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

shell: Opadrai II (polyvinyl alcohol 2,800 mg, titanium dioxide 1,695 mg, macrogol 1,414 mg, talc 1,036 mg, dye red charming 0.048 mg, dye quinoline yellow 0.005 mg, indigocarmine 0.002 mg) 7.00 mg.

Description:Round biconvex tablets, covered with a film coating of pink color. On a cross-section the nucleus is from white to yellowish white.

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Inhibitor of platelet aggregation. Clopidogrel is a prodrug, one of its metabolites is an inhibitor of platelet aggregation. Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor P2Y12 and the subsequent ADP-mediated activation of the glycoprotein complex IIb/IIIa, thereby suppressing platelet aggregation.

Due to the irreversibility of binding, platelets exposed to damage are damaged for the rest of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the platelet cycle. Aggregation of platelets,caused by agonists other than ADP, is also inhibited by blocking the increase in platelet activation that occurs under the action of released ADP. Since the active metabolite of clopidogrel is formed with the participation of the CYP2C19 isoenzyme, which has polymorphism or can be inhibited by other drugs, not all patients have platelet suppression. Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular, in lesions of the cerebral, coronary or peripheral arteries. With a daily intake of clopidogrel at a dose of 75 mg from the first day, there is a significant suppression of ADP-induced platelet aggregation, which gradually increases for 3-7 days and then reaches the equilibrium state (reaches a constant level). In the equilibrium state, platelet aggregation is suppressed on average by 40-60%. After stopping the use of clopidogrel, platelet aggregation and bleeding time return to the baseline level on average for 5 days.

Pharmacokinetics:

Suction and distribution: with regular ingestion of clopidogrel at a dose of 75 mg / day, it is rapidly absorbed. However, its concentration in the blood plasma is insignificant and after 2 hours after administration it does not reach the measurement limit (0.25 μg / l). Based on the data on excretion of the metabolite of clopidogrel by the kidneys, the absorption of clopidogrel is not less than 50%.

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

Metabolism: the main metabolite of clopidogrel (carboxyl derivative) is about 85% of circulating blood plasma metabolites of clopidogrel and does not possess pharmacological activity, but is able to inhibit the in vitro activity of the 2S9 isoenzyme of the cytochrome P450 family. FROM_m_Oh (maximum concentration) of this metabolite in the blood plasma after repeated administration of the drug at a dose of 75 mg is about 3 mg / l and is observed approximately 1 hour after ingestion. The pharmacokinetics of the main metabolite is linear (plasma concentrations increase in proportion to the dose) when clopidogrel is used in a dose range of 50 to 150 mg.

Being a prodrug, clopidogrel intensively metabolized in the liver.Its active metabolite, a thiol derivative, is formed by oxidizing clopidogrel to 2-oxo-clopidogrel followed by hydrolysis. Oxidation of clopidogrel occurs mainly with the participation of cytochrome P450 2B6 and 3A4 isoenzymes, and to a lesser extent isoenzymes IA1, IA2 and 2C19. The active thiol metabolite, which was derived in in vitro studies, quickly and irreversibly binds to platelet receptors, thereby suppressing platelet aggregation. This metabolite in the blood plasma is not found.

Excretion: within 120 hours after ingestion by a human ¹⁴C-labeled clopidogrel about 50% of the dose is excreted by the kidneys and approximately 46% through the intestine. The half-life of the main circulating metabolite is 8 hours after a single and repeated administration.

Pharmacogenetics

With the help of the CYP2C19 isoenzyme, both an active metabolite and an intermediate metabolite of 2-oxo-clopidogrel are formed. 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. The allele of the CYP2C19 * 1 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 CYP2C19M, * 5, * 6, * 7, and * 8 genes. Patients with a low activity of the isoenzyme CYP2C19 should have the two alleles of the loss-of-function gene mentioned 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.

Pharmacokinetics in special clinical cases

Concentrations of the main circulating metabolite in blood plasma at a regular dose of 75 mg / day were lower in patients with severe renal insufficiency (creatinine clearance (QC 5-15 ml / min) compared with patients with moderate renal insufficiency (QC 30 -60 ml / min) and healthy volunteers Although the inhibitory effect on ADP-induced platelet aggregation was reduced (25%) compared to the same effect in healthy volunteers, the bleeding time was increased to the same extent as in zdo volunteers who received clopidogrel in a dose of 75 mg / day.

