Clopidogrel - instructions for use, dose, side effects, contraindications

Inhibitor of platelet aggregation. Clopidogrel is a prodrug, one of its metabolites is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to P2Y₁₂platelet receptor and subsequent ADP-mediated activation of the glycoprotein complex IIb/IIIa, leading to suppression of platelet aggregation. Due to the irreversibility of binding, platelets remain immune to stimulation of ADP for the rest of their life span (about 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet renewal.

Aggregation of platelets caused by agonists other than ADP is also inhibited by blockade of enhanced platelet activation by the released ADP.

Due to the fact that the formation of an active metabolite occurs with the participation of P450 isoenzymes, some of which are polymorphic or inhibited by other drugs, adequate platelet suppression is not possible in all patients.

With a daily intake of clopidogrel at a dose of 75 mg, a significant inhibition of ADP-induced platelet aggregation is noted from the first day of administration, which gradually increases for 3-7 days and then reaches a constant level (upon reaching the equilibrium state). 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.

Pharmacokinetics:

Suction

With a single and repeated oral administration at a dose of 75 mg per day clopidogrel quickly absorbed. After oral administration in a single dose of 75 mg, the average values of C_max unchanged clopidogrel in blood plasma is achieved after about 45 minutes and is approximately 2.2-2.5 ng / ml. According to excretion of metabolites of clopidogrel with urine, its absorption is approximately 50%.

Distribution

In vitro clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to plasma proteins (98% and 94%, respectively). This bond is unsaturated in a wide range of concentrations.

Metabolism

Clopidogrel is extensively metabolized in the liver. In vitro and in vivo clopidogrel is metabolized in two ways: the first through esterases and the subsequent hydrolysis with the formation of an inactive derivative of carboxylic acid (85% of the circulating metabolites), the second through the isoenzymes of the cytochrome P450 system. at first clopidogrel is metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel results in the formation of an active metabolite, the thiol clopidogrel derivative. In vitro metabolism along this pathway is carried out with the participation of isoenzymes CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol clopidogrel metabolite, which was isolated in in vitro studies, quickly and irreversibly binds to platelet receptors, thus blocking the platelet aggregation.

FROM_max active metabolite of clopidogrel after receiving its loading dose of 300 mg is 2 times higher than C_max after 4 days of taking a maintenance dose of clopidogrel 75 mg.In this case, when taking 300 mg clopidogrel C_max is achieved within about 30-60 minutes.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel approximately 50% of radioactivity is excreted in the urine and approximately 46% - with feces. After a single oral administration at a dose of 75 mg T_1/2Clopidogrel is approximately 6 hours. After a single dose and repeated doses of T_1/2the main circulating inactive metabolite is 8 hours.

Pharmacogenetics

With the help of the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite, 2-oxo-clopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, when examining platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19. The allele of the CYP2C19 * gene corresponds to a fully functional metabolism, while the CYP2C19 * 2 and CYP2C19 * 3 gene alleles are non-functional. Alleles of CYP2C19 * 2 and CYP2C19 * 3 genes cause a decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the alleles of the CYP2C19 * 4, * 5, * 6, * 7, and * 8 genes.Patients with a low activity of the CYP2C19 isoenzyme should have the two alleles of the loss-of-function gene indicated above. Published frequency of occurrence of phenotypes of persons with low activity of the isoenzyme CYP2C19 is 2% for Caucasians, 4% for Negroid people and 14% for Chinese. There are corresponding tests to determine the patient's genotype of the CYP2C19 isoenzyme.

Reduced CYP2C19-mediated metabolism in intermediate and low metabolizers leads to a decrease in C_max in plasma and AUC of the active metabolite by 30-50% after loading doses of 300 mg or 600 mg and a maintenance dose of 75 mg. As a result of less exposure of the active metabolite, less pronounced inhibition of platelet activity or more pronounced residual platelet activity is observed.

Individual patient groups

The pharmacokinetics of the active metabolite of clopidogrel in certain groups of patients has not been studied.

Elderly people

In elderly volunteers (over 75 years old), when compared with young volunteers, there was no difference in platelet aggregation and bleeding time. Do not require dose adjustment for the elderly.

Children of the age

No data available.

Patients with impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal disease (creatinine clearance from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation was lower (25%) than in healthy volunteers, however, lengthening bleeding time was similar to that of healthy volunteers who received clopidogrel in a dose of 75 mg per day.

