Clexane: instructions for using the medicine, structure, Contraindications

Active material: Enoxaparin sodium
When ATH: B01AB05
CCF: The anticoagulant of direct action – Heparin nizkomolyekulyarnyi
ICD-10 codes (testimony): I20.0, I21, i26, I74, I82
When CSF: 01.12.11.06.02
Manufacturer: SANOFI-AVENTIS France (France)

Clexane: dosage form, composition and packaging

Solution for injection clear, colorless to pale yellow.

0.2 ml – syringes (2) – blisters (1) – packs cardboard.
0.2 ml – syringes (2) – blisters (5) – packs cardboard.

Solution for injection clear, colorless to pale yellow.

0.4 ml – syringes (2) – blisters (1) – packs cardboard.
0.4 ml – syringes (2) – blisters (5) – packs cardboard.

Solution for injection clear, colorless to pale yellow.

0.6 ml – syringes (2) – blisters (1) – packs cardboard.

Solution for injection clear, colorless to pale yellow.

0.8 ml – syringes (2) – blisters (1) – packs cardboard.
0.8 ml – syringes (2) – blisters (5) – packs cardboard.

Solution for injection clear, colorless to pale yellow.

1 ml – syringes (2) – blisters (1) – packs cardboard.

Clexane: pharmachologic effect

The preparation of low molecular weight heparin (molecular weight of about 4500 Dalton: less 2000 Dalton – < 20%, from 2000 to 8000 Dalton – >68%, more 8000 Dalton – < 18%). Enoxaparin sodium is obtained by alkaline hydrolysis of the benzyl ester of heparin, isolated from the mucous membrane of the small intestine porcine. Its structure is characterized by non-reducing moiety 2-O-sulfo-4-enpirazinosuronovoy acid moiety and recovering 2-N,6-O-disulfo-D-glucopyranoside. Enoxaparin structure contains about 20% (between 15% to 25%) 1,6-angidroproizvodnogo in restoring fragment polysaccharide chain.

It is characterized by high activity against clotting factor Xa (anti-Xa activity of about 100 IU / mL) and lower activity against clotting factor IIa (anti-IIa or antithrombin activity of about 28 IU / mL).

In applying the drug in prophylactic doses, He slightly modifies the activated partial thromboplastin time (APTT), virtually no effect on platelet aggregation and the level of binding of fibrinogen to platelet receptors.

Anti-IIa activity in plasma is about 10 times lower, than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3-4 h after s / to the introduction and reaches 0.13 IU / mL and 0.19 IU / ml after repeated administration 1 mg / kg body weight administered twice and 1.5 mg / kg of body weight in a single administration, respectively.

Average maximum anti-Xa activity is observed in plasma 3-5 h after p / administration and approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU / ml after s / to the introduction 20, 40 mg 1 mg / kg 1.5 mg / kg, respectively,.

Clexane: pharmacokinetics

The pharmacokinetics of enoxaparin dosing regimens of these is linear.

Suction and paspredelenie

After repeated p / to the introduction of enoxaparin sodium dose 40 mg, and the dose 1.5 mg / kg body weight 1 time / day in healthy volunteers C_ss to be achieved 2 Day, wherein on average AUC 15% higher, than after a single injection. After repeated p / to the introduction of enoxaparin sodium in a daily dose 1 mg / kg body weight 2 times / day C_ss achieved through 3-4 day, wherein on average AUC 65% higher, than after a single injection and the mean values ​​C_max are respectively 1.2 IU / mL and 0.52 IU / mL.

The bioavailability of enoxaparin sodium p / to the introduction, evaluated on the basis of the anti-Xa activity, close to 100%. V_d enoxaparin sodium (by anti-IIa activity) is approximately 5 l and approaching blood volume.

Metabolism

Enoxaparin sodium mainly biotransformed in the liver by desulfation and / or depolymerization to inactive metabolites.

