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

Excipients: lactose anhydrous - 108,125 mg, microcrystalline cellulose - 30,00 mg, pregelatinized starch - 12,00 mg, macrogol 6000 - 8,00 mg, castor oil, hydrogenation - 4,00 mg.

Casing of the tablet: hypromellose 5.60 mg, titanium dioxide (E 171) 1.46 mg, talc 0.50 mg, iron oxide red (E 172) 0.04 mg, propylene glycol 0.40 mg.

Description:

Round, slightly biconcave tablets, covered with a film membrane of pink color. View of the fracture: a white or almost white rough mass with a film shell of pink color.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

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 its receptor P2Y₁₂ on platelets and the subsequent ADP-dependent activation of the glycoprotein complex GPIIb/IIIa, which leads to inhibition of platelet aggregation. Due to the irreversible nature of binding, platelet function is lost throughout the rest of life (about 7-10 days), and the restoration of normal platelet function occurs in accordance with the rate of platelet renewal. Clopidogrel also inhibits platelet aggregation caused by other agonists, blocking the activation of platelets by the released ADP.

Since the active metabolite is formed with the participation of enzymes CYP450, some of which are polymorphic or are inhibited by other drugs, adequate platelet inhibition will not occur in all patients.

With a daily intake of clopidogrel at a dose of 75 mg from the first day of administration, a significant inhibition of ADP-induced platelet aggregation is noted, which reaches an equilibrium state from day 3 to day 7. When applying a dose of 75 mg per day in an equilibrium state, platelet aggregation is suppressed by an average of 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time return to the baseline level on average for 5 days. Clopidogrel can prevent the development of atherothrombosis with atherosclerotic damage to vessels of any location, in particular in patients with atherosclerotic lesions of the cerebral, coronary and peripheral arteries.

Pharmacokinetics:

Suction

Clopidogrel is rapidly absorbed at a dose of 75 mg / day. Plasma concentrations of the unchanged drug are insignificant and, as a rule, do not reach the lower limit of quantitative determination (about 2.2-2.5 ng / l) 2 hours after administration.Based on the data on excretion of the metabolite of clopidogrel in the urine, the absorption of clopidogrel is not less than 50%.

Distribution

In vitro Clopidogrel and the main (inactive) metabolite bind reversibly to blood plasma proteins (98% and 94%, respectively).

Metabolism

Clopidogrel is actively metabolized in the liver. In conditions in vitro and in vivo, Clopidogrel is metabolized by two major metabolic pathways: with the mediation of esterases, leading to hydrolysis to its inactive carboxylic acid derivatives (85% of circulating metabolites) and mediated by cytochromes P450. Clopidogrel first metabolized to the intermediate metabolite 2-oxo-clopidogrel followed by hydrolysis and the formation of an active metabolite - a thiol derivative of clopidogrel.

In vitro, this metabolic pathway is mediated by participation CYP3A4, CYP2C19, CYP1A2 and CYP2B6. Active thiol metabolite, isolated in vitro, quickly and irreversibly binds to platelet receptors, thereby suppressing platelet aggregation. With a single administration of clopidogrel at a loading dose of 300 mg, C_mOh active metabolite is 2 times more than after 4 days of taking the drug in a maintenance dose of 75 mg. FROM_mOh is achieved through 30- 60 minutes after taking the drug.

Excretion

Within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel about 50% is excreted by the kidneys and 46% by the intestine. The half-life (T_1/2) is about 6 hours. T_1/2the main circulating metabolite is 8 hours after a single and repeated administration.

Pharmacogenetics

FROM using isoenzyme CYP2C19 are formed as an active metabolite, as well as an intermediate metabolite - 2-oxo-clopidogrel. Pharmacokinetics and antiplatelet effect of the active metabolite clopidogrel, in the study of platelet aggregation ex vivo, vary depending on the genotype of the isoenzyme CYP2C19. Gene allele CYP2C19 * 1 is responsible for the normally functioning metabolism, whereas the alleles of the isoenzyme gene CYP2C19 * 2 and isoenzyme CYP2C19 * 3 are responsible for reduced metabolism. These alleles are responsible for the decrease in metabolism in the majority of representatives of the Caucasoid (85%) and Mongoloid races (99%). Other alleles that are associated with a lack or decrease in metabolism are less common and include, but are not limited to, the isoenzyme alleles CYP2C19 * 4, * 5, * 6, * 7 and * 8. Patients, which are weak metabolizers, should have the two alleles of the gene with loss of function indicated above.Published frequency of occurrence of phenotypes of weak metabolizers CYP2C19 are 2% in Caucasians, 4% in Negroid people and 14% in Chinese.