Patients with impaired hepatic function

After daily, within 10 days of taking clopidogrel at a daily dose of 75 mg in patients with severe liver damage, inhibition of ADP-induced platelet aggregation was similar to that of healthy volunteers. The mean bleeding time was also comparable in both groups.

Ethnicity

The prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate and decreased metabolism is different in representatives of different ethnic groups. There are very small literature data among representatives of the Mongoloid race, which does not allow to assess the significance of genotyping of the isoenzyme CYP2C19 on the clinical outcome of events.

Indications:

Prevention of atherothrombotic complications:

- in adult patients with myocardial infarction (with a duration of several days to 35 days), with ischemic stroke (with a duration of 7 days to 6 months), with diagnosed occlusive disease of peripheral arteries;

- in adult patients with acute coronary syndrome without ST segment elevation (unstable angina or Q-free myocardial infarction), including patients who underwent stenting for percutaneous coronary intervention (in combination with acetylsalicylic acid);

- in adult patients with acute coronary syndrome with ST segment elevation (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolysis (in combination with acetylsalicylic acid).

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

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

Contraindications:

- Hypersensitivity to any component of the drug;

severe hepatic impairment;

- Acute bleeding (eg, with peptic ulcer or intracranial hemorrhage);

- pregnancy, lactation period;

- age to 18 years (safety of application not established).

Carefully:

Clopidogrel, like other antiplatelet agents, should be used with caution in patients with:

- liver and kidney disease (moderate hepatic and / or renal failure);

- pathological conditions that increase the risk of bleeding, including in trauma and surgery;

- simultaneous administration of acetylsalicylic acid, non-steroidal anti-inflammatory drugs (including cyclooxygenase-2 inhibitors), heparin and glycoprotein inhibitors IIb/IIIa.

Pregnancy and lactation:

In experiments on animals it was shown that clopidogrel and its metabolites penetrate into breast milk, do not affect fertility and do not have toxic effects on the fetus. However, in the absence of sufficient safety data, it is not recommended to use the drug in pregnant and lactating women.

Dosing and Administration:

The drug is taken orally, regardless of food intake.

Adults and elderly patients with normal activity of the isoenzyme CYP2C19

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

Clopidogrel appoint a dose of 75 mg 1 time / day.

Acute coronary syndrome without ST segment elevation (unstable angina, myocardial infarction without Q-wave)

Treatment with drug Clopidogrel should start with a single dose of 300 mg loading dose, and then continue at a dose of 75 mg 1 time / day (in combination with acetylsalicylic acid in doses of 75-325 mg / day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid at this indication does not exceed 100 mg. The optimal duration of treatment is not officially defined. Clinical trials support the use of the drug for up to 12 months, and the maximum beneficial effect was observed by 3 months of treatment

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

Clopidogrel prescribe once in a dose of 75 mg once a day with the initial single dose loading in combination with acetylsalicylic acid and thrombolytic agents or without combination with thrombolytics.

Patients older than 75 years treatment with the drug should begin without taking a loading dose. Combination therapy starts as soon as possible after the onset of symptoms and lasts for at least 4 weeks. The effectiveness of the use of a combination of clopidogrel and acetylsalicylic acid with this indication over 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel prescribe once a day at a dose of 75 mg. In combination with clopidogrel, you should start and then continue taking acetylsalicylic acid (75-100 mg / day).

Skipping the next dose

If less than 12 hours have passed after missing the next dose, the missed dose of the drug should be taken immediately, and then taken at the usual time in the following doses.

If more than 12 hours have passed after missing the next dose, the patient should take the next dose at the usual time (do not take a double dose).

Application for violations of liver function

With caution should prescribe the drug for liver diseases (including with moderate hepatic insufficiency, which may predispose to bleeding (limited clinical experience of use)).

Contraindicated in patients with severe hepatic impairment.

Application for violations of kidney function

With caution should prescribe the drug for kidney disease (including with moderate renal failure).

Application in elderly patients

In patients older than 75 years, treatment with the drug Clopidogrel should be started without taking a loading dose.

Use in children

Contraindicated: children under 18 years of age (safety and efficacy not established).

Side effects:

When taking therapeutic doses, the drug is usually well tolerated. Frequency of development of side effects: often (1-10%), infrequently (0.1-1%), rarely (0.01-0.1%), very rarely (less than 0.01%, including individual reports).

