Bluehep

Clear, colourless solution filled in clear glass vials.
Heparin Sodium Injection, USP is a sterile, non-pyrogenic solution of a highly purified sodium salt of heparin, a high molecular weight polysaccharide derived from porcine intestinal mucosa or beef lung. It is standardized in vitro according to the method of USP and is labeled in terms of USP units for use as an anticoagulant. It acts very rapidly and, even in large doses, is metabolized in the body and eliminated within 24 hours. It will not lyse existing thrombi or emboli.
Each mL contains: Heparin Sodium USP 1,000 IU (Derived from porcine intestinal mucosa).

Pharmacotherapeutic group: Heparin group.
Pharmacology: Pharmacodynamics: Heparin is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.
Pharmacokinetics: Heparin is not absorbed from the gastrointestinal tract. After intravenous or subcutaneous injection heparin is extensively bound to plasma proteins. It does not cross the placenta and it is not distributed into breast milk. The half-life of heparin depends on the dose and route of administration as well as the method of calculation and is subject to wide inter- and intra-individual variation; a range of 1 to 6 hours with an average of 1.5 hours has been cited. It may be slightly prolonged in renal impairment, decreased in patients with pulmonary embolism, and either increased or decreased in patients with liver disorders. Heparin is taken up by the reticuloendothelial system. It is excreted in the urine, mainly as metabolites, although after large doses up to 50% may be excreted unchanged.

It is used for the treatment and prophylaxis of thromboembolic disorders, venous thromboembolism (deep-vein thrombosis and pulmonary embolism), especially prophylaxis in surgical patients and in those pregnant women at particular risk. It is also used in the management of arterial thromboembolism including that associated with unstable angina pectoris, myocardial infarction, acute peripheral arterial occlusion and stroke. It is often used as a precursor to oral anticoagulation and is withdrawn once the oral anticoagulant is exerting its full effect. It has been tried in the treatment of disseminated intravascular coagulation. It is also used to prevent coagulation during haemodialysis and other extracorporeal circulatory procedures such as cardiopulmonary bypass.

Administration and dosage: Heparin is given intravenously, preferably by continuous infusion, or by subcutaneous injection. It may be given as the calcium or sodium salt and it is generally accepted that there is little difference in their effects.
For treatment of venous thromboembolism, an intravenous loading dose of 5,000 units (10,000 units may be required in severe pulmonary embolism) is followed by continuous intravenous infusion of 1,000 to 2,000 units/hour or subcutaneous injection of 15,000 units every 12 hours.
Alternatively, intermittent intravenous injection of 5,000 to 10,000 units every 4 to 6 hours is suggested in some product literature.
Children and small adults are given a lower intravenous loading dose followed by maintenance with continuous intravenous infusion of 15 to 25 units/kg per hour or subcutaneous injection of 250 units/kg every 12 hours.
For prophylaxis of post-operative venous thromboembolism, subcutaneous doses used are 5,000 units 2 hours before surgery then every 8 to 12 hours for 7 days or until the patient is ambulant. Similar doses are used to prevent thromboembolism during pregnancy in women with a history of deep-vein thrombosis or pulmonary embolism; the dosage may need to be increased to 10,000 units every 12 hours during the third trimester.
In the management of unstable angina or acute peripheral arterial embolism, heparin may be given by continuous intravenous infusion in the same doses as those recommended for the treatment of venous thromboembolism. Doses that have been recommended for the prevention of re-occlusion of the coronary arteries following thrombolytic therapy in myocardial infarction include 5,000 units intravenously followed by 1,000 units/hour intravenously with alteplase; a dose of 12,500 units subcutaneously every 12 hours for at least 10 days may be used to prevent mural thrombosis. Or as prescribed by the physician.

Symptoms: Overdose may be manifested by excessive prolongation of the APTT or by bleeding. Bleeding may be internal or external, major or minor. Note: Intramuscular injection (especially in the arm or thigh) and shallow subcutaneous injection is not recommended. The duration of effect is shortened and it is more likely to produce pain and hematoma.
Heparin sodium activity is expressed in USP units and should be prescribed in units only. The route of administration may be I.V. or S.C., depending upon the situation and the choice of the prescriber. Adequate heparin-induced anticoagulant therapy is present when the clotting time is elevated from 2 to 3 times normal as measured by the Lee-White method. Two types of dosage schedule are suggested: Heparin Sodium Injection, USP may be administered intravenously in a dose of 5,000 USP units every 4 hours or in a dose of 10,000 USP units every 6 hours, depending upon the results of a whole blood clotting time test performed at the bedside just prior to each additional dose. If the clotting time is less than twice normal, the next dose is increased by one-third to one-half. If the clotting time is more than 2 1/2 times normal, the next dose is decreased by one-third to one-half. If the clotting time is between 2 and 2 1/2 times normal, the regular dose is repeated.

Patients with a generalized clotting disorder such as hemophilia, Christmas disease, idiopathic thrombocytopenic purpura and patients with active bleeding from a local lesion such as an acute ulcer or ulcerating carcinoma; patients who have had recent cranial, spinal, eye or ear surgery or trauma; hypersensitivity to heparin, including thrombocytopenia; severe liver damage; shock.