In patients with cirrhosis of the liver (class A or B on the Child-Pugh scale), daily administration of clopidogrel for 10 days at a dose of 75 mg / day was safe and also tolerated well, as in healthy volunteers. In patients with cirrhosis of the liver (class A or B on the Child-Pugh scale) C_m_Oh Clopidogrel after its single ingestion and clearance of creatinine after taking another dose of the drug against the background of course treatment were many times higher than in patients without cirrhosis. However, the plasma concentration of the main circulating metabolite in the blood and the degree of clopidogrel suppression of ADP-induced platelet aggregation, as well as the bleeding time in patients with and without cirrhosis, were comparable.

Individual patient groups

The pharmacokinetics of the active metabolite of clopidogrel in elderly patients and children, patients with diseases of the kidneys and liver has not been studied.

Indications:

Prevention of atherothrombotic complications:

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

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

Patients with atrial fibrillation (atrial fibrillation) who 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 the components of the drug;

severe hepatic impairment;

- Acute bleeding (including, with peptic ulcer of the stomach or duodenum or intracranial hemorrhage);

- Pregnancy and lactation (breastfeeding);

- age to 18 years.

Carefully:

- Moderate hepatic failure, which may predispose to bleeding (experience in clinical use is limited);

- chronic renal failure (clinical experience of use is limited);

- traumas, surgical interventions;

- diseases in which there is a predisposition to the development of bleeding (especially gastrointestinal or intraocular);

- with the simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs) (including cyclooxygenase-2 (COX-2) inhibitors), heparin, warfarin, glycoprotein inhibitors IIb/IIIa;

- hypersensitivity to other thienopyridines (ticlodipine, prasugrel);

- in patients with a genetically determined decrease in the isoenzyme function CYP2C19 (there is literature data suggesting that patients with a genetically determined decrease in the isoenzyme function CYP2C19 are exposed to less systemic exposure to the active metabolite of clopidogrel and have less pronounced antiplatelet effect of the drug,In addition, they may have a greater incidence of cardiovascular complications after myocardial infarction compared to patients with a normal CYP2C19 isoenzyme function).

Pregnancy and lactation:

Pregnancy

As a precautionary measure, the use of the drug is not recommended Clopidogrel during pregnancy due to the lack of clinical data on its use by pregnant women, although animal studies have revealed neither direct nor indirect adverse effects during pregnancy, embryonic development, childbirth and postnatal development.

Breastfeeding period

It is not known whether clopidogrel in breast milk, in studies on rats it was shown that clopidogrel and / or its metabolites are secreted into the milk of lactating rats. During the period of drug treatment Clopidogrel breast-feeding should be discontinued.

Dosing and Administration:

Clopidogrel is recommended to be taken orally regardless of the time of ingestion.

Adults and elderly patients with normal activity of the isoenzyme CYP2C19

Myocardial infarction, ischemic stroke and diagnosed peripheral arterial occlusive disease

The drug is taken 75 mg once a day.

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

Treatment with drug Clopidogrel should be started with a single intake of a loading dose of 300 mg. And then continued taking a dose of 75 mg once a day (in combination with acetylsalicylic acid in doses of 75-325 mg per day). Since the use of higher doses of acetylsalicylic acid 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 third month of therapy.

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

A drug Clopidogrel should be taken once a day at a dose of 75 mg with the initial single dose loading dose of Clopidogrel 300 mg in combination with acetylsalicylic acid in combination with thrombolytics or without combination with thrombolytics.In patients older than 75 years, treatment with the drug Clopidogrel should begin without taking its loading dose. Combination therapy is started as soon as possible after the onset of symptoms, and continues for at least 4 weeks. The effectiveness of the combination of clopidogrel and acetylsalicylic acid on this indication lasting more than 4 weeks has not been studied.