Based on the results of a cross-sectional study (40 volunteers) and a meta-analysis of six studies (335 volunteers), which included patients with very high, high, intermediate and low isoenzyme activity CYP2C19, there were no significant differences in the exposure of the active metabolite and the average inhibition of platelet aggregation (IAT) in volunteers with very high, high and intermediate activity. In volunteers with low isoenzyme activity CYP2C19, the exposure of the active metabolite was lower compared to volunteers with a high isoenzyme activity CYP2C19.

When volunteers with low isoenzyme activity CYP2C19 received a treatment regimen of 600 mg loading dose / 150 mg maintenance dose (600 mg / 150 mg), the exposure of the active metabolite was higher than with the 300 mg / 75 mg treatment regimen. In addition, the IAT was similar to that in groups of patients with a higher metabolic rate by isoenzyme CYP2C19, who received a treatment regimen of 300 mg / 75 mg.

However, in studies with clinical outcomes, the dosing regimen of clopidogrel for patients in this group (patients with low isoenzyme activity CYP2C19) is not yet installed.

Clinical studies conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low isoenzyme activity CYP2C19.

Individual patient groups

The pharmacokinetics of the active metabolite of clopidogrel in elderly patients and children has not been studied.

Impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe chronic renal failure (creatinine clearance 5-15 ml / min), inhibition of ADP-induced platelet aggregation was 25% lower than in healthy volunteers, however, lengthening the time of bleeding was not noted (see section "Method of administration and dose").

Impaired liver function

Upon receiving clopidogrel at a dose of 75 mg per day for 10 days in patients with severe liver inhibition of ADP-induced platelet aggregation did not differ from that in healthy volunteers.The average bleeding time in patients with severe liver damage and in healthy volunteers was comparable (see section "Method of administration and dose").

Indications:

Prevention of atherothrombotic complications:

In adults with myocardial infarction (from a few days to 35 days old), ischemic stroke (with a prescription from 7 days to 6 months) or with a diagnosed occlusive disease of peripheral arteries.

In adults with acute coronary syndrome:

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

- with the rise of the ST segment (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,can not take indirect anticoagulants and have a low risk of bleeding (in combination with acetylsalicylic acid).

Contraindications:

- Hypersensitivity to clopidogrel or any of the components of the drug;

- severe hepatic impairment;

- acute bleeding (eg bleeding from peptic ulcers or intracranial hemorrhage);

- rare hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

- pregnancy and the period of breastfeeding;

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

Carefully:

- If hypersensitivity to other thienopyridines (eg, ticlopidine, prasugrel) (see section "Special instructions");

- with moderate hepatic insufficiency, which may predispose to bleeding (limited clinical experience of use);

- with renal failure (limited clinical experience of use);

- with injuries, surgical interventions (see section "Special instructions");

- at diseases at which there is a predisposition to development of bleedings (especially gastrointestinal and intraocular);

- while taking non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase-2 (COX-2) inhibitors), oral anticoagulants, heparin, glycoprotein receptor blockers IIb/IIIa;

- in patients with low isoenzyme activity CYP2C19 (since they have less active metabolite of clopidogrel in recommended doses at recommended doses, and its antiplatelet effect is less pronounced, and therefore, when taking the usually recommended doses of clopidogrel in acute coronary syndrome or percutaneous coronary intervention, a higher incidence of cardiovascular complications is possible , than in patients with normal activity CYP2C19).

Pregnancy and lactation:

Pregnancy

The drug is not recommended for use in pregnancy because of the lack of clinical data on its intake by pregnant women, although animal studies have not revealed any direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development.