Administration of large doses of Heparin Sodium Injection should be delayed 4 hours post-operatively.
When any of the conditions mentioned under Precautions are present, the advantages of Heparin Sodium Injection therapy must be carefully weighed against the possibility of deleterious results.

When considered for use in any of the following conditions, the advantages of heparin therapy must be carefully weighed against the risks: subacute bacterial endocarditis; increased capillary permeability; dissecting aneurysm; severe hypertension; during and immediately following major surgery, especially of the brain, spinal cord, eye or ear; conditions associated with increased bleeding tendencies such as hemophilia, thrombocytopenia and some purpuras; inaccessible gastrointestinal ulcers; ulcerative colitis; continuous tube drainage of stomach or small intestine; threatened abortion; menstruation; malignant hypertension. Heparin Sodium Injection should be used with caution in the immediate postoperative period. Bleeding may be concealed, as in the case of hemothorax. In patients with a history of heparin-induced thrombocytopenia (HIT), heparinoids (e.g., danaparoid), lepirudin and ancrod are considered appropriate alternatives to heparin. When used in therapeutic doses, heparin should be regulated by frequent blood coagulation indicators, particularly the APTT. If the indicator is unduly prolonged or if hemorrhage occurs, heparin should be at least temporarily discontinued.
Heparin can prolong the prothrombin time. Apparent resistance to heparin may be encountered in patients with acquired or familial AT III deficiency, because adequate levels of AT III are required for heparin's anticoagulant effect. Larger doses of heparin may be required initially in patients with various disease states due to alterations in their physiology, the pharmacokinetics of the drug, or elevations in levels of acute phase heparin binding proteins. Among these are febrile illness, infections associated with thrombosing tendencies, pulmonary embolism, myocardial infarction, extensive thrombotic disorders especially those associated with neoplastic disease and following surgery. Heparin should be used with caution in the presence of severe hepatic or renal disease, or in patients with indwelling catheters. A higher incidence of bleeding may be seen in women over 60 years of age. IM injections of other drugs should be avoided during heparin therapy to reduce the risk of hematoma formation and bleeding from the site. Most drugs can be given by another route (I.V. or S.C.). For these reasons, strict laboratory control of dosage is necessary. Heparin Sodium Injection should be used with caution in patients with allergy. Patients on long-term daily administration of Heparin Sodium Injection should be observed for the possible development of osteoporosis and spontaneous fractures of ribs and/or vertebrae.

Pregnancy: Heparin does not cross the placenta and has not been related to congenital defects. However, its use during pregnancy has been associated with a 13 to 22% risk of fetal mortality or prematurity. It is not clear whether severity of maternal disease or an indirect effect of heparin is responsible. Coumarin anticoagulants have been associated with a 31% incidence of unfavourable outcome and a definite drug-induced pattern of malformations has been demonstrated (fetal warfarin syndrome). However, the incidence of warfarin-induced fetopathic effects in the second and third trimesters is very low. In general, heparin is considered to be the anticoagulant of choice in pregnancy. Long-term usage (>3 to 5 months) of therapeutic doses of heparin during pregnancy increases the risk of osteoporosis and warrants careful monitoring of patients.
Heparin therapy during the last trimester and immediate postpartum period is associated with a risk of maternal hemorrhage. Changes in pharmacokinetics during pregnancy require caution and close patient monitoring if heparin is used. Reports of therapeutic failure with adjusted-dose heparin therapy in pregnant patients with prosthetic heart valves may have been due to inadequate dosing and/or monitoring, or to an inherent lack of efficacy in these patients. The American College of Chest Physicians recommends that if subcutaneous heparin is used in pregnant patients with mechanical heart valves, it be administered every 12 hours and the dose adjusted to keep the mid-interval APTT at least twice the control, or an anti-Xa heparin level of 0.35 to 0.7 U/mL. In addition, some clinicians suggest an initial dose of 17,500 to 20,000 units s.c. every 12 hours.
Lactation: Heparin is not excreted in breast milk because of its high molecular weight.

Bone and Joint: Therapeutic doses of heparin administered for longer than 3 months have been associated with osteoporosis and spontaneous vertebral fractures. Recent reports indicate that osteoporosis may be reversible after discontinuation of heparin.
Hematologic: Bleeding is the most common side effect of heparin and is an extension of its pharmacological effect. The rate of occurrence is approximately 10% overall but may increase up to 20% in patients treated with high-dose therapy. Risk of bleeding likely increases with APTT ratios above the recommended target range. Other risk factors associated with bleeding are: a serious concurrent illness, chronic heavy consumption of alcohol, use of platelet-inhibiting drugs, renal failure, age and female sex. Bleeding may range from minor local ecchymosis to major hemorrhagic events. Often, the first sign of bleeding may be epistaxis, hematuria or melena. Bleeding may be from any site and can be difficult to detect, e.g., retroperitoneal bleeds. Bleeding may also occur from surgical sites. Petechiae or easy bruising may precede frank hemorrhage. A supratherapeutic APTT or minor bleeding during therapy can usually be controlled by adjusting the dosage or withdrawing the drug.
Thrombocytopenia has also been described with heparin treatment. Heparin-Induced Thrombocytopenia (HIT) is an allergic reaction. It has been reported to occur in 1 to 30% of patients treated with standard heparin. It has also occurred with the use of LMWHs, both in patients with a history of HIT and patients with no previous exposure to heparin. