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

core: active substance: clopidogrel hydrogen sulfate 97.88 mg (equivalent to clopidogrel 75.0 mg); Excipients: betadex 10.0 mg, croscarmellose sodium 4.0 mg, cellulose microcrystalline 104.12 mg, corn starch 18.0 mg, talc 10.0 mg, magnesium stearate 3.0 mg;

shell: hypromellose 5.50 mg, titanium dioxide 1.0 mg, propylene glycol 1.50 mg, ferric oxide red oxide 0.08 mg.

Description:

Heart-shaped tablets covered with a film coat, pink, smooth on both sides.

The color of the inner layer on the cut is white or almost white.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Antiaggregant agent. Selectively reduces the binding of adenosine diphosphate (ADP) to platelet receptors and activation of the glycoprotein IIb / IIIa receptors under the action of ADP, violating the so-called. aggregation of platelets.

Reduces platelet aggregation caused by other agonists, preventing their activation by liberated ADP, does not affect the activity of phosphodiesterase (PDE). Irreversibly binds to the platelet ADP receptors that remain impervious to ADP stimulation throughout the life cycle (about 7 days).

The inhibition of platelet aggregation is observed 2 hours after admission (40% inhibition) of the initial dose of 400 mg. With the long-term administration of therapeutic doses of clopidogrel (75 mg / day), a marked inhibition of platelet aggregation is noted as early as the first day of treatment.The maximum effect (60% suppression of aggregation) develops after 4-7 days of constant admission in a dose of 50-100 mg / day. Antiaggregant effect persists throughout the life span of platelets (7-10 days). After the end of treatment, the effect of clopidogrel on aggregation and bleeding time usually decreases within 5 days.

Pharmacokinetics:

Suction. Absorption and the bioavailability of the drug is high. After a repeated oral dose of 75 mg / day clopidogrel quickly absorbed.

The concentration of the main compound in the plasma is low, after 2 hours after administration it does not reach the measurement limit (0.025 μg / l). Clopidogrel and its main circulating metabolite reversibly bind to plasma proteins (98% and 94%, respectively).

Metabolism. Clopidogrel is rapidly metabolized in the liver. Its main metabolite is inactive and accounts for about 85% of the compound circulating in the plasma. The maximum concentration (C_mOh) of the given metabolite in plasma (about 3 mg / l after application of repeated oral doses of 75 mg) is observed one hour after administration. The kinetics of the main metabolite showed a linear dependence (increase in plasma concentration depending on the dose) within the dose range of 50 to 150 mg of clopidogrel.The concentration of the main metabolite in the plasma after taking 75 mg / day is lower in patients with severe kidney disease (creatinine clearance 5-15 ml / min) compared with patients with moderate kidney disease (creatinine clearance from 30 to 60 ml / min) and healthy persons.

Clopidogrel is a precursor of the active substance. Its active metabolite is formed by oxidation of clopidogrel and subsequent hydrolysis. The oxidative stage is regulated primarily by cytochrome P450 isoenzymes: 2B6 and 3A4. The active metabolite quickly and irreversibly binds to platelet receptors and suppresses platelet aggregation. This metabolite is not detected in plasma.

Excretion. About 50% of the drug is excreted by the kidneys with urine and approximately 46% with feces within 120 hours after administration. The half-life (T_1/2) of the main metabolite is 8 h after a single and repeated intake. The concentration of kidney metabolites is 50%.

Pharmacogenetics

Several polymorphic enzymes of the P450 system are involved in the activation of clopidogrel.

The CYP2C19 isozyme is involved in the formation of both an active metabolite and an intermediate metabolite, 2-oxoclopidogrel.Pharmacokinetics and antiplatelet effects of the active metabolite of clopidogrel, studied by platelet aggregation ex vivo, differ depending on the genotype of the isoenzyme CYP2C19. The allele of the CYP2C19 * 1 gene is responsible for the normally functioning metabolism, whereas the alleles of the CYP2C19 * 2 isoenzyme and the CYP2C19 * 3 isoenzyme are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in about 85% of the representatives of the Caucasoid race and 99% in the representatives of the Mongoloid race. Other alleles associated with reduced metabolism are represented by CYP2C19 * 4, * 5, * 6, * 7 and * 8 isoenzymes, but they are rarely found in the general population.

Published data on the frequency of occurrence of the phenotype and genotype of the isoenzyme CYP2C19 are presented in the table.

The frequency of occurrence of the phenotype and genotype of the isoenzyme CYP2C19 Frequency%
	Europeoids (n=1356)	Negroids (n=966)	Mongoloids (n=573)
Intensive isoenzyme metabolism CYP2C 191/1	74	66	38
Intermediate isoenzyme metabolism CYP2C19l/2 or * 1 / * 3	26	29	50
Reduced metabolism of isoenzyme CYP2C192/2 or * 2 / * 3 or * 3 / * 3	2	4	14

Effect of the genotype of isoenzyme CYP2C19 on the pharmacokinetics of the active metabolite of clopidogrel was studied in 227 people in 7 published studies. In individuals with reduced isoenzyme metabolism CYP2C19, a decrease in the maximum concentration (C_mOh) and the area under the curve "concentration-time" (AUC) of the active metabolite by 30-50% after taking a loading dose of 300 mg or 600 mg and a subsequent maintenance dose of 75 mg. Reduced activity of the metabolite clopidogrel may lead to a lesser degree of platelet inhibition or to their increased reactivity. A weakened antiplatelet response to clopidogrel was described for individuals with intermediate and decreased metabolism in 21 studies on 4520 subjects. The relative difference in the antiplatelet response between groups with different genotypes differed in studies due to the use of different methods of assessing the response, but was more than 30%.