Breastfeeding period

Breastfeeding with clopidogrel should be discontinued, as a study in rats has shown that clopidogrel and / or its metabolites are excreted into breast milk. Does it penetrate clopidogrel in human breast milk is unknown.

Fertility

In animal studies, the adverse effects of clopidogrel on fertility have not been demonstrated.

Dosing and Administration:

Inside, regardless of food intake.

Adults and elderly people with normal isoenzyme activity CYP2C19

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

Clopidogrel-TAD is prescribed in a dose of 75 mg (1 tablet) once a day.

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

Treatment should be started with a single dose of 300 mg loading dose (4 tablets), and then continue taking 75 mg once a day (in combination with acetylsalicylic acid at doses of 75-325 mg per day). Since the use of acetylsalicylic acid in higher doses is associated with an increased risk of bleeding, the recommended dose of acetylsalicylic acid should 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 is observed by the 3rd month of treatment.

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

Clopidogrel-TAD is prescribed at a dose of 75 mg (1 tablet) once a day with an initial single dose 300 mg loading dose (4 tablets) in combination with acetylsalicylic acid, and in combination with thrombolytic agents or without combination with thrombolytics. In patients older than 75 years, treatment with clopidogrel should be started 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-TAD is prescribed in a dose of 75 mg (1 tablet) once a day. In combination with the drug, you must begin and then continue taking acetylsalicylic acid (75-100 mg per day).

Skipping the next dose:

- if less than 12 hours have elapsed after missing the next dose, the missed dose of the drug should be taken immediately, and then the following doses should be taken at the usual time;

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

Patients with genetically determined reduced isoenzyme activity CYP2C19

Low isoenzyme activity CYP2C19 is associated with a decrease in the antiplatelet effect of clopidogrel. The high dose regimen (600 mg (8 tablets) - loading dose, then 150 mg (2 tablets) once a day) in patients with low isoenzyme activity CYP2C19 increases the antiplatelet effect of clopidogrel (see the section "Pharmacokinetics"), However, the optimal dosage regimen for patients with reduced metabolism by isoenzyme CYP2C19 has not yet been established in clinical trials.

Special patient groups

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

There is no experience of using the drug in children.

Patients with impaired renal function

After repeated visitsClopidogrel 75 mg / day in patients with severe renal disease (SC from 5 to 15 ml / min) inhibition of ADP-induced platelet aggregation (25%) was lower than that of healthy volunteers, but the lengthening of bleeding time was similar to that of in healthy volunteers who received clopidogrel in a dose of 75 mg / day. In addition, all patients had good tolerability of the drug.

Patients with impaired hepatic function

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

Patients of different race

Prevalence of alleles of isoenzyme genes CYP2C19, responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite, is different in representatives of different racial groups (see section "Pharmacogenetics"). There are only limited data for members of the Mongoloid race to assess the effect of the isoenzyme genotype CYP2C19 on the clinical outcome events.

Female and male patients

In a large controlled study CAPRIE (clopidogrel in comparison with acetylsalicylic acid in patients with the risk of developing ischemic complications), the frequency of clinical outcomes, other side effects and deviations from the norm of clinical and laboratory indicators was the same for both men and women.

Side effects:

To assess the frequency of adverse reactions, the following criteria were used: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); rarely (≥1/10000, <1/1000); very rarely (<1/10000), including individual messages; the frequency is unknown (according to available data, it is not possible to establish the frequency of development of an undesirable phenomenon).

From the immune system: very rarely - serum sickness, anaphylactoid reactions; frequency unknown - cross-over hypersensitivity to other thienopyridines (eg, ticlopidine, prasugrel).

On the part of the blood and lymphatic system: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely: neutropenia, including severe neutropenia; very rarely thrombotic thrombocytopenic purpura (TTP), aplastic anemia, pancytopenia, agranulocytosis, severe thrombocytopenia,granulocytopenia, anemia.

From the nervous system: infrequently - intracranial hemorrhages (several fatal cases), headache, paresthesia, dizziness; very rarely - hallucinations, confusion.

From the side of the cardiovascular system: very rarely - serious bleeding from the operating wound, vasculitis, arterial hypotension.

