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

Excipients: pregelatinized starch 27 mg, lactose anhydrous 63,125 mg, macrogol (polyethylene glycol-6000) 8 mg, magnesium stearate 1 mg, microcrystalline cellulose 40 mg, hydrogenated castor oil 3 mg;

film coating: Opadney II pink 9 mg, including: lactose monohydrate 3,6 mg, hypromellose (hydroxycipropilmetiltsellyuloza) 2.52 mg, 2.0484 mg of titanium dioxide, 0.72 mg of triacetin, red dye amazing 0.108 mg, 0.0036 mg of dye indigo.

Description:

The tablets covered with a film cover of pink color, round, biconcave form.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel is a specific and active inhibitor of platelet aggregation; has a coronarodilating effect. Selectively reduces binding of ADP to receptors on platelets and activation of receptors GPIIb/IIIa under the action of ADP, weakening the aggregation of platelets.

Reduces platelet aggregation, caused by other agonists, preventing their activation by released 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. 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).

In the presence of an atherosclerotic lesion, the vessel interferes with the development of atherothrombosis regardless of the localization of the vascular process (cerebrovascular, cardiovascular or peripheral lesions).

Pharmacokinetics:

Clopidogrel is rapidly absorbed with oral administration of 75 mg per day.

Bioavailability is high. However, the concentration of the starting material in the plasma is low and already within 2 hours after administration it does not reach the measurement limit (0.025 μg / l). Connection with blood plasma proteins - 94-98%.

Clopidogrel is rapidly metabolized in the liver. Its main metabolite is the inactive derivative of carboxylic acid, the time to reach the maximum concentration (TC_m_Oh) which after repeated oral doses of 75 mg is achieved after 1 hour (C_m_Oh - about 3 mg / l).

About 50% of the drug is excreted by the kidneys and approximately 46% with feces within 120 hours after administration.The half-life of the main metabolite after a single and repeated administration is 8 hours. The concentration of kidney metabolites is 50%.

The concentration of the main metabolite in the plasma after taking 75 mg / day is lower in patients with severe kidney diseases (creatinine clearance (CK) - 5-15 ml / min) compared with patients with moderate kidney disease (QC from 30 to 60 ml / min ) and healthy faces.

Indications:

Prevention of atherothrombotic events in patients with myocardial infarction, ischemic stroke or with diagnosed occlusive disease of peripheral arteries.

Prevention of atherothrombotic events (in combination with acetylsalicylic acid) in patients with acute coronary syndrome:

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

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

Contraindications:

- Hypersensitivity to the active or any auxiliary component of the drug;

severe hepatic impairment;

- active bleeding (including bleeding from peptic ulcers or intracranial hemorrhage);

- pregnancy and lactation;

- age to 18 years (effectiveness and safety of application not established);

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:

- Moderate hepatic impairment;

- chronic renal failure (CRF);

- pathological conditions that increase the risk of bleeding (including trauma, surgery);

- concurrent administration of ASA, warfarin, non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-2 inhibitors), heparin and glycoprotein inhibitors IIb/IIIa;

- hereditary decrease in the isoenzyme function of CYP2C19.

Pregnancy and lactation:

In the absence of data, it is not recommended to take clopidogrel during pregnancy and lactation.

Dosing and Administration:

Adults and Seniors clopidogrel should be taken orally 75 mg once a day, regardless of food intake.

Treatment should be started from the first days on the 35th day after myocardial infarction, in the period from 7 days to 6 months after an ischemic stroke.

For prophylaxis of thrombotic complications in acute coronary syndrome without ST segment elevation (unstable angina or myocardial infarction without Q wave) treatment with clopidogrel should be started with a single loading dose of 300 mg, and then continued with a dose of 75 mg once a day (with ASA - 75-325 mg per day).

Since the use of high dosages of ASA is associated with a high risk of bleeding, the recommended dose should not be more than 100 mg. The maximum favorable effect occurs after 3 months. The course of treatment is up to 1 year.