Deduction

Enoxaparin sodium is a low clearance drug. After the on / in the for 6 h dose 1.5 mg / kg body weight of the average value of the clearance of anti-Xa activity in plasma is 0.74 l /.

Withdrawal is monophasic character. T_1/2 is 4 no (after a single s / c administration) and 7 no (after repeated administration). 40% of the administered dose is excreted by the kidneys, and 10% – in unchanged form.

Pharmacokinetics in special clinical situations

Possible delay launch of enoxaparin sodium in elderly patients due to a decrease in renal function.

In patients with impaired renal function, a marked decrease in clearance of enoxaparin sodium. In patients with low (CC 50-80 ml / min) and moderate (CC 30-50 ml / min) renal impairment after repeated p / to the introduction 40 mg of enoxaparin sodium 1 times / day an increase of anti-Xa activity, represented by AUC. In patients with severe renal impairment (CC less than 30 ml / min) at repeated n / to a drug at a dose 40 mg 1 times / day AUC at steady state on average 65% higher.

Patients who are overweight when s / to a clearance of the drug is somewhat less. If not make a correction dose based on patient body weight, after a single s / c administration of enoxaparin sodium dosage 40 mg anti-Xa activity will be 50% higher in women weighing less than 45 kg, and 27% higher in men with a body weight of less than 57 kg, compared with patients with normal average body weight.

Clexane: testimony

• prevention of venous thrombosis and thromboembolism, especially in orthopedics and general surgery;
• prevention of venous thrombosis and thromboembolism in patients with acute therapeutic diseases, It is on bed rest (chronic heart failure III or IV functional class NYHA classification, acute respiratory failure, acute infection, acute rheumatic diseases in combination with one of the risk factors of venous thrombus);
• treatment of deep vein thrombosis with or without pulmonary embolism;
• treatment of unstable angina and non-Q wave myocardial infarction in combination with acetylsalicylic acid;
• prevention of thrombus formation in the extracorporeal circulation system during hemodialysis.

Clexane: dosing regimen

The drug is administered s / c. The drug should not be administered i / m!

To prevention of venous thrombosis and thromboembolism Patients with moderate risk (abdominalynaya surgery) prescribed Clexane^® by 20-40 mg (0.2-0.4 ml) n / a 1 time / day. The first injection is made for 2 hours prior to surgery.

Patients at high risk (Orthopedic surgery) appoint 40 mg (0.4 ml) n / a 1 time / day, and wherein the first dose is administered for 12 hours prior to surgery or 30 mg (0.3 ml) n / a 2 times / day starting administration via 12-24 hours after surgery.

The duration of treatment Kleksanom^® is 7-10 days. If necessary, treatment can be continued until, while keeping the risk of thrombosis or embolism (eg, orthopedics Clexane^® administered at a dose of 40 mg 1 times / day for 5 weeks).

To prevention of venous thrombosis in patients with acute therapeutic conditions, It is on bed rest, appoint 40 mg 1 times / day for 6-14 days.

To treatment of deep vein thrombosis administered by 1 mg / kg n / k every 12 no (2 times / day) or 1.5 mg / kg 1 time / day. In patients with complicated thromboembolic disorders it is recommended to use the drug in a dose 1 mg / kg 2 times / day.

The duration of treatment on average 10 days. It is advisable to immediately start treatment with indirect anticoagulants, while therapy Kleksanom^® should continue until a sufficient anticoagulant effect, ie. INR should be 2.0-3.0.

At unstable angina and myocardial infarction without Q wave the recommended dose of Clexane^® is 1 mg / kg n / k every 12 no. At the same time prescribe acetylsalicylic acid at a dose of 100-325 mg 1 time / day. The average duration of therapy is 2-8 days (to stabilize the clinical condition of the patient).

To prevention of thrombus formation in the extracorporeal circuit during hemodialysis dose Kleksana^® averages 1 mg / kg body weight. At high risk of bleeding dose should be reduced to 0.5 mg / kg when double vascular access or 0.75 mg / kg for single vascular access.