Atrial fibrillation (atrial fibrillation)

Clopidogrel should be taken once a day at a dose of 75 mg. In combination with clopidogrel, you must 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 of the drug, you should immediately take the missed dose of the drug, and then take the following doses at the usual time;

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

Patients with genetically determined reduced activity of the isoenzyme CYP2C19

The low activity of the isoenzyme CYP2C19 is associated with a decrease in the antiaggregant effect of clopidogrel.The mode of application of higher doses (600 mg - loading dose, and then 150 mg once a day daily) in patients with a low activity of the isoenzyme CYP2C19 increases the antiplatelet effect of clopidogrel.

Currently, clinical studies that take into account clinical outcomes have not established an optimal dosing regimen of Clopidogrel for patients with reduced metabolism due to the genetically determined low activity of the CYP2C19 isoenzyme.

Special patient groups

Elderly patients

No dose adjustment is required.

Patients with impaired renal function

The experience of use is limited in patients with moderate or severe renal insufficiency.

In patients with moderate (KK 30-60 ml / min) or severe (KK 5-15 ml / min) renal failure inhibition of ADP-induced platelet aggregation decreases, but the prolongation of bleeding time is similar to that in healthy individuals. There are no data on dose adjustment.

Patients with impaired hepatic function

In patients with mild to moderate (class A or B on Child-Pugh) hepatic insufficiency, inhibition of ADP-induced platelet aggregation is close to that in healthy individuals. The average bleeding time is comparable in both groups.Dose adjustment in patients with mild and moderate hepatic dysfunction is not required.

Since the drug is metabolized in the liver and patients with liver diseases are predisposed to coagulation disorders, monitoring of side effects is recommended.

Ethnicity

The prevalence of the alleles of the CYP2C19 isoenzyme genes responsible for the intermediate and decreased metabolism of clopidogrel to its active metabolite differs among representatives of different ethnic groups. There are limited data for members of the Mongoloid race to assess the effect of the CYP2C19 isoenzyme genotype on clinical outcomes.

Female and male patients

In a small study comparing the pharmacodynamic properties of clopidogrel in men and women, women had less inhibition of ADP-induced platelet aggregation, but there was no difference in bleeding time elongation. 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:

The frequency of adverse reactions is presented according to the following frequency of development: very often more than 1/10, often more than 1/100 and less than 1/10, infrequently more than 1/1000 and less than 1/100, rarely more than 1 / 10,000 and less than 1/1000, very rarely - less than 1/10000, including isolated cases.

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

From the coagulation system of the blood: often - hematoma, epistaxis, gastrointestinal bleeding, bruising, bleeding at the puncture site; sometimes - intracranial bleeding, bleeding in the eye (conjunctival, ocular, retinal), lengthening bleeding time; rarely - retroperitoneal bleeding; very rarely - heavy bleeding from the operating wound, bleeding from the respiratory system (hemoptysis, pulmonary hemorrhage), hemarthrosis.

Allergic reactions: very rarely - anaphylactic reactions, serum sickness.From the side of the nervous system: infrequently - headache, dizziness, paresthesia, intracranial hemorrhage, including fatal; very rarely - confusion, hallucinations, violations of taste perception.

From the side of the organ of vision: infrequently - eye hemorrhage (conjunctival, in the tissue and retina of the eye).

From the side of the hearing organ: 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: often - epistaxis; very rarely - bronchospasm, interstitial pneumonitis, pulmonary hemorrhage, hemoptysis.

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

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

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: infrequently - prolongation of bleeding time, decrease of neutrophils, platelets.

Other: very rarely - a fever.

Overdose:

Symptoms: prolongation of bleeding time, hemorrhagic complications.

Treatment: stop bleeding, transfusion of platelet mass. The antidote of clopidogrel is not established.

Interaction:

Simultaneous reception warfarin with clopidogrel may increase the intensity of bleeding, so the use of this combination is not recommended.