The relationship between the genotype of the isoenzyme CYP2C19 and the outcome of clopidogrel therapy was evaluated in two postgraduate clinical trials (study CLARITY-TIMI 28 (n= 465) and TRITON-TIMI 38 (n= 1477) and 5 cohort studies (n= 6489). AT CLARITY-TIMI 28 and in one of the cohort studies (Trenk, n= 765), the incidence of cardiovascular events did not differ significantly depending on the genotype. AT TRITON-TIMI 38 and three cohort studies (Collet, Sibbing, Giusti, n= 3516) patients with intermediate and decreased metabolism had a greater incidence of cardiovascular events (myocardial infarction, stroke, death) or stent thrombosis compared to patients with good metabolism. In the fifth cohort study (Simon, n= 2208), an increase in the incidence of cardiovascular events was observed only in patients with reduced metabolism.

Pharmacogenetic testing allows to determine the genotype with the variability of the activity of the isoenzyme CYP2C19.

Genetic variants of other enzymes of the P450 system with effects on the ability of formation of active metabolites of clopidogrel are also possible.

Indications:

Prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusion.

In combination with acetylsalicylic acid (ASA) for the prevention of thrombotic complications in acute coronary syndrome with segment elevation ST if possible, thrombolytic therapy; without segment elevation ST (unstable angina, myocardial infarction without a tooth Q), incl. in patients undergoing stenting.

Contraindications:

Hypersensitivity, severe hepatic insufficiency, acute bleeding (including bleeding from peptic ulcer or intracranial hemorrhage), pregnancy and the period of breastfeeding, children under 18 years.

Carefully:

In patients with moderate hepatic impairment, with chronic renal failure (CRF), in pathological conditions that increase the risk of bleeding (including trauma, surgery), with a tendency to bleeding, while taking ASA, warfarin, non-steroidal anti-inflammatory drugs ( NSAIDs) (including cyclooxygenase-2 inhibitors), heparin and glycoprotein inhibitors IIb/IIIa, with a hereditary decrease in the isoenzyme function CYP2C19.

Pregnancy and lactation:

The use of clopidogrel is contraindicated in pregnancy.

For the duration of treatment, breastfeeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake.

For the prevention of thrombotic complications in patients with myocardial infarction, ischemic stroke or peripheral arterial occlusion - 75 mg once a day.

In patients with myocardial infarction, treatment can begin from the first days of the 35th day of myocardial infarction,and in patients with ischemic stroke - in the period from 7 days to 6 months after ischemic stroke.

For prophylaxis of thrombotic complications in acute coronary syndrome without segment elevation ST (unstable angina, myocardial infarction without a tooth Q) - start with a single dose loading dose of 300 mg, and then take 75 mg / day (in combination with ASA in doses of 75-325 mg / day, the recommended dose is 100 mg / day). The maximum favorable effect occurs after 3 months. The course of treatment is up to 1 year.

For the prevention of thrombotic complications in acute coronary syndrome with segment elevation ST (acute myocardial infarction with segment elevation ST) - 75 mg / day with the initial single dose loading in combination with ASA and thrombolytic (or without thrombolytics).

Combination therapy begins as soon as possible after the onset of symptoms and lasts for at least 4 weeks.

In patients older than 75 years, treatment with clopidogrel should begin without taking its loading dose.

In patients with a genetically determined decrease in the isoenzyme function CYP2C19 possibly reducing the effect of clopidogrel. The optimal dosage regimen in these patients is not established.

Patients of advanced age. In the absence of violations of the kidneys should follow the usual dosage regimen. The experience of using in patients with chronic renal failure (CRF), and / or moderate degree of hepatic insufficiency is limited.

Side effects:

Clopidogrel, as a rule, is well tolerated. Undesirable effects rarely require withdrawal of clopidogrel treatment.

On the part of the organs of hematopoiesis: infrequently - thrombocytopenia, leukopenia, eosinophilia; rarely - neutropenia, incl. expressed; very rarely - thrombotic thrombocytopenic purpura, anemia, incl. aplastic, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia.

Allergic reactions: very rarely - anaphylactic reactions, serum sickness.

From the nervous system: infrequently - headache, dizziness, paresthesia, intracranial hemorrhage, incl. with lethal outcome; very rarely - confusion, hallucinations, a taste disorder.

From the sense organs: infrequently - hemorrhage in the conjunctiva, eyes, retina; rarely - vertigo.

From the side of the cardiovascular system: often - hematoma; very rarely - heavy bleeding, bleeding from the operating wound, vasculitis, lowering blood pressure.

