Clopidex - instructions for use, doses, side effects, contraindications

Excipients: giprolose 6,125 mg, mannitol 120.175 mg, cellulose microcrystalline 17,150 mg, macrogol-6000 2,450 mg, castor oil hydrogenated 1,225 mg;

tablet shell: opadrai pink (lactose monohydrate 2,800 mg, hypromellose (15 CPS) 1,921 mg, titanium dioxide (E171) 1.656 mg, triacetin 0.560 mg, iron oxide red (E172) 0.063 mg) 7,000 mg.

Description:

Round, biconvex tablets, covered with a film coat of light pink color.

Pharmacotherapeutic group:antiplatelet agent

ATX: & nbsp

B.01.A. C.04 Clopidogrel

Pharmacodynamics:

Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor on platelets and subsequent ADP-mediated activation of the complex GPIIb/IIIa, leading to suppression of platelet aggregation.

Due to irreversible binding, platelets remain immune to stimulation of ADP for the rest of their life (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 released ADP.

Since the formation of the active metabolite occurs with the enzymes of the P450 system, some of which may differ in polymorphism or can be inhibited by other drugs, not all patients can adequately suppress platelets. Clopidogrel is able to prevent the development of atherothrombosis in any localization of atherosclerotic vascular lesions. In particular, with lesions of the cerebral, coronary or peripheral arteries. 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 (when the equilibrium state is reached). 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 baseline, usually for 5 days.

Pharmacokinetics:

Suction

After oral administration at a dose of 75 mg per day is rapidly absorbed, characterized by high absorption and bioavailability.However, the concentration of the starting material in the plasma is low and after 2 hours after taking it does not reach the measurement limit (0.025 μg / l).

According to renal secretion of clopidogrel metabolites, absorption is about 50%.

Distribution

In vitro Clopidogrel and its main circulating non-active metabolite in the blood reversibly bind to plasma proteins by 98% and 94%, respectively.

Metabolism

Clopidogrel is actively metabolized in the liver, and the main metabolite, an inactive derivative of carboxylic acid, is about 85% of the circulating substance in the blood plasma. Time to reach the maximum concentration (TC_mOh) of this metabolite (C_mOh - about 3 mg / l after repeated oral administration at a dose of 75 mg) is achieved 1 hour after ingestion.

The active metabolite, thiol clopidogrel derivative, is formed by oxidizing clopidogrel to 2-oxoclopidogrel and subsequent hydrolysis. In vitro This pathway of metabolism occurs with the help of P450 isoenzymes, CYP2C19, CYP1A2 and CYP2B6. Active thiol metabolite of clopidogrel, isolated in vitro, quickly and irreversibly binds to platelet receptors, blocking the aggregation of platelets.

Excretion

About 50% of the drug is excreted by the kidneys and about 46% by the intestine within 120 hours after ingestion. After a single oral dose of 75 mg half-life (T_1/2) of clopidogrel is approximately 6 hours. The half-life of the main circulating inactive metabolite after a single and repeated administration is 8 hours.

The concentration of the main circulating metabolite in plasma after taking 75 mg per day in patients with severe chronic renal insufficiency (creatinine clearance 5 to 15 ml / min) is lower compared to patients with chronic renal insufficiency of moderate severity (QC from 30 to 60 ml / min) and healthy volunteers. Although the inhibition of ADP-induced platelet aggregation in patients with renal insufficiency was also lower than in healthy volunteers, the lengthening of bleeding time was the same as in healthy volunteers taking 75 mg of clopidogrel per day. In addition, clinical tolerability was good in all patients.

In patients with cirrhosis of the liver, taking clopidogrel at a daily dose of 75 mg for 10 days was safe and well tolerated. FROM_max Clopidogrel at a single and repeated use in patients with cirrhosis of the liver was significantly higher than in healthy volunteers. However, plasma concentrations of the main circulating metabolite and ADP-induced platelet aggregation, as well as bleeding time were comparable in both groups.

Pharmacogenetics

Several polymorphic enzymes of the P450 system are involved in the activation of clopidogrel. Isozyme CYP2C19 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. Gene allele CYP2C19 * 1 is responsible for the normally functioning metabolism, whereas the allele of the isoenzyme gene CYP2C19 * 2 and isoenzyme CYP2C19 * 3 are responsible for reduced metabolism. These alleles are responsible for a decrease in metabolism in about 85% of the Caucasoid and 99% in the Mongoloid race. Other alleles associated with reduced metabolism are represented by isoenzymes CYP2C19 * 4, * 5, * 6, * 7 and * 8, but they are rarely found in the general population.

Individual patient groups

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

Elderly age

Differences in platelet aggregation rates and bleeding time between elderly people (over 75 years old) and young volunteers were not observed. Do not require dose adjustment for the elderly.

Impaired renal function

After repeated use of clopidogrel at a dose of 75 mg / day in patients with severe renal dysfunction (SC from 5 to 15 ml / min), inhibition of ADP-induced platelet aggregation is lower by 25% than in healthy volunteers; the lengthening of bleeding time is the same in comparison with healthy volunteers taking 75 mg of clopidogrel per day.

Impaired liver function

The average bleeding time and inhibition of ADP-induced aggregation with clopidogrel at a dose of 75 mg / day for 10 days in patients with severe liver damage is comparable to healthy volunteers.

Indications:

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

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

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

- with segment lift ST (acute myocardial infarction) with drug treatment and the possibility of carrying out thrombolytic therapy.

Contraindications:

- Hypersensitivity;

- lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome; severe hepatic impairment;

- Acute bleeding (including peptic ulcer or intracranial hemorrhage);

- pregnancy and lactation;

- Children under 18 years.

Carefully:

- Moderate hepatic impairment;

- chronic renal failure (CRF);

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

- simultaneous administration of ASA, warfarin, non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of COX-2), heparin, glycoprotein inhibitors IIb/IIIa, hereditary function decline CYP2C19.

Pregnancy and lactation:

Pregnancy

Since there are no clinical data on the use of the drug during pregnancy, the use of clopidogrel in pregnant women is not recommended. The drug can be used during pregnancy only if the benefit to the mother exceeds the potential risk to the fetus.

Animal testing does not indicate direct or indirect adverse effects on the course of pregnancy, embryonic development, childbirth and postnatal development.

Breast-feeding

If necessary, clopidogrel therapy should stop breastfeeding, as tests in rats have shown that clopidogrel and / or its metabolites are excreted into breast milk. Data on the penetration of clopidogrel into human breast milk are not known.

Dosing and Administration:

Inside, regardless of food intake.

For the prevention of atherothrombotic events in patients with myocardial infarction, ischemic stroke or diagnosed peripheral artery occlusion - 75 mg once a day. In patients with myocardial infarction, treatment should 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.

To prevent atherothrombotic events 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 per day (in combination with ASA in doses of 75-325 mg per day, the recommended dose is 100 mg per day). The maximum favorable effect occurs after 3 months. The course of treatment is up to 1 year.

To prevent atherothrombotic events in acute coronary syndrome with segment elevation ST (acute myocardial infarction with segment elevation ST) - 75 mg per day with the initial single dose loading dose in combination with ASA and thrombolytics (or without thrombolytics).

Combination therapy starts 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.

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

Side effects:

The frequency of side effects is determined according to the following definitions: 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 1/10000 and less than 1 / 1000, very rarely - less than 1/10000, including isolated cases.

The most frequent reaction is bleeding, which occurs during the first month of taking the drug. Cases of severe bleeding have been reported in patients taking clopidogrel simultaneously with ASA or clopidogrel with ASA and heparin.

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

From the nervous system: infrequently - headache, dizziness, paresthesia, intracranial bleeding, including fatal; 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; infrequently - stomach ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence; rarely - retroperitoneal bleeding; 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; 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.