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

For patients older than 75 years treatment with clopidogrel should be carried out without the use of a loading dose. Combination therapy should begin as soon as possible after the development of symptoms and last at least four weeks.

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

Experience of application in patients with CRF or moderate degree of hepatic insufficiency is limited.

Side effects:

The incidence of adverse reactions described below was determined respectively the following: very often ≥1 / 10; often ≥ 1/100, <1/10; infrequently ≥ 1/1000, <1/100; rarely ≥ 1/10 000, <1/1000; very rarely <1/10 000, including individual messages.

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

From the nervous system: infrequently - headache, dizziness and paresthesia, intracranial hemorrhage; rarely - systemic dizziness; very rarely - confusion, hallucinations, eating disorders.

From the gastrointestinal tract: often: gastrointestinal bleeding, diarrhea, abdominal pain, indigestion; infrequently - a stomach ulcer, duodenal ulcer, gastritis, nausea, vomiting, constipation, flatulence; rarely - retroperitoneal hematoma; very rarely - pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis, acute liver failure, hepatitis, severe gastrointestinal bleeding with a fatal outcome.

On the part of the hematopoiesis system: infrequently: thrombocytopenia, leukopenia, eosinophilia; rarely: neutropenia, including severe; very rarely: thrombotic thrombocytopenic purpura (TTP) (see "Special instructions"), severe thrombocytopenia (platelet count ≤ 30 x 10⁹/ l), agranulocytosis, granulocytopenia, anemia, including aplastic, pancytopenia.

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

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

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

On the part of the respiratory system: very often - nosebleeds; very rarely - bronchospasm, interstitial pneumonitis, pulmonary bleeding, hemoptysis.

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

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

Laboratory indicators: very rarely - violations of functional liver tests, increased levels of creatinine, prolonged bleeding time.

Others: often bleeding at the injection site; very rarely: fever.

Overdose:

An overdose of clopidogrel may lead to prolonged bleeding time and hemorrhagic complications. If a bleeding is detected, appropriate treatment should be applied.

Antidotes of the pharmaceutical activity of clopidogrel have not been found.

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

Interaction:

Warfarin: simultaneous administration with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended. Blockers IIb / IIIa-receptors: the appointment of IIb / IIIa receptor blockers together with clopidogrel requires caution in patients who have an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions).

Acetylsalicylic acid: acetylsalicylic acid does not alter the effect of clopidogrel, which inhibits ADP-induced platelet aggregation, but clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. Nevertheless, simultaneous reception with clopidogrel, an intake of acetylsalicylic acid 500 mg twice a day for 1 day did not cause a significant increase in bleeding time caused by the use of clopidogrel. Between clopidogrel and acetylsalicylic acid, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when they are used simultaneously, care must be taken. Although in clinical trials, patients received combination therapy with clopidogrel and acetylsalicylic acid for up to one year.

Heparin: according to the clinical trial conducted with the participation of healthy individuals with the use of clopidogrel did not require a change in the dose of heparin and did not change its anticoagulant effect. The simultaneous use of heparin did not alter the antiplatelet effect of clopidogrel. Between clopidogrel and heparin, pharmacodynamic interaction is possible,which can increase the risk of bleeding, so the simultaneous use of these drugs requires caution.

Thrombolytics: the safety of the joint use of clopidogrel, fibrin-specific or fibrin-specific drugs and heparin was investigated in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the joint use of thrombolytic agents and heparin with acetylsalicylic acid.

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.