From the respiratory system: often - epistaxis; very rarely - bleeding from the respiratory tract (hemoptysis, pulmonary hemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

From the gastrointestinal tract: very often - gastrointestinal bleeding, diarrhea, abdominal pain, indigestion; infrequently: peptic ulcer of stomach and duodenum, gastritis, vomiting, nausea, constipation, bloating; rarely - retroperitoneal hemorrhage; very rarely - gastrointestinal bleeding and retroperitoneal hemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative colitis or lymphocytic colitis), stomatitis.

From the hepatobiliary system: very rarely - acute liver failure, hepatitis, deviation from the norm of liver functional parameters.

From the genitourinary system: infrequently - hematuria, very rarely - glomerulonephritis, an increase in the concentration of creatinine in the blood.

From the skin: often - bruises (local subcutaneous hemorrhage); infrequent - rash, itchy skin, purpura (small-spotted capillary hemorrhage into the skin, under the skin or mucous membranes); rarely bullous dermatitis (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), angioedema, erythematous rash, urticaria, eczema, flat lichen.

From the side of the musculoskeletal system: very rarely - hemorrhages in the muscles and joints, arthritis, arthralgia, myalgia.

From the sense organs: infrequently - intraocular hemorrhages (conjunctival, retinal); rarely - vertigo.

Other: often bleeding from the point of vascular puncture; very rarely - a fever. Laboratory indicators: infrequently - an increase in bleeding time, a decrease in the number of neutrophils, a decrease in the number of platelets in the peripheral blood.

Overdose:

Symptoms: prolongation of bleeding time and subsequent complications in the form of development of bleeding.

Treatment: the transfusion of platelet mass is recommended to correct the prolonged bleeding time. There is no specific antidote.

Interaction:

Joint use of clopidogrel with oral anticoagulants it is not recommended, since it is possible to increase the intensity of bleeding. Despite the fact that the use of clopidogrel at a dose of 75 mg does not affect the pharmacokinetics of warfarin and the international normalized ratio (INR) in patients taking long-term therapy with warfarin, co-administration of clopidogrel with warfarin increases the risk of bleeding, as a result of independent effects on hemostasis.

Appointment inhibitors of glycoprotein receptors IIb/IIIa together with clopidogrel requires caution, especially in patients with an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions).

Acetylsalicylic acid (ASA) does not affect clopidogrel-induced platelet aggregation-induced platelet-induced inhibition of ADP, but clopidogrel potentiates the effect of ASA on collagen-induced platelet aggregation.However, simultaneous administration of 500 mg ASA twice daily did not significantly affect the increase in bleeding time caused by the use of clopidogrel. Between clopidogrel and ASA, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, with their simultaneous use, care should be taken, although in clinical trials patients received combined therapy with clopidogrel and ASA for one year.

When used simultaneously with heparin, according to a clinical study conducted on healthy volunteers, when taking clopidogrel did not require a change in the dose of heparin and did not change the anticoagulant effect of heparin. The combined use of heparin did not alter the inhibitory effect of clopidogrel on platelet aggregation. Between clopidogrel and heparin, pharmacodynamic interaction is possible, which may increase the risk of bleeding, so the use of this combination requires caution. The safety of the combined use of clopidogrel, fibrin-specific or non-specific thrombolytic and heparin was investigated in patients with acute myocardial infarction.The incidence of clinically significant bleeding was similar to that observed in the joint use of thrombolytics and heparin with ASA.

Appointment NSAIDs (including inhibitors of COX-2) together with clopidogrel requires caution. In a clinical study conducted with the participation of healthy volunteers, the combined use of clopidogrel and naproxen increased latent gastrointestinal bleeding. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is currently unknown whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel along with other NSAIDs.

Because the clopidogrel metabolized to its active metabolite in part with CYP2C19, the use of drugs that inhibit the activity of this enzyme may lead to a decrease in the level of the active metabolite. The clinical significance of this interaction is unknown. As a precaution, it is recommended to avoid simultaneous reception of clopidogrel with drugs that inhibit CYP2C19 (omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol). If it becomes necessary to prescribe proton pump inhibitors simultaneously with clopidogrel, the drug with the lowest inhibition CYP2C19 (e.g., pantoprazole or lansoprazole).

