Ksimiksan^® (Solution) Instructions for Use

Marketing Authorization Holder

Pharmaceutical Technologies, LLC (Russia)

Manufactured By

Dalkhimpharm, JSC (Russia)

ATC Code

B01AB05 (Enoxaparin)

Active Substance

Enoxaparin sodium (Rec.INN registered by WHO)

Dosage Forms

	Ksimiksan®	Solution for injection 2000 anti-Xa IU/0.2 ml
		Solution for injection 4000 anti-Xa IU/0.4 ml
		Solution for injection 6000 anti-Xa IU/0.6 ml
		Solution for injection 8000 anti-Xa IU/0.8 ml
		Solution for injection 10000 anti-Xa IU/1.0 ml

Dosage Form, Packaging, and Composition

Solution for injection

0.2 ml – ampoules (10 pcs.) – cardboard boxes – By prescription
0.2 ml – ampoules (10 pcs.) – cardboard packs – By prescription
0.2 ml – ampoules (5 pcs.) – cardboard packs – By prescription

Solution for injection

0.4 ml – ampoules (10 pcs.) – cardboard boxes – By prescription
0.4 ml – ampoules (10 pcs.) – cardboard packs – By prescription
0.4 ml – ampoules (5 pcs.) – cardboard packs – By prescription

Solution for injection

0.6 ml – ampoules (10 pcs.) – cardboard boxes – By prescription
0.6 ml – ampoules (10 pcs.) – cardboard packs – By prescription
0.6 ml – ampoules (5 pcs.) – cardboard packs – By prescription

Solution for injection

0.8 ml – ampoules (10 pcs.) – cardboard boxes – By prescription
0.8 ml – ampoules (10 pcs.) – cardboard packs – By prescription
0.8 ml – ampoules (5 pcs.) – cardboard packs – By prescription

Solution for injection

1 ml – ampoules (10 pcs.) – cardboard boxes – By prescription
1 ml – ampoules (10 pcs.) – cardboard packs – By prescription
1 ml – ampoules (5 pcs.) – cardboard packs – By prescription

Clinical-Pharmacological Group

Direct-acting anticoagulant – low molecular weight heparin

Pharmacotherapeutic Group

Direct-acting anticoagulant agent

Pharmacological Action

Direct-acting anticoagulant. It belongs to the group of low molecular weight heparins (molecular weight about 4500 daltons). It has an antithrombotic effect. It has pronounced activity against factor Xa and weak activity against factor IIa. Unlike unfractionated standard heparin, antiplatelet activity is more pronounced than anticoagulant activity. It does not affect platelet aggregation.

In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified. This includes AT-III-dependent inhibition of other coagulation factors, such as factor VIIa, activation of tissue factor pathway inhibitor (TFPI) release, and reduction of von Willebrand factor release from the vascular endothelium into the bloodstream. These factors provide the anticoagulant effect of enoxaparin sodium as a whole.

Pharmacokinetics

After subcutaneous administration, it is rapidly and almost completely absorbed from the injection site. The peak of anti-Xa activity of enoxaparin in blood plasma is reached after 3-5 hours, which corresponds to a concentration of 1.6 µg/ml after administration of 40 mg. Anti-IIa activity in blood plasma is approximately 10 times lower than anti-Xa activity.

The V_d of anti-Xa activity of enoxaparin sodium is about 4.3 L and approaches the blood volume.

Enoxaparin sodium is mainly metabolized in the liver by desulfation and/or depolymerization to form low molecular weight substances with very low biological activity.

Elimination is monophasic with a T_1/2 of about 5 hours (after a single subcutaneous administration) and about 7 hours (after multiple administrations). Renal excretion of active fragments of enoxaparin sodium is approximately 10% of the administered dose, total renal excretion of active and inactive fragments is approximately 40% of the administered dose.

Indications

Prevention of thromboembolism, especially in orthopedic practice and general surgery; treatment of deep vein thrombosis; prevention of hypercoagulation in the extracorporeal circulation system during hemodialysis. Treatment of unstable angina and myocardial infarction without pathological Q wave on ECG (in combination with acetylsalicylic acid).

ICD codes

Dosage Regimen

Administer subcutaneously, intravenously, or into the dialysis system.

For thrombosis prevention in general surgery, use 2000 anti-Xa IU (20 mg) subcutaneously once daily, starting 2 hours preoperatively.

For thrombosis prevention in high-risk orthopedic surgery, use 4000 anti-Xa IU (40 mg) subcutaneously once daily, starting 12 hours preoperatively.

For treatment of deep vein thrombosis with or without pulmonary embolism, administer 150 anti-Xa IU/kg (1.5 mg/kg) subcutaneously once daily or 100 anti-Xa IU/kg (1 mg/kg) subcutaneously every 12 hours.

For treatment of unstable angina and non-Q-wave myocardial infarction, use 100 anti-Xa IU/kg (1 mg/kg) subcutaneously every 12 hours in combination with acetylsalicylic acid.

For prevention of clotting in the extracorporeal circulation during hemodialysis, administer an initial 100 anti-Xa IU/kg (1 mg/kg) dose intravenously into the arterial line of the circuit.

In patients with severe renal impairment (CrCl 15-30 ml/min), reduce the dose for therapeutic indications by administering 100 anti-Xa IU/kg (1 mg/kg) once daily.

Avoid use in patients with CrCl <15 ml/min, except for hemodialysis.

Do not use an initial intravenous bolus in patients aged 75 years and older.

Monitor platelet counts regularly before and during therapy.