On the part of the blood and organs of hemopoiesis: infrequently - thrombocytopenia, leukopenia, neutropenia and eosinophilia; very rarely - cases of serious bleeding,mainly in the subcutaneous fat tissue, muscles and joints, eye hemorrhages (conjunctival, in the tissue and retina of the eye), nasal bleeding, bleeding from the respiratory system, postoperative wounds, cases of bleeding with fatal outcome (mainly intracranial, gastrointestinal and retroperitoneal); very rarely - agranulocytosis, aplastic anemia / pancytopenia, thrombotic thrombocytopenic purpura.

From the immune system: very rarely anaphylactoid reactions (including angioedema, urticaria), maculopapular or erythematous rash, serum sickness, bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme).

From the nervous system: infrequently - headache, dizziness, paresthesia; rarely - vertigo; very rarely - confusion, hallucinations, changes in taste.

From the cardiovascular system: very rarely - vasculitis, lowering blood pressure.

From the respiratory system: very rarely - bronchospasm, interstitial pneumonitis.

From the digestive system: often - diarrhea, abdominal pain, indigestion; infrequently - stomach ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; very rarely - pancreatitis, colitis (including ulcer or lymphocytic), stomatitis, acute liver failure, hepatitis (non-infectious).

From the skin: very rarely - eczema and flat lichen.

From the musculoskeletal system: very rarely - arthralgia, arthritis, myalgia.

From the genitourinary system: infrequently - hematuria; very rarely glomerulonephritis.

Laboratory indicators: infrequent - prolongation of bleeding time; very rarely - an increase in the activity of hepatic transaminases, an increase in the concentration of serum creatinine.

Other: very rarely - a fever.

Overdose:

With a single oral dose of 1050 mg clopidogrel (14 tablets of 75 mg), no adverse events and the need for special therapeutic measures were noted.

With a single oral dose of 600 mg clopidogrel (8 tablets of 75 mg), healthy volunteers, side effects not are marked. The increase in bleeding time corresponded to the value recorded after taking a therapeutic dose (75 mg / day).

If it is necessary to quickly correct the increased bleeding time, a transfusion of platelet mass is recommended.

The specific antidote is not known.

Interaction:

Oral anticoagulants: simultaneous use of clopidogrel with oral anticoagulants is not recommended, tk. this combination can increase bleeding. Despite the fact that taking 75 mg of clopidogrel per day did not change the pharmacokinetics of S-warfarin and INR in patients who had been taking warfarin for a long time, the simultaneous use of clopidogrel and warfarin increases the risk of bleeding due to the effects that both drugs exert on haemostasis.

Inhibitors of glycoprotein IIb/IIIa: Clopidogrel should be used with caution in patients who simultaneously receive glycoprotein inhibitors IIb/IIIa.

Acetylsalicylic acid: ASA does not alter clopidogrel-induced platelet aggregation-induced inhibition of ADP, however clopidogrel enhances the effect of ASA on platelet aggregation, induced by collagen. Nevertheless, the simultaneous administration of ASA 500 mg 2 times / day throughout the day did not cause a significant increase in bleeding time due to the use of clopidogrel.Between clopidogrel and acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, the simultaneous use of these drugs should be done with caution. Nevertheless, clopidogrel and ASK were appointed jointly up to one year.

Heparin: clopidogrel did not require a change in the dose of heparin or did not affect the effect of heparin on clotting. Simultaneous use of heparin did not affect the inhibition of platelet aggregation caused by clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Consequently, the simultaneous use of these drugs should be done with caution.

Thrombolytic preparations: The safety of the combined use of clopidogrel with fibrin-specific and fibrin-specific thrombolytic agents and heparins was investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed with the use of thrombolytic agents and heparin in conjunction with ASA.

NSAIDs: the combined use of clopidogrel and naproxen increased latent blood loss from the gastrointestinal tract. However, due to the lack of sufficient clinical studies on interactions with other NSAIDs, it is not clear at present whether the increased risk of gastrointestinal bleeding is common to all NSAIDs. Therefore, the simultaneous use of NSAIDs (including inhibitors of COX-2) and clopidogrel requires caution.

Other concurrent therapy: because the clopidogrel is metabolized to its active metabolite in part by CYP2C19, it is expected that the use of drugs that suppress the activity of this enzyme will lead to a decrease in drug concentrations of the active metabolite clopidogrel. As a precaution, the simultaneous use of drugs that suppress CYP2C19 should be avoided.

