Megaparin

Uses

Megaparin is used for:

Treatment of deep vein thrombosis, with or without pulmonary embolism.

Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin.

Prevention of thrombus formation in the extra-corporal circulation during haemodialysis.

Prophylaxis of venous thromboembolic disease (prevention of blood clot formation in the veins), in particular those which may be associated with orthopedic or general surgery.

Prophylaxis of venous thromboembolic disease in medical patients bedridden due to acute illness, including cardiac insufficiency, respiratory failure, severe infections, rheumatic diseases.

Megaparin is also used to associated treatment for these conditions: Acute Coronary Syndrome (ACS), Acute ST-segment Elevation Myocardial Infarction, Deep Vein Thrombosis, Ischemic complications caused by non-q wave myocardial infarction, Ischemic complications caused by unstable angina, Percutaneous Coronary Intervention (PCI)

How Megaparin works

Megaparin binds to antithrombin III, a serine protease inhibitor, forming a complex that irreversibly inactivates factor Xa, which is frequently used to monitor anticoagulation in the clinical setting. Following factor Xa inactivation, enoxaparin is released and binds to other anti-thrombin molecules. Factor IIa (thrombin) is directly inhibited by enoxaparin, however with less potency than unfractionated heparin (UFH). Due to the cascade of effects resulting from enoxaparin binding, thrombin is unable to convert fibrinogen to fibrin and form a clot, preventing thromboembolic events.

Dosage

Megaparin dosage

Adults:

Prophylaxis of venous thromboembolism: In patients with a low to moderate risk of venous thromboembolism the recommended dosage is 20 mg (2,000 IU) once daily by subcutaneous injection for 7 to 10 days, or until the risk of thromboembolism has diminished. In patients undergoing surgery, the initial dose should be given approximately 2 hours pre-operatively. In patients with a higher risk, such as in orthopaedic surgery, the dosage should be 40 mg (4,000 IU) daily by subcutaneous injection with the initial dose administered approximately 12 hours before surgery.

Prophylaxis of venous thromboembolism in medical patients: The recommended dose of enoxaparin sodium is 40 mg (4,000 IU) once daily by subcutaneous injection. Treatment with enoxaparin sodium is prescribed for a minimum of 6 days and continued until the return to full ambulation, for a maximum of 14 days.

Treatment of venous thromboembolism: Megaparin should be administered subcutaneously as a single daily injection of 1.5 mg/kg (150 IU/kg). Megaparin treatment is usually prescribed for at least 5 days and until adequate oral anticoagulation is established.

Treatment of unstable angina and non-Q-wavemyocardial infarction: The recommended dose is 1 mg/kg Megaparin every 12 hours by subcutaneous injection, administered concurrently with oral aspirin (100 to 325 mg once daily). Treatment with Megaparin in these patients should be prescribed for a minimum of 2 days and continued until clinical stabilisation. The usual duration of treatment is 2 to 8 days.

Treatment of acute ST-segment Elevation Myocardial Infarction: The recommended dose of enoxaparin sodium is a single IV bolus of 30 mg plus a 1mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (max 100mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses).

Prevention of extracorporeal thrombus formation during haemodialysis: A dose equivalent to 1 mg/kg (100 IU/kg) introduced into the arterial line at the beginning of a dialysis session is usually sufficient for a 4 hour session. If fibrin rings are found, such as after a longer than normal session, a further dose of 0.5 to 1 mg/kg (50 to 100 IU/kg) may be given. For patients at a high risk of haemorrhage the dose should be reduced to 0.5 mg/kg (50 IU/kg) for double vascular access or 0.75 mg/kg (75 IU/kg) for single vascular access.

Elderly:

For treatment of acute ST-segment Elevation Myocardial Infarction in elderly patients 75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses). For other indications, no dosage adjustments are necessary in the elderly, unless kidney function is impaired.

Children:

Not recommended, as dosage not established.

Side Effects

Haemorrhage (bleeding), Thrombocytopenia, elevations of serum aminotransferase. Pain, bluish marks at injection sites to skin rash at injection sites. Cases of neuraxial hematomas with the concurrent use of Megaparin and spinal/epidural anesthesia or spinal puncture have resulted in varying degrees of neurologic injuries.

Toxicity

The oral LD50 for enoxaparin in mice is >5000 mg/kg; the subcutaneous LD50 of enoxaparin in mice is >2500 mg/kg. Accidental overdose after the administration of enoxaparin may cause hemorrhage. Megaparin administered by injection is mainly neutralized by gradual intravenous injection of a 1% protamine sulfate solution. The dose of protamine sulfate should be equal to the dose of enoxaparin administered: 1 mg protamine sulfate for 1 mg enoxaparin, of enoxaparin was administered in the previous 8 hours. If a minimum of 12 hours has passed since the last enoxaparin dose, protamine may not be necessary; it is important to avoid an overdose with protamine, as fatal reactions may occur.

