokinetics and antiaggregant effects of clopidogrel were studied when administered according to two regimens: 1) 300 mg once followed by a dose of 75 mg per day for 5 days and 2) 600 mg once followed by a dose of 150 mg per day for 5 days (until equilibrium was reached). No significant differences in active metabolite exposure and mean platelet aggregation inhibition (IAT) were detected between the groups of volunteers with very rapid extensive and intermediate metabolism. Volunteers with reduced metabolic rate had 63-71% lower exposure to active metabolite compared to volunteers extensively metabolizing clopidogrel.

When the drug was administered at 300 mg once / 75 mg daily, the platelet response (when stimulated by 5 μm ADP) was reduced in volunteers with delayed clopidogrel metabolism: IAT was 24% (after 24 hours) and 37% (Day 5). In comparison, volunteers with extensive metabolism had an IAT of 39% (after 24 hours) and 60% (Day 5).

When clopidogrel was administered at 600 mg once/150 mg daily in volunteers with reduced clopidogrel metabolic rate, the effects of the drug were more pronounced than when the drug was administered at 300 mg once/75 mg daily doses: IAT was 32% (after 24 hours) and 61% (Day 5), which was comparable to IAT in groups of volunteers with other clopidogrel metabolic rates receiving the drug at the 300 mg/75 mg regimen. A suitable dosing regimen for a population of patients with reduced clopidogrel metabolic rate has not been established in clinical trials.

A similar meta-analysis of six studies that included data from 335 healthy volunteers who received clopidogrel and were at equilibrium concentration reached showed that intermediate metabolizers had a 28% reduction in exposure to the active metabolite and weak metabolizers had a 72% reduction. Compared to intensive metabolizers, inhibition of platelet aggregation was reduced by 59% and 214% in intermediate and weak metabolizers, respectively.

The effect of SUR2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective randomized controlled trials. Existing data from retrospective analyses of clinical trials for which patient genotyping results are available do not have sufficient power to assess differences in clinical outcomes in weak clopidogrel metabolizers compared with intensive and intermediate metabolizers.

Particular patient groups

Elderly persons

There were no differences in platelet aggregation and bleeding time in elderly volunteers (over 75 years) when compared with younger volunteers. No dose adjustment of clopidogrel in the elderly is required.

Age under 18 years

The pharmacokinetics of clopidogrel in children has not been studied.

Kidney function impairment

. After repeated administration of clopidogrel at a dose of 75 mg/day in patients with severe chronic renal failure (creatinine clearance (CK) 5-15 ml/min), inhibition of ADP-induced platelet aggregation was 25% lower than in healthy volunteers, but no prolongation of bleeding time was observed.

Hepatic impairment

After administration of clopidogrel at a dose of 75 mg daily for 10 days in patients with severe liver injury, inhibition of ADP-induced platelet aggregation did not differ from that in healthy volunteers. The mean bleeding time in patients with severe liver injury and in healthy volunteers was comparable.

Raciality

The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate or reduced metabolism differs among racial groups. The available literature is insufficient to evaluate the value of CYP2C19 isoenzyme genotyping for predicting ischemic complications.

Indications

Prevention of atherothrombotic disorders in adult patients:

– after myocardial infarction (from several days to less than 35 days) ischemic stroke (from 7 days to less than 6 months) or with diagnosed peripheral artery occlusive disease;

– with acute coronary syndrome:

Active ingredient

Composition

Per tablet:

The active ingredient: clopidogrel hydrosulfate – 97.88 mg, in terms of clopidogrel – 75.00 mg.

Excipients (core): lactose – 70.00 mg, microcrystalline cellulose – 17.00 mg, croscarmellose sodium – 5.52 mg, colloidal silicon dioxide – 1.80 mg, magnesium stearate – 1.80 mg.

Excipients (coating): hypromellose – 3.30 mg, macrogol-4000 – 0.90 mg, iron oxide red dye – 0.06 mg, titanium dioxide – 1.74 mg.

How to take, the dosage

Clopidogrel should be taken orally regardless of the time of meals.

Adults and elderly patients with normal CYP2C19 isoenzyme activity:

Myocardial infarction ischemic stroke and diagnosed peripheral artery occlusive disease

Clopidogrel is taken 75 mg once daily.

Acute coronary syndrome without ST-segment elevation (unstable angina pectoris without Q-wave)

The treatment with Clopidogrel is started with a single loading dose of 300 mg and then 75 mg/day (in combination with acetylsalicylic acid 75-325 mg/day). Since the use of higher doses of acetylsalicylic acid is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid for this indication should not exceed 100 mg. The maximum favorable effect develops after 3 months. Results of clinical studies confirm the advisability of taking the drug up to 12 months after the development of acute coronary syndrome without ST-segment elevation.

Acute coronary syndrome with ST-segment elevation (acute myocardial infarction with ST-segment elevation)

Clopidogrel should be taken once daily at a dose of 75 mg with an initial single loading dose of 300 mg in combination with acetylsalicylic acid in combination with thrombolytics or without combination with thrombolytics.

In patients older than 75 years, 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 4 weeks.

The efficacy of combination therapy with Clopidogrel and acetylsalicylic acid for this indication beyond 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once daily in a dose of 75 mg. In combination with Clopidogrel, acetylsalicylic acid (75-100 mg/day) should be started and then continued.

Missing another dose

Patients with genetically determined reduced CYP2C19 isoenzyme activity

Low CYP2C19 isoenzyme activity is associated with decreased antiaggregant effect of Clopidogrel.

The higher dose regimen (600 mg-load dose then 150 mg once daily) in patients with low CYP2C19 isoenzyme activity increases the antiplatelet effect of clopidogrel.

The optimal dosing regimen for clopidogrel in patients with impaired metabolism due to genetically determined low CYP2C19 isoenzyme activity has not been established in clinical studies considering clinical outcomes.

Special patient groups

Elderly patients

There were no differences in platelet aggregation and bleeding time in elderly volunteers (over 75 years) when compared to younger volunteers. No dose adjustment of clopidogrel is required in elderly subjects.

Patients with impaired renal function

. After repeated administration of clopidogrel at dose 75 mg/day in patients with severe renal impairment (creatinine clearance (CK) of 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation (25%) was lower compared with that in healthy volunteers, but prolongation of bleeding time was similar with healthy volunteers who received clopidogrel at dose 75 mg/day.

Patients with impaired hepatic function

The experience with clopidogrel in patients with hepatic impairment is limited. After daily use of clopidogrel at a daily dose of 75 mg for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was comparable in both groups.

Ethnicity

The prevalence of CYP2C19 isoenzyme gene alleles responsible for intermediate and reduced metabolism of clopidogrel to its active metabolite varies among ethnic groups.

Limited data are available only for mongoloid races to assess the impact of CYP2C19 isoenzyme genotype on clinical outcomes (see section Pharmacogenetics).

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 controlled clinical trial CAPRIE (clopidogrel versus acetylsalicylic acid in patients at risk for ischemic complications), the rates of clinical outcomes of adverse events and clinical and laboratory abnormalities were similar in men and women.

Interaction

The simultaneous use of clopidogrel and oral anticoagulants may increase the intensity of bleeding in connection with this combination is not recommended. Clopidogrel at a dose of 75 mg per day does not affect warfarin pharmacokinetics and does not change the International Normalized Ratio (INR) in patients taking warfarin for a long time. However, concomitant administration of warfarin with clopidogrel may increase the risk of bleeding due to the independent effect of these drugs on hemostasis.

The administration of glycoprotein IIbIIIa receptor inhibitors together with clopidogrel requires caution especially in patients with increased risk of bleeding (trauma and surgery or other pathological conditions).

Acetylsalicylic acid (ASA) does not affect clopidogrel-induced suppression of platelet aggregation induced by ADP, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation. Nevertheless, concomitant administration of 500 mg of ASA twice daily had no significant effect on the increase in bleeding time caused by clopidogrel administration. Pharmacodynamic interaction is possible between clopidogrel and ASA, which leads to an increased risk of bleeding. Therefore, caution should be exercised when using them concomitantly, although in clinical trials patients received combined therapy with clopidogrel and ASA for one year.

When concomitant use with heparin according to data from a clinical study conducted in healthy volunteers when taking clopidogrel no change in heparin dose was required and the anticoagulant effect of heparin was not altered.

The co-administration of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. There is possible pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding; therefore, the use of this combination requires caution.

The safety of co-administration of clopidogrel with fibrin-specific or nonspecific thrombolytics and heparin has been studied in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytics and heparin were used together with ASA.

The administration of NSAIDs (including COX-2 inhibitors) together with clopidogrel requires caution. In a clinical study in healthy volunteers, concomitant use of clopidogrel and naproxen increased latent gastrointestinal bleeding. However, due to a lack of studies on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when clopidogrel is taken together with other NSAIDs.

Selective serotonin reuptake inhibitors (SSRIs)

Because SSRIs disrupt platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be performed with caution.

As clopidogrel is metabolized to its active metabolite partially with participation of CYP2C19 isoenzyme, use of drugs that inhibit the activity of this enzyme may lead to decreased levels of the active metabolite. The clinical significance of this interaction is unknown. As a precautionary measure, it is recommended to avoid concomitant administration of clopidogrel with drugs that inhibit CYP2C19 isoenzyme (omeprazole esomeprazole fluvoxamine fluoxetine moclobemide voriconazole fluconazole ticlopidine ciprofloxacin cimetidine carbamazepine oxcarbazepine chloramphenicol). If it is necessary to prescribe proton pump inhibitors simultaneously with clopidogrel, preparations with the least CYP2C19 isoenzyme inhibition (for example, pantoprazole or lansoprazole) should be used.

There is no evidence that other drugs that reduce gastric acidity, such as H2-blockers (except for cimetidine which is a CYP2C19 inhibitor) or antacids, have an effect on the antiaggregant activity of clopidogrel.

A number of clinical studies have been performed with clopidogrel and other concomitantly administered drugs to investigate possible pharmacodynamic and pharmacokinetic interactions which showed that:

Special Instructions

Patients with a history of hypersensitivity to other thienopyridine derivatives (ticlopidine prasugrel) should be specified, since cases of cross-allergic reactions between thienopyridines have been described. Patients with previous hypersensitivity to other thienopyridines require close monitoring during the whole period of therapy to detect signs of hypersensitivity to clopidogrel.

Hemostatic parameters (activated partial thromboplastin time (APT) platelet count and platelet function tests) should be monitored during treatment; liver function tests should be performed regularly.

. Clopidogrel should be used with caution in patients at risk of significant bleeding during trauma surgery in patients with bleeding-prone injuries (especially gastrointestinal and intraocular) and in patients receiving acetylsalicylic acid non-steroidal anti-inflammatory drugs (including COX-2 inhibitors) heparin or glycoprotein IIb/IIIa inhibitors SSRIs and thrombolytics. Patients should be closely monitored for any signs of bleeding, including hidden bleeding especially during the first weeks of use and/or after invasive cardiac procedures or surgery.

The concomitant use of clopidogrel and warfarin should be used with extreme caution because it may increase bleeding.

In case of surgical interventions if antiaggregant effect is undesirable, the course of treatment should be discontinued 7 days before surgery.

Patients should be warned that since it takes longer to stop bleeding when using clopidogrel (with or without acetylsalicylic acid), they should inform their physician about each bleeding event. Patients should also inform their doctor about taking the drug if they are going to have surgical interventions.

After taking clopidogrel, thrombotic thrombocytopenic purpura (TTP) has been found very rarely sometimes after short-term use. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia combined with neurologic signs of impaired renal function or fever. TTP is a potentially fatal condition requiring immediate treatment, including the use of plasmapheresis.

The administration of clopidogrel should not be recommended in the acute period (less than 7 days) of ischemic stroke due to lack of data on efficacy and safety of its use.

In patients with recent ischemic stroke or transient ischemic attack and a high risk of recurrent atherothrombotic events, combined therapy with clopidogrel and acetylsalicylic acid has not demonstrated greater efficacy compared with clopidogrel monotherapy but may increase the risk of major bleeding.

Acquired hemophilia

Cases of acquired hemophilia have been reported while taking clopidogrel. If there is a confirmed isolated increase in activated partial thromboplastin time (APT) with or without bleeding, the possibility of acquired hemophilia should be suspected. Patients with a confirmed diagnosis of acquired hemophilia should be monitored and treated by specialists in this disease. Clopidogrel should be discontinued.

Cross-allergic and/or hematological reactions between thienopyridines

The presence of allergic and/or hematological reactions to other thienopyridine derivatives (such as ticlopidine and prasugrel) in patients’ history should be specified, since there are described cases of cross-allergic and/or hematological reactions between thienopyridines. Thienopyridines can cause moderate to severe allergic reactions (angioedema rash) or hematological reactions (thrombocytopenia neutropenia).

Patients who have previously had allergic and/or hematological reactions to one of the drugs – thienopyridine derivatives may have an increased risk of developing such reactions when taking another drug from the thienopyridine group. Such patients require close monitoring during the entire period of therapy for signs of hypersensitivity to clopidogrel.

The experience of using clopidogrel in patients with impaired renal function is limited; therefore, clopidogrel should be prescribed with caution in these patients.

In severe hepatic impairment, be aware of the risk of hemorrhagic diathesis; experience with the drug in patients with moderate hepatic impairment is limited, so clopidogrel should be prescribed with caution in these patients.

As the drug contains lactose as an excipient, Clopidogrel should not be used in patients with rare hereditary lactose intolerance with lactase deficiency and glucose-galactose malabsorption syndrome (see section “Contraindications”).

Clopidogrel may cause nervous system side effects (headache dizziness systemic dizziness confusion hallucinations) which may affect the ability to drive vehicles and engage in other potentially dangerous activities that require increased concentration and rapid psychomotor reactions. Nevertheless, in most cases clopidogrel has no significant effect on the ability to drive vehicles and operate mechanisms.

Contraindications

– Hypersensitivity to clopidogrel or any of the excipients of the drug.

– Severe hepatic insufficiency.

– Active bleeding (including bleeding from a peptic ulcer or intracranial hemorrhage).

– Pregnancy and breastfeeding.

– Age under 18 years (effectiveness and safety of use have not been established).

– Rare hereditary lactose intolerance lactase deficiency and glucose-galactose malabsorption syndrome (due to the presence of lactose in the drug).

– Moderate hepatic insufficiency (7-9 points on the Child-Pugh scale) (in which there may be a predisposition to bleeding) – experience with clinical use is limited;

– mild to moderate chronic renal failure (CKD) (creatinine clearance 60-30 ml/min) – limited clinical experience;

– conditions with a predisposition to bleeding (especially gastrointestinal or intraocular) including.ч.

– concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase-2 inhibitors (COX-2 inhibitors);

– concomitant use of oral anticoagulants heparin glycoprotein IIb/IIIa receptor inhibitors selective serotonin reuptake inhibitors (SSRIs) and thrombolytics;

– hereditary reduced CYP2C19 isoenzyme activity (because less of the active metabolite clopidogrel and less of its antiplatelet effect are formed at recommended doses in these patients, and therefore a higher incidence of cardiovascular complications may occur with commonly recommended doses of clopidogrel for acute coronary syndrome or percutaneous coronary intervention than in patients with normal CYP2C19 activity);

If there is a history of hypersensitivity reactions to other thienopyridines (such as ticlopidine prasugrel) due to the possibility of cross-over hypersensitivity reactions (see section “Specific information”). section “Special Indications”).

Side effects

The incidence of adverse reactions is defined as follows: very common – more than 1/10 common – more than 1/100 and less than 1/10 infrequent – more than 1/1000 and less than 1/100 rare – more than 1/10000 and less than 1/1000 very rare – less than 1/10000 including individual reports unknown frequency (the incidence of adverse reactions cannot be determined from available data). Within each system-organ frequency class, adverse effects are presented in decreasing order of severity.

Hematopoietic organs: infrequent – thrombocytopenia leukopenia eosinophilia; rare – neutropenia incl. severe neutropenia; very rare – thrombotic thrombocytopenic purpura aplastic anemia pancytopenia agranulocytosis severe thrombocytopenia granulocytopenia anemia; frequency unknown – acquired hemophilia A.

Immune system disorders:unknown frequency – anaphylactoid reactions serum sickness cross-allergic and hematological reactions with other thienopyridines (such as ticlopidine prasugrel)

Blood clotting system disorders: frequent – hematoma nasal bleeding gastrointestinal bleeding bruising bleeding at the puncture site; sometimes – intracranial hemorrhage bleeding in the eye (conjunctival ocular retinal) prolongation of bleeding time; rare – retroperitoneal bleeding; very rare – severe bleeding from the operating wound bleeding from the respiratory system (hemoptysis pulmonary bleeding) hemarthrosis.

Nervous system disorders: infrequent – intracranial hemorrhage including fatal headache paresthesia dizziness; very rare – disorders of sense of taste.

Psychiatric disorders: very rare – confusion, hallucinations.

An organ of vision: infrequent – ocular hemorrhages (conjunctival in the tissue and retina).

Hearing organ: rarely – vertigo.

The cardiovascular system: often – hematoma; very rare – severe bleeding from the operating wound vasculitis decreased blood pressure.

Respiratory system: frequent – nasal bleeding; very rare – bronchospasm interstitial pneumonitis pulmonary bleeding hemoptysis; eosinophilic pneumonia.

The digestive system: very often – gastrointestinal bleeding diarrhea abdominal pain dyspepsia; infrequent – gastric and duodenal ulcer gastritis vomiting nausea constipation flatulence; rare – retroperitoneal bleeding; very rare – gastrointestinal bleeding and retroperitoneal bleeding with lethal outcome pancreatitis (including ulcerative colitis).including ulcerative colitis or lymphocytic colitis) stomatitis.

Hepatic and biliary tract disorders: very rarely hepatitis (non-infectious) acute liver failure hepatitis abnormal liver function tests.

Skin disorders:frequent – subcutaneous hemorrhages; infrequent – skin rash skin itching purpura; very rare/unknown frequency – bullous dermatitis (toxic epidermal necrolysis Stevens-Johnson syndrome erythema multiforme) angioedema drug hypersensitivity syndrome drug rash with eosinophilia and systemic manifestations (DRESS syndrome) erythematous or exfoliative rash urticaria eczema red lichen planus/p>

Musculoskeletal system disorders:very rare – skeletal-muscular hemorrhages (hemarthrosis) arthritis arthralgia (joint pain) myalgia.

Urogenital system: infrequent – hematuria; very rare – glomerulopathy (including glomerulonephritis) hypercreatininemia.

Laboratory measures: infrequent – prolongation of bleeding time decrease of platelet neutrophil count in peripheral blood disorders of liver function tests increase of creatinine concentration in plasma.

General disorders and disorders at the site of administration: often – bleeding from the site of vascular puncture very rarely – increase in body temperature.

Overdose

Symptoms: clopidogrel overdose may lead to prolonged bleeding time and subsequent hemorrhagic complications in the form of bleeding development.

Treatment: If bleeding is detected, appropriate treatment should be given.

The antidote for clopidogrel has not been established.

If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.

Pregnancy use

The use of the drug Clopidogrel is not recommended in pregnancy due to the lack of clinical data on its use in pregnant women, although animal studies have shown no direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development.

In studies in rats, clopidogrel and/or its metabolites have been shown to be excreted with the milk of lactating rats. There are no data on excretion of clopidogrel into breast milk. During the therapy with Clopidogrel it is recommended to stop breastfeeding.

Fertility

In animal studies no adverse effects of clopidogrel on fertility have been found.

Similarities