The drugs that suppress CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton Pump Inhibitors (PPI): Omeprazole in a dose of 80 mg 1 time / day, taken either concomitantly with clopidogrel or with a 12-hour interval between doses of two drugs, reduced the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with 39% (loading dose) and 21% (maintenance dose) with a decrease in platelet aggregation inhibition. Expected that esomeprazole, taken simultaneously with clopidogrel, will also lead to a decrease in the exposure of the active metabolite.

As a precaution, do not use clopidogrel at the same time omeprazole or esomeprazole. Less pronounced decrease in metabolite exposure was observed in the case of pantoprazole and lansoprazole.

Plasma concentrations of the active metabolite were reduced by 20% (loading dose) and by 14% (maintenance dose) during treatment with pantoprazole at a dose of 80 mg 1 time / day. This was accompanied by a decrease in the average inhibition of platelet aggregation by 15% and 11%, respectively. These results mean that clopidogrel can be used together with pantoprazole. Evidence that other drugs,gastric acid-lowering agents such as histamine H2 receptor blockers (with the exception of cimetidine, which is an inhibitor of CYP2C19) and antacids, affect the antiplatelet activity of clopidogrel, no.

Other medications: clinically important pharmacodynamic interaction was not observed when clopidogrel was applied together with atenolol or nifedipine or with these two substances.

Simultaneous application phenobarbital or estrogen had no significant effect on the pharmacodynamic activity of clopidogrel.

Pharmacokinetics digoxin and theophylline did not change with the simultaneous use of clopidogrel.

Antacid agents did not change the degree of absorption of clopidogrel. Phenytoin and tolbutamide, which are metabolized by CYP2C9, can be safely applied simultaneously with clopidogrel.

Special instructions:

Bleeding and hematologic disorders

Because of the risk of bleeding and haematological adverse reactions during treatment, clinical bleeding symptoms should immediately be analyzed and / or other appropriate tests should be performed. Just like other antiplatelet agents, clopidogrel should be used with caution in the case of patients who may be at risk of increased bleeding due to trauma, surgical or other pathological conditions, as well as for patients treated with ASA, heparin, glycoprotein inhibitors IIb/IIIa or NSAIDs, including COX-2 inhibitors. Patients should be carefully monitored for any signs of bleeding, including concealed bleeding, especially in the first weeks of treatment and / or after invasive procedures at the heart or surgery. It is not recommended simultaneous use of clopidogrel with oral anticoagulants, tk. as this can increase bleeding.

If the patient has to undergo elective surgery, and the antiplatelet effect is temporarily undesirable, clopidogrel should be discontinued 7 days before the surgery. Before any planned operation and reception of any new drug, patients should warn therapists and dentists that they are taking clopidogrel.

Clopidogrel prolongs the time of bleeding and should be used with caution in patients with pathological changes,predisposing to bleeding (especially, gastrointestinal and intraocular). Patients should be informed that taking clopidogrel (alone or in combination with ASA) to stop bleeding may take longer, and that they should be notified to their doctor if they have an unintended (for localization or duration) bleeding.

Thrombotic thrombocytopenic purpura (TTP)

Very rarely, after the use of clopidogrel, and sometimes after a short exposure, there were cases of thrombotic thrombocytopenic purpura (TTP). It is characterized by thrombocytopenia and microangiopathic hemolytic anemia accompanied by neurologic changes, renal dysfunction or fever. TTP is a life-threatening condition requiring immediate treatment, including plasmapheresis.

Acute ischemic stroke

In the absence of data Clopidogrel can not be recommended in the first 7 days after an acute ischemic stroke.

During the treatment it is necessary to monitor the functional activity of the liver. With severe liver damage, the risk of developing hemorrhagic diathesis should be considered.

Effect on the ability to drive transp. cf. and fur:

Clopidogrel does not have a significant impact on the ability to drive vehicles or engage in other potentially hazardous activities.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

10 tablets per contour cell pack. By 1, 2, 3, 6 or 9 contour squares together with instructions for use in a pack of cardboard.

For 14 tablets in a contour mesh package. For 1 or 2 contour packs with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Obsolete name of the trade product: & nbspListab® 75

Date renamed: & nbsp10.04.17

Registration number:LSR-007018/08

Date of registration:02.09.2008 / 10.04.2017

Expiration Date:Unlimited

The owner of the registration certificate:REPLEK FARM Skopje, OOOREPLEK FARM Skopje, OOO Macedonia

Manufacturer: & nbsp

REPLEK PHARM, Ltd. Macedonia

Information update date: & nbsp11.04.2018

Illustrated instructions

Instructions

Clopidogrel (Clopidogrel)