With hemodialysis drug should be administered in the arterial portion of the shunt at the beginning of hemodialysis. One dose, usually, enough for a four-hour session, However, upon detection of the fibrin ring with a longer dialysis can enter the drug calculation of 0.5-1 mg / kg body weight.

At impaired renal function necessary to adjust the dose depending on QC. At CC < 30 ml / min Clexane^® is introduced at the rate of 1 mg / kg body weight 1 time / day for therapeutic purposes and 20 mg 1 time / day as a prophylactic measure. The dosage regimen does not apply to cases of hemodialysis. At CC > 30 ml / min dose adjustment is required, but it should be more thoroughly carried out laboratory monitoring of therapy.

Terms of administration of the solution

The injection is preferably carried out with the patient lying. Clexane^® injected deep subcutaneously. When using pre-filled syringes 20 mg 40 mg prior to injection is not necessary to remove air bubbles from the syringe in order to avoid the loss of the drug. Injections should be held alternately in the left or right, or verhnebokovuyu inferolateral part of the anterior abdominal wall.

The needle must enter vertically over the entire length in the skin, holding a fold of skin between your thumb and forefinger. Folds of skin are released only after completion of injections. Do not massage the injection site after administration.

Clexane: side effects

Bleeding

If you want to cancel the development of bleeding drug, to establish the cause and start the appropriate treatment.

IN 0.01-0.1% cases may develop hemorrhagic syndrome, including retroperitoneal and intracranial bleeding. Some of these cases were fatal character.

When using Clexane^® against the backdrop of spinal / epidural anesthesia and postoperative use of penetrating catheters described cases of spinal hematoma (in 0.01-0.1% cases), which leads to neurological disorders of varying severity, including persistent or irreversible paralysis.

Thrombocytopenia

In the first days of treatment may develop slightly pronounced transient asymptomatic thrombocytopenia. Less than 0.01% cases of immune thrombocytopenia may develop in combination with thrombosis, which can sometimes be complicated by myocardial organ or limb ischemia.

Local reactions

After n / k administration may occur at the injection site pain, less than 0.01% cases – hematoma at the injection site. In some cases, the formation of solid inflammatory infiltrates, containing drug, to resolve in a few days, it does not require discontinuation of the drug. IN 0.001% at the injection site may develop skin necrosis, preceded by purpura or erythematous plaques (infiltrated and painful); In this case, the drug should be revoked.

Other

IN 0.01-0.1% – cutaneous or systemic allergic reactions. Cases of allergic vasculitis (less than 0.01%), demanded the abolition of the drug in some patients.

Perhaps asymptomatic and reversible increase in liver enzymes.

Clexane: Contraindications

• conditions and diseases, where there is a high risk of bleeding (threatened abortion, cerebral aneurysm, or dissecting aortic aneurysm / except surgery /, hemorrhagic stroke, Uncontrolled bleeding, Heavy enoxaparin- or geparin-indutsirovannaya thrombocytopenia);
• Age to 18 years (efficacy and safety have not been established);
• hypersensitivity to enoxaparin, heparin and its derivatives, including other low molecular weight heparins;
• the use of the drug in pregnant women with artificial heart valves is not recommended.

FROM caution is used in the following states: disorders of hemostasis (incl. hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease), tyazhelыy vasculitis, gastric ulcer and duodenal ulcers, or other erosive and ulcerative lesions of the gastrointestinal tract, recent myocardial ischemic stroke, uncontrolled severe arterial hypertension, diabeticheskaya or gemorragicheskaya retinopathy, severe diabetes, recently transferred or suspected neurological or ophthalmological surgery, holding a spinal or epidural anesthesia (potential risk of hematoma), spinnomozgovaya puncture (recently transferred), Recent childbirth, bacterial endocarditis (acute or subacute), pericarditis or pericardial effusion, kidney and / or liver failure, intrauterine contraception, severe injury (especially the central nervous system), open wounds with a large wound surface, concomitant use of drugs, affecting hemostasis.