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

Laboratory indicators: infrequent - prolongation of bleeding time.

Other: very rarely - fever.

Overdose:

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

Treatment: stop bleeding, transfusion of platelet mass.

Interaction:

It is not recommended simultaneous use of clopidogrel and warfarin in connection with an increased risk of bleeding.

Purpose of glycoprotein inhibitors IIb/IIIa together with clopidogrel increases the risk of bleeding, so it is recommended to use caution when they are used simultaneously.

ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, but clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. Joint use of these drugs requires caution. However, in patients with acute coronary syndrome without segment elevation ST, long-term combined use of clopidogrel and ASA (up to 1 year) is recommended.

When used simultaneously with NSAIDs, the risk of bleeding may increase, so caution should be exercised when using them simultaneously. Simultaneous reception with inhibitors CYP2C19 (e.g., omeprazole) Not recommended.

The active metabolite of clopidogrel inhibits isoenzyme activity CYP2C9, resulting in increased concentrations of phenytoin, tolbutamide and NSAIDs in blood plasma.

Numerous clinical studies have not revealed significant clinical interaction with simultaneous administration of clopidogrel and such drugs as atenolol, ACE inhibitors, cholesterol lowering agents, nifedipine, digoxin, phenobarbital, cimetidine, estrogens, theophylline. Antacids do not affect the absorption of clopidogrel.

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.

Clopidogrel should be used with caution in patients at risk of severe bleeding associated with trauma, surgery, in patients with bleeding lesions (especially gastrointestinal and intraocular), and in patients receiving ASA, non-steroidal anti-inflammatory drugs including COX-2), heparin or glycoprotein inhibitors IIb/IIIa. 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.

The simultaneous use of clopidogrel and warfarin may increase the intensity of bleeding, therefore, with the exception of special rare clinical situations (such as the presence of a floating thrombus in the left ventricle, stenting in patients with atrial fibrillation), joint use with warfarin is not recommended.

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 taking clopidogrel (alone or in combination with ASA) to stop bleeding may take longer, and that if they have an unusual (localized or prolonged) bleeding, they should be informed of this doctor. Patients should also inform the doctor about the taking of the drug if they are to undergo surgery (including dental surgery).

Very rarely, when taking clopidogrel, thrombotic thrombocytopenic purpura (TTP) developed, sometimes after short-term use. This condition is characterized by thrombocytopenia and microangiopathic hemolytic anemia in combination with neurological signs, kidney damage and fever. Thrombotic thrombocytopenic purpura is a potentially life-threatening condition requiring immediate treatment, including plasmapheresis.

Due to lack of data it is not recommended to assign clopidogrel Patients with acute ischemic stroke less than 7 days old.

In case of severe violations of the liver function, one should remember about the risk of developing hemorrhagic diathesis, so these patients should be cautious about prescribing clopidogrel because of the limited experience of using the drug in these patients.

The experience of using clopidogrel in patients with impaired renal function is limited, so these patients clopidogrel should be administered with caution. Dosage forms containing hydrogenated castor oil can induce dyspepsia and diarrhea.

The drug Klopidex® contains lactose, therefore, the drug should not be used for patients with hereditary intolerance to galactase, lactase deficiency or malabsorption of glucose and galactase.

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

Clopidogrel does not affect the ability to drive vehicles and mechanisms.

Form release / dosage:

Tablets coated with a film coating, 75 mg.

Packaging:

For 15 tablets in PVC / PVDC / Al blister.

2 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

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-001246

Date of registration:21.11.2011

The owner of the registration certificate:Beluga, medicines and cosmetics.Beluga, medicines and cosmetics. Croatia

Manufacturer: & nbsp

BELUPO, Pharmaceuticals & Cosmetics, d.d. Croatia

Representation: & nbspBeluga, medicines and cosmetics. Beluga, medicines and cosmetics. Croatia

Information update date: & nbsp05.08.2015

Illustrated instructions

Instructions

Clopidex® (Klopidex® )