From the respiratory system: very often - nosebleeds; very rarely - bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.

From the digestive system: often - diarrhea, abdominal pain, indigestion, bleeding from the gastrointestinal tract (GIT); infrequently - stomach ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rarely - retroperitoneal bleeding; very rarely - pancreatitis, colitis, incl. ulcerative or lymphocytic, stomatitis, acute hepatic insufficiency, hepatitis, a violation of functional liver tests, bleeding from the gastrointestinal tract with lethal outcome.

From the skin: often - subcutaneous hemorrhage; infrequently - skin rash, itching, purpura; very rarely - angioedema, urticaria, erythematous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, eczema, lichen planus.

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

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

Local reactions: often - bleeding at the injection site.

Laboratory indicators: infrequent - prolongation of bleeding time.

Other: very rarely - a fever.

IF any of the side effects listed in the manual are aggravated, or noticed-any other side effects not listed in the instructions, you should notify the doctor.

Overdose:

Symptoms: prolonged bleeding time, hemorrhagic complications.

Measures to help with overdose: stop bleeding, transfusion of platelet mass.

Interaction:

Joint use of clopidogrel with warfarin can increase the intensity of bleeding, so this combination is not recommended.

Acetylsalicylic acid does not alter the ADP-induced platelet aggregation caused by clopidogrel. Clopidogrel strengthens the action acetylsalicylic acid on collagen-induced platelet aggregation, so when using these drugs together, care must be taken.

Blockers IIb/IIIa-receptors: appointment of blockers IIb/IIIa-receptors together with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions).

Simultaneous application heparin does not alter the inhibitory effect of clopidogrel on platelet aggregation. Clopidogrel at a joint admission does not change the need for heparin and the action of heparin on blood coagulation. However, the simultaneous use of these drugs requires caution.

Non-steroidal anti-inflammatory drugs (NSAIDs): 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. However, due to the lack of research on the interaction of clopidogrel with other NSAIDs, it is not currently known whether there is an increased risk of gastrointestinal bleeding when taking clopidogrel together with other NSAIDs. Therefore, the appointment of NSAIDs, including COX-2 inhibitors in combination with clopidogrel, should be performed with caution.

Combined use with other drugs: no significant clinical interactions were detected with simultaneous administration of clopidogrel and such drugs as atenolol, angiotensin-converting enzyme (ACE) inhibitors, hypolipidemic agents, nifedipine, digoxin, phenobarbital, cimetidine, estrogens, theophylline, phenytoin, tolbutamide. Clopidogrel inhibits enzyme activity CYP2C9 systems of cytochrome P450 with simultaneous use with drugs that are metabolized with the participation of this enzyme (phenytoin, tolbutamine), so it is possible to increase them in blood plasma.

As clopidogrel metabolized to the formation of its active metabolite partially by means of the system CYP2C19, the use of drugs that inhibit this system can lead to a decrease in the level of the active metabolite of clopidogrel and a decrease in its clinical efficacy. Simultaneous reception drugs inhibiting the system CYP2C19 (eg, omeprazole), Not recommended.

Antacids do not affect the absorption of clopidogrel.

Simultaneous reception of clopidogrel with food and drink, eating does not have any effect. Clopidogrel can be taken regardless of food intake.

Special instructions:

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

Patients should be warned that because the stoppage of the bleeding that occurs when the drug is used requires more time, they should inform the doctor about every case of unusual bleeding. Patients should also inform the doctor about taking the medication if they are undergoing surgery (including dental surgery) or if the doctor prescribes a new drug for the patient.

During the treatment period it is necessary to monitor the parameters of the hemostatic system (active partial thromboplastin time (APTT), the number of platelets, tests of the functional activity of platelets); regularly investigate the functional activity of the liver.

In case of severe violations of liver function, one should remember about the risk of hemorrhagic diathesis.

It is not recommended to prescribe to patients with ischemic stroke less than 7 days old.

LF containing hydrogenated castor oil can cause dyspepsia and diarrhea.

Very rarely, when taking clopidogrel, thrombotic thrombocytopenic purpura developed, sometimes after short-term use.The condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with neurologic disorders, kidney damage and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Features of the drug at the first admission or when it is canceled

No features of the action when the first reception or withdrawal of clopidogrel is registered.

The actions of the doctor (paramedic), the patient, while missing one or more doses of clopidogrel

No special action by the doctor (paramedic) or the patient while skipping one or more doses of the drug is required.

Effect on the ability to drive transp. cf. and fur:Clopidogrel does not significantly affect the abilities necessary for driving or working with machinery.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 7 tablets in a blister (contour cell pack) from Al / Al or Al / PVC.

For 1, 2 or 4 blisters per pack of cardboard along with instructions for use.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2.5 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001003

Date of registration:18.10.2011

Expiration Date:18.10.2016

The owner of the registration certificate:PROTEK-SVM, LLC PROTEK-SVM, LLC Russia

Manufacturer: & nbsp

ACCURE LABS, Pvt.Ltd. India

Information update date: & nbsp29.01.2018

Illustrated instructions

Instructions

Clopidogrel-LEXMM® (Klopidogrel-LEKSVM®)