Discontinue immediately if thrombocytopenia occurs or platelet count drops by 30-50%.

Use with caution in patients weighing less than 45 kg (women) or less than 57 kg (men) due to increased exposure and bleeding risk.

Adverse Reactions

From the hematopoietic system and blood coagulation system bleeding, thrombocytopenia, thrombocytosis, autoimmune thrombocytopenia with thrombosis, organ infarction or limb ischemia, hemorrhagic anemia, eosinophilia.

From the immune system allergic reactions, anaphylactic/anaphylactoid reactions, including shock.

From the nervous system headache; when using enoxaparin sodium against the background of spinal/epidural anesthesia or spinal puncture, cases of spinal hematoma (or neuroaxial hematoma) have been noted. These reactions led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis.

From the liver and biliary tract increased activity of liver enzymes, mainly increased activity of transaminases, hepatocellular liver damage, cholestatic liver damage.

From the skin and subcutaneous tissues urticaria, skin itching, erythema, bullous dermatitis, alopecia.

From the musculoskeletal system with long-term therapy (more than 3 months) – osteoporosis.

From laboratory parameters hyperkalemia.

Local reactions at the injection site, hematoma, pain, swelling, infiltration, inflammation, formation of indurations, irritation, skin necrosis are possible. Cutaneous vasculitis, skin necrosis may develop at the injection site, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful). In these cases, therapy with enoxaparin sodium should be discontinued.

Contraindications

Hypersensitivity to enoxaparin; conditions with a high risk of uncontrolled bleeding (including ulcerative lesions of the gastrointestinal tract, recent hemorrhagic stroke); spinal or epidural anesthesia or locoregional anesthesia when Enoxaparin sodium was used for treatment in the previous 24 hours; immune-mediated heparin-induced thrombocytopenia (in history) within the last 100 days or the presence of circulating antiplatelet antibodies in the blood; children and adolescents under 18 years of age.

With caution

Conditions in which there is a potential risk of bleeding: hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease), severe vasculitis; gastric or duodenal ulcer or other erosive-ulcerative lesions of the gastrointestinal tract in history; recent ischemic stroke; uncontrolled severe arterial hypertension; diabetic or hemorrhagic retinopathy; severe diabetes mellitus; recently performed or anticipated neurological or ophthalmic surgery; spinal or epidural anesthesia (potential risk of hematoma development), spinal puncture (recently performed); recent childbirth; bacterial endocarditis (acute or subacute); pericarditis or pericardial effusion; renal and/or hepatic insufficiency; intrauterine contraception (IUC); severe trauma (especially CNS), open wounds on large surfaces; simultaneous use of drugs affecting the hemostasis system; heparin-induced thrombocytopenia without circulating antibodies in history (more than 100 days).

There are no data on the clinical use of enoxaparin sodium in the following diseases: active tuberculosis, radiation therapy (recently performed).

Use in Pregnancy and Lactation

During pregnancy, it is possible to use only in exceptional cases when there is an urgent need for its use, established by a doctor. It is believed that Enoxaparin sodium can be used during breastfeeding.

Use in Hepatic Impairment

It should be used with caution in patients with impaired liver function.

Use in Renal Impairment

It should be used with caution in renal failure.

The use of enoxaparin sodium is not recommended for patients with CrCl <15 ml/min, except for cases of prevention of thrombus formation in the extracorporeal circulation system during hemodialysis. In patients with CrCl >15 and <30 ml/min, dose adjustment is required.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

It should be used with caution in elderly patients. When used in therapeutic doses in elderly patients (especially aged 80 years and older), there is an increased risk of bleeding. In patients aged 75 years and older, initial intravenous bolus administration is not used.

Special Precautions

Do not administer intramuscularly. Low molecular weight heparins are not interchangeable.

If there is a history of heparin-induced thrombocytopenia, Enoxaparin sodium can be used only in cases of extreme necessity.

Before starting and during treatment, the number of platelets in the peripheral blood should be regularly monitored. If this indicator decreases by 30-50% from the initial value, Enoxaparin sodium should be immediately discontinued and appropriate therapy should be prescribed. Before starting use, agents that could potentially affect hemostasis should be discontinued; if this is not possible, then simultaneous therapy is carried out under careful monitoring of coagulation parameters.

An increase in the exposure of enoxaparin sodium during its prophylactic use was noted in women weighing less than 45 kg and in men weighing less than 57 kg, which may lead to an increased risk of bleeding. It is recommended to carefully monitor the condition of such patients.

Obese patients have an increased risk of thrombosis and embolism. It is recommended to monitor patients for the development of symptoms and signs of thrombosis and embolism.

Enoxaparin sodium should be used with particular caution in patients with a history (more than 100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in this situation should be made only after assessing the benefit/risk ratio and in the absence of a heparin-free alternative therapy.

Prevention of venous thrombosis and embolism in patients with acute therapeutic diseases who are on bed rest. In case of development of acute infection, acute rheumatic conditions, prophylactic use of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombosis: age over 75 years, malignant neoplasms, history of thrombosis and embolism, obesity, hormonal therapy, heart failure, chronic respiratory failure.

Drug Interactions

With simultaneous use with drugs that affect hemostasis (salicylates, other NSAIDs, dextran 40, ticlopidine, clopidogrel, corticosteroids, thrombolytics, anticoagulants), the anticoagulant effect of enoxaparin sodium is enhanced, and hemorrhagic complications may develop.

With simultaneous use with drugs that increase the potassium content in the blood serum, clinical and laboratory monitoring should be carried out.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.