Other combination therapy: as clopidogrel metabolized to the formation of its active metabolite partially by means of the CYP2C19 system, the use of drugs inhibiting this system (for example, omeprazole) Not recommended. A number of clinical studies with clopidogrel and other concomitantly prescribed drugs were conducted to study possible pharmacodynamic pharmacokinetic interactions that showed that:

- when clopidogrel was used together with atenolol, nifedipine or both drugs, clinically significant pharmacodynamic interaction was not observed;

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

- pharmacokinetic indices of digoxin and theophylline did not change when they were used together with clopidogrel;

- antacids did not reduce the absorption of clopidogrel;

- phenytoin and tolbutamide can safely be used concomitantly with clopidogrel (CAPRIE study), despite the fact that the data obtained from studies with human liver microsomes show that,that the carboxylic metabolite of clopidogrel can inhibit the activity of the 2C9 isoenzyme of the cytochrome P450 family, which can lead to an increase in the plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized with the 2S9 isoenzyme of the cytochrome P450 family;

- ACE inhibitors, diuretics, β- adrenoblockers, blockers of "slow" calcium channels, lipid-lowering agents, coronary vasodilators, lipid-lowering agents (including insulin), antiepileptic drugs, hormone replacement therapy and blockers of GPIIb / IIIa receptors; in clinical studies, there were no clinically significant adverse interactions.

Special instructions:

During the treatment period, it is necessary to monitor the parameters of the hemostasis system (activated partial thromboplastin time (APTT), platelet count, functional platelet function tests); regularly investigate the functional activity of the liver.

Patients should be carefully monitored to detect any signs of bleeding, including latent, especially during the first weeks of the drug and / or after invasive procedures on the heart or surgical procedures. Clopidogrel should be used with caution in patients with an increased risk of bleeding in trauma, surgery, other pathological conditions, with diseases predisposing to the development of bleeding (especially the gastrointestinal and ocular), as well as in patients receiving ASA, nonsteroidal anti-inflammatory drugs (including including COX-2 inhibitors), heparin or glycoprotein inhibitors IIb/IIIa.

The simultaneous use of clopidogrel and warfarin is not recommended, as it can increase the intensity of bleeding (with the exception of special rare clinical situations).

In the case of surgical interventions, if antiaggregant effect is undesirable, the course of treatment should be discontinued 7 days before the operation. Clopidogrel prolongs bleeding time and should be used with caution in patients with diseases predisposing to the development of bleeding (especially, gastrointestinal and intraocular). Patients should be warned that since stopping the bleeding due to the use of clopidogrel (in combination with or without ASA) requires more time, they should inform the doctor about every case of bleeding.Patients should also inform the doctor (including the dentist) about taking the medication if they are due to surgery, dental procedures, and before starting any new drug.

Very rarely, after taking clopidogrel (including short-term use), thrombotic thrombocytopenic purpura (TTP) was observed. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with neurological signs, impaired renal function or fever. TTP is a potentially life-threatening disease requiring immediate treatment, including with the use of plasmapheresis.

The experience of using clopidogrel in patients with impaired renal function is limited, so these patients clopidogrel should be administered with caution.

In case of serious violations of liver function, one should remember about the risk of hemorrhagic diathesis development, the experience of using the drug in patients with moderate violations of the liver function is limited, therefore, these patients clopidogrel should be administered with caution.

Clopidogrel should not be taken to patients with a rare hereditary intolerance to galactose,deficiency of lactase and glucose-galactose malabsorption syndrome.

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

In connection with the possibility of dizziness when taking clopidogrel should be careful when driving vehicles and other potentially dangerous activities that require increased concentration and speed.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

By 7, 10, 15 or 30 tablets in a contour mesh box made of polyvinylchloride film and foil of aluminum printed lacquered or aluminum foil multilayered foil and aluminum foil printed lacquer.

2, 4 contour packs of 7 tablets or 1, 3, 5, 6 contour packs of 10 tablets or 1, 2, 4 contourcell packs of 15 tablets or 1, 2 circuit packs of 30 tablets together 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:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-004881/09

Date of registration:19.06.2009

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp02.08.2015

Illustrated instructions

Instructions

Clopidogrel (Clopidogrel)