A number of clinical studies with clopidogrel and other concomitantly prescribed drugs were conducted to study possible pharmacodynamic and pharmacokinetic interactions that showed that:

- There is no clinically significant pharmacodynamic interaction when using clopidogrel together with atenolol and / or nifedipine;

- simultaneous use of phenobarbital, cimetidine and estrogens does not significantly affect the pharmacodynamics of clopidogrel;

- the pharmacokinetics of digoxin and theophylline did not change;

- antacids do not reduce the absorption of clopidogrel;

- phenytoin and tolbutamide can be safely used simultaneously with clopidogrel, it is unlikely that clopidogrel can affect the metabolism of other drugs, such as phenytoin and tolbutamide and NSAIDs, which are metabolized by isoenzyme CYP2C19 groups of cytochrome P450.

In addition to the information presented above, no studies of other drug interactions have been conducted. However, patients who participated in clinical trials with clopidogrel received simultaneously a number of other drugs, including diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, lipid-lowering drugs, coronary vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs and glycoprotein receptor blockers IIb/IIIa, without signs of clinically significant adverse interaction.

Special instructions:

In the treatment of clopidogrel, especially during the first weeks of treatment and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients should be conducted to exclude signs of bleeding, incl. hidden.

In connection with the risk of bleeding and hematological adverse effects in the event of clinical symptoms appearing during treatment, suspicious for the occurrence of bleeding, it is urgent to do a clinical blood test, determine APTT, the number of platelets,indicators of the functional activity of platelets and conduct other necessary studies.

Because the clopidogrel increases bleeding time, it should be used with caution in patients with trauma, surgical interventions or other pathological conditions, as well as in patients receiving ASA, NSAIDs (including COX-2 inhibitors), heparin or glycoprotein receptor blockers IIb/IIIbut because of the increased risk of bleeding.

If the patient is scheduled surgery, and there is no need for an antiplatelet effect, then for 5-7 days before the operation, the use of clopidogrel should be discontinued.

Patients should be warned that when taking clopidogrel (alone or in combination with ASA) to stop bleeding may take longer, they should inform the doctor about every case of unusual bleeding. Before any future operation and before starting any new drug, patients should inform the doctor (including the dentist) about taking clopidogrel.

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

In patients with recent ischemic stroke or transient ischemic attack and a high risk of recurrent atherothrombotic events, combination therapy with clopidogrel and ASA did not demonstrate a higher efficacy in comparison with clopidogrel monotherapy, but may increase the risk of major bleeding.

It should be clarified the presence in the patient's history of hypersensitivity to other derivatives of thienopyridine (ticlopidine, prasugrel), t. cases of cross-allergic reactions between thienopyridines are described. Patients who have previously experienced hypersensitivity to other thienopyridine require careful follow-up throughout the treatment period to identify signs of hypersensitivity to clopidogrel.

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

The experience of using clopidogrel in patients with chronic renal failure is limited, in connection with which clopidogrel in this category of patients should be used with caution.

During the treatment it is necessary to monitor the functional activity of the liver. With severe violations of liver function, the use of clopidogrel is contraindicated because of the high risk of hemorrhagic diathesis. The experience of using the drug in patients with moderate violations of the liver is limited, so these patients clopidogrel should be administered with caution.

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

Clopidogrel-TAD has no significant effect on the ability to drive vehicles and work with technical means that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 7 or 10 tablets in a contour mesh packaging of foil combined OPA / PVC / Al and aluminum foil.

By 2, 4, 8 or 12 out-of-round cell packs of 7 tablets together with instructions for use in a cardboard bundle.

For 3 or 9 contour packs of 10 tablets together with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature of no higher than 25 ° C, in the original packaging. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002493

Date of registration:06.06.2014 / 31.10.2017

Expiration Date:06.06.2019

The owner of the registration certificate:TAD Pharma GmbHTAD Pharma GmbH Germany

Manufacturer: & nbsp

UNICHEM Laboratories, Ltd. India

Representation: & nbspTAD Pharma GmbHTAD Pharma GmbHRussia

Information update date: & nbsp29.01.2018

Illustrated instructions

Instructions

Clopidogrel-TAD (Clopidogrel-TAD)