The company has no data on the clinical use of the drug Clexane^® in the following states: active tuberculosis, radiation therapy (The recent).

Clexane: Pregnancy and lactation

Clexane^® should not be used during pregnancy except, when the intended benefits to the mother outweighs the potential risk to the fetus. For information about, that enoxaparin sodium crosses the placental barrier in II trimester, no, there is no information on the I and III trimesters of pregnancy.

When using Clexane^® lactation should stop breastfeeding.

Clexane: Special instructions

When administering the drug for prevention showed no tendency to increase bleeding. In appointing the drug for therapeutic purposes there is a risk of bleeding in patients older (especially in people over 80 years). It is recommended that a careful observation of the patient.

Before therapy with this drug should be repealed other drugs, affecting the hemostatic system due to the risk of bleeding: salicilaty, incl. acetylsalicylic acid, NSAIDs (including ketorolac); dextran 40, ticlopidine, clopidogrel, GCS, thrombolytics, antykoahulyantы, antiagregantы (including antagonists of glycoprotein IIb / IIIa), except, when their application is necessary. If necessary, the combined use of Clexane^® with these drugs need to be very careful (careful monitoring of the patient and the appropriate laboratory blood parameters).

In patients with impaired renal function are at risk of bleeding, by increasing the activity of anti-Xa. Unnecessarily. This increase is significantly increased in patients with severe renal impairment (CC < 30 ml / min), It is recommended as the correct dose for prophylactic, and therapeutic administration of drug. Although not required to carry out the dose adjustment in patients with mild and moderate renal impairment (CC > 30 ml / min), recommended that a close monitoring of such patients.

Increased anti-Xa activity of enoxaparin sodium when administered prophylactically in females weighing less than 45 kg male weighing less than 57 kg may lead to an increased risk of bleeding.

The risk of immune thrombocytopenia, heparin-induced, It exists when using low molecular weight heparins. If thrombocytopenia develops, then it is usually detected between 5 and 21 th days after initiation of therapy enoxaparin sodium. In this connection, it is recommended to regularly monitor the platelet count before treatment enoxaparin sodium and during its use. If there is evidence of substantial reduction in the number of platelets (on 30-50% compared to baseline) immediately cancel the enoxaparin sodium and transfer the patient to another therapy.

Spinalynaya / эpiduralynaya anesthesia

As with other anticoagulants, describes cases of spinal hematoma with the introduction of Clexane^® against the backdrop of spinal / epidural anesthesia with the development of persistent or irreversible paralysis. The risk of these effects is reduced when using the drug in doses 40 mg or below. The risk increases with the dose, and using penetrating epidural catheters after surgery, or by the concomitant use of additional drugs, has the same effect on hemostasis, NSAID. Risk is also increased by traumatic or repeated exposure lumbar puncture.

To reduce the risk of bleeding from the spinal canal with epidural or spinal anesthesia is necessary to take into account the pharmacokinetic profile of the drug. Installation or removal of the catheter is best performed at a low anticoagulant effect of enoxaparin sodium.

Installing or removing the catheter must be carried out later 10-12 h after administration of prophylactic doses of Clexane^® deep vein thrombosis. Where, when patients receiving higher doses of enoxaparin sodium (1 mg / kg 2 times / day or 1.5 mg / kg 1 time / day), These procedures should be postponed for a longer period of time (24 no). The subsequent administration of the drug should be administered no earlier than 2 hours after removal of the catheter.

If the doctor prescribes anticoagulant therapy during epidural / spinal anesthesia, It should be particularly careful continuous monitoring of the patient to identify any neurological signs and symptoms, such as: back pain, disorders of sensory and motor functions (numbness or weakness in the lower extremities), dysfunction of the bowel and / or bladder. The patient should be instructed to immediately inform the doctor in the event of the above symptoms. When signs or symptoms, characteristic bruising of the brain stem, need urgent diagnosis and treatment, including, if necessary, spinal decompression.