Appointment inhibitors of glycoprotein IIb/IIIa simultaneously with clopidogrel requires caution, especially in patients with an increased risk of bleeding (with trauma and surgical interventions or other pathological conditions). Acetylsalicylic acid does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but Clopidogrel potentiates the effect of acetylsalicylic acid on collagen-induced platelet aggregation. Nevertheless, simultaneous with clopidogrel intake of acetylsalicylic acid 500 mg twice a day for 1 day did not cause a significant increase in bleeding time caused by clopidogrel. Between acetylsalicylic acid and clopidogrel, pharmacodynamic interaction is possible, which leads to an increased risk of bleeding. Therefore, when they are used simultaneously, care should be taken, although in clinical trials patients received combination therapy with clopidogrel and acetylsalicylic acid for 1 year.

When used simultaneously with heparin, according to a clinical study conducted on healthy volunteers, when taking clopidogrel, there was no need to correct the dose of heparin and its anticoagulant effect did not change.The simultaneous 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 caution should be exercised when using this combination.

The safety of simultaneous application of clopidogrel, fibrin-specific or fibrin-specific thrombolytic agents and heparin was studied in patients with acute myocardial infarction. The frequency of clinically significant bleeding was similar to that observed in the case of simultaneous use of thrombolytic agents and heparin with acetylsalicylic acid.

Appointment non-steroidal anti-inflammatory drugs (NSAIDs) (including inhibitors of COX-2) simultaneously with clopidogrel requires caution. In a clinical study conducted with the participation of healthy volunteers, the simultaneous 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 NSAIDs is currently unknown,is there an increased risk of gastrointestinal bleeding when taking clopidogrel simultaneously with other NSAIDs.

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

When using clopidogrel with atenolol, nifedipine or with both drugs simultaneously clinically significant pharmacodynamic interaction was not observed.

Simultaneous application phenobarbital, cimetidine and estrogens had no significant effect on the pharmacodynamics of clopidogrel.

Pharmacokinetic parameters digoxin and theophylline did not change with their simultaneous use with clopidogrel.

Antacid agentsand did not reduce the absorption of clopidogrel.

Phenytoin and tolbutamide can safely be used concomitantly with clopidogrel, even though the data obtained from studies with human liver microsomes indicate that the carboxylic metabolite of clopidogrel can inhibit the activity of the isoenzyme CYP2C19, which can lead to an increase in plasma concentrations of certain drugs (phenytoin, tolbutamide and some NSAIDs) that are metabolized by isoenzyme CYP2C19.

In clinical trials, there was no clinically relevant undesirable interaction of clopidogrel with angiotensin-converting enzyme inhibitors, diuretics, beta-blockers, slow calcium channel blockers, lipid-lowering agents, vasodilators, hypoglycemic agents (including insulin), antiepileptic drugs, hormone replacement drugs, glycoprotein antagonists IIb/IIIa.

Special instructions:

When Clopidogrel is used, especially during the first weeks of therapy and / or after invasive cardiac procedures / surgical intervention, careful monitoring of patients should be performed to exclude signs of bleeding, including latent.

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

Patients should be warned that because the stoppage of the resulting bleeding due to the use of the drug takes a long 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), as well as when combining the drug with acetylsalicylic acid, heparin, glycoprotein inhibitors IIb/IIIa, NSAIDs (including those with COX-2 inhibitors).

During the period of treatment, it is necessary to monitor the parameters of the hemostatic system (activated partial thromboplastin time (APTT), the number of platelets, the test for the functional activity of platelets), to 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.

Very rarely, clopidogrel used to develop thrombotic thrombocytopenic purpura, 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.

The drug should be administered with caution to patients with impaired renal function.

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

Clopidogrel does not have a significant effect on the ability to drive vehicles or work with machinery. However, given the side effects of the drug, patients should be careful when driving vehicles and working with mechanisms.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 14 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 14 or 28 tablets in a can of polymer.

For 1 or 2 contourcell packs or 1 can of polymer along with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, protected from light 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:LP-002215

Date of registration:03.09.2013 / 04.06.2014

Expiration Date:03.09.2018

The owner of the registration certificate:RAFARMA, CJSC RAFARMA, CJSC Russia

Manufacturer: & nbsp

RAFARMA, JSC Russia

Information update date: & nbsp29.01.2018

Illustrated instructions

Instructions

Clopidogrel (Clopidogrel)