Precaution

Megaparin injection should not be administered by intramuscular route. Megaparin should be used with caution in conditions with increased potential for bleeding, such as impaired hemostasis, history of peptic ulcer, recent ischemic stroke, uncontrolled severe arterial hypertension, diabetic retinopathy, recent neuro or opthalmologic surgery and low weight patients. It is recommended that the platelet count be measured befored the initiation of the treatment and regularly thereafter during treatment.

Interaction

It is recommended that agents which affect haemostasis should be discontinued prior to enoxaparin therapy unless their use is essential, such as: systemic salicylates, acetylsalicylic acid, NSAIDs including ketorolac, dextran, and clopidogrel, systemic glucocorticoids, thrombolytics and anticoagulants. If the combination cannot be avoided, enoxaparin should be used with careful clinical and laboratory monitoring.

Food Interaction

• Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Megaparin Hypertension interaction

[Major] Heparin should be used with extreme caution in patients with uncontrolled or severe hypertension as these conditions may predispose the patient to hemorrhage during heparin administration.

Blood coagulation tests (e.g., whole blood clotting time, activated partial thromboplastin time) should be performed at appropriate intervals during full-dose heparin administration.

In addition, periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy.

Clinical monitoring of blood pressure is recommended.

[Moderate] Anticoagulants should be used with extreme caution in patients at increased risk for hemorrhage, including those patients with severe hypertension.

Megaparin Drug Interaction

Major: aspirin, aspirinModerate: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acidsUnknown: albuterol / ipratropium, albuterol / ipratropium, insulin isophane, insulin isophane, acetaminophen, acetaminophen, senna, senna, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Megaparin Disease Interaction

Major: hemophilia, liver disease, peptic ulcer disease, retinopathy, subacute bacterial endocarditis, active bleeding, hypertension, renal dysfunction, thrombocytopenia, prematurityModerate: hypertension, kidney disease

Volume of Distribution

The volume of distribution of enoxaparin is approximately 4-5L, similar to normal blood volume.

Elimination Route

Mean absolute bioavailability of enoxaparin, after 1-2 mg/kg given subcutaneously is approximately 100% in healthy volunteers. The absorption of enoxaparin is proportional to the dose, demonstrating linear absorption. The average maximum plasma anti-Xa activity is reached 3 to 5 hours after a subcutaneous injection. A 30 mg IV bolus preceding an immediate 1 mg/kg SC every twice a day led to maximum anti-Factor Xa levels of 1.16 IU/mL. Steady-state is reached within 3-4 days of treatment with a Cmax of 1.2 IU/mL. The AUC under the thrombin generation curve was 305 +/- 48.

Half Life

The half-life of enoxaparin is about 4 hours after a single dose administered subcutaneously and about 7 hours after several doses. One source mentions a half-life ranging from 1 hour to 4.5 hours.

Clearance

The mean clearance of enoxaparin is 0.74 L/h after a 1.5 mg/kg intravenous infusion over 6 hours; clearance of enoxaparin is significantly decreased in patients with severe renal impairment.

Elimination Route

Megaparin is mainly excreted by the kidneys. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

Pregnancy & Breastfeeding use

Pregnancy category B. In humans, there is no evidence that Megaparin crosses the placental barrier Megaparin should be used during pregnancy only if the physician has established a clear need. Megaparin is not recommended for use in pregnant women with prosthetic heart valves.

Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Megaparin injection is administered to nursing women.

Contraindication

Hyper-sensitivity to either Megaparin, heparin or other low molecular weight heparins; major clotting disorders like history of thrombocytopenia, active gastro-intestinal ulcer or organic lesion likely to bleed, recent haemorrhagic vascular cerebral stroke. Although rare, cutaneous or systemic allergic reactions may occur.

Special Warning

Dose in Renal Impairment: Although no dosage adjustment is recommended in patients with moderate (creatinine clearance: 30-50 ml/min) and mild (creatinine clearance: 50-80 ml/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding. For patients with severe (creatinine clearance <30 ml/min) renal impairment, following dosage adjustments are recommended: Prophylactic dose ranges: 2000 anti Xa IU once daily; Therapeutic dose ranges: 100 anti-Xa lU/kg once daily.

Dose in Hepatic Impairment: Caution should be used in hepatically impaired patients.

Acute Overdose

Accidental overdosage following administration of Megaparin may lead to hemorrhagic complications. Injected Megaparin may be largely neutralized by the slow i.v. injection of protamine sulfate (1% solution) The dose of protamine sulfate should be equal to the dose of Megaparin injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Megaparin.

Storage Condition

Store below 25° C. Do not freeze. Keep out of the reach of children.

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