Geparin-indutsirovannaya thrombocytopenia

With extreme caution Clexane^® should be administered to patients, a history there is evidence of thrombocytopenia, heparin-induced, in combination with or without thrombosis.

The risk of thrombocytopenia, heparin-induced, may persist for several years. If on the basis of history it is supposed presence of thrombocytopenia, heparin-induced, the tests on platelet aggregation in vitro have limited value in predicting the risk of its development. The decision to appoint Clexane^® in such a case can be taken only after consultation with the appropriate specialist.

Chreskozhnaя koronarnaя angioplasty

To reduce the risk of bleeding, invasive vascular manipulation in the treatment of unstable angina and myocardial infarction without Q wave, the catheter should not be removed for 6-8 h after s / to the introduction Clexane^®. Following estimated dose should be administered no earlier than, than 6-8 hours after removal of the catheter. In the site of administration should be monitored, to timely detect signs of bleeding or hematoma formation.

Artificial heart valves

No studies have been conducted, allow to reliably estimate the efficacy and safety of Clexane^® preventing thromboembolic complications in patients with artificial heart valves, therefore, use of the drug for that purpose is not recommended.

Laboratory Tests

At doses, used for prevention of thromboembolic complications, Clexane^® no significant effect on bleeding time and overall performance of coagulation, as well as on platelet aggregation or the binding of fibrinogen.

At higher doses can be prolonged and aPTT clotting time. Image and APTT clotting time is not in direct linear function of increasing the antithrombotic activity of the drug, so there is no need for them to monitor.

Prevention of venous thrombosis and embolism in patients with acute therapeutic diseases, It is on bed rest

In the case of acute infection, acute rheumatic conditions prophylactic enoxaparin sodium is justified only if there is risk of venous thrombotic events (Age more 75 years, malignant neoplasms, thrombosis and embolism in history, obesity, gormonalynaya therapy, heart failure, chronic respiratory failure).

Effects on ability to drive vehicles and management mechanisms

Clexane^® no effect on the ability to drive and mechanisms.

Clexane: overdose

Symptoms. Accidental overdose at / in, ektrakorporalnom or s / c administration may lead to hemorrhagic complications. When administered in high doses even absorption of the drug is unlikely.

Treatment: as a neutralizing agent shown to slow in / in a Protamine sulfate, dose which depends on the dose administered Clexane^®. It should be taken into account, what 1 mg protamine neutralizes the anticoagulant effect 1 mg enoxaparin, if Clexane^® It imposes no more than, than 8 hours before the administration of protamine. 0.5 mg protamine neutralizes the anticoagulant effect 1 mg Clexane^®, if it introduced more 8 h ago or optionally second dose of protamine. If after administration Clexane^® It passed more 12 no, the administration of protamine is not required. However, even with large doses of protamine sulphate, anti-Xa activity Clexane^® completely neutralized (a maximum of 60%).

Clexane: drug interaction

With simultaneous use of Clexane^® with drugs, that affect hemostasis (salicylates / except for unstable angina and myocardial infarction without ST elevation ST /, other NSAIDs / including ketorolac /, dextran 40, ticlopidine, SCS for systemic use, thrombolytics, antykoahulyantы, antiplatelet agents / antagonists including glycoprotein IIb / IIIa /), may develop bleeding complications. If using such a combination can not be avoided, enoxaparin should be used under careful supervision of indicators blood clotting.

Do not alternate the use of enoxaparin sodium and other low molecular weight heparins, tk. they differ from each other in the way of production, molecular weight, specific anti-Xa activity, units and doses. These drugs, Consequently, different pharmacokinetics, Biological Activity (anti-IIa activity, and platelet interactions).

Pharmaceutical interaction

The solution Clexane^® should not be mixed with other drugs.

Clexane: terms of dispensing from pharmacies

The drug is released under the prescription.

Clexane: terms and conditions of storage

List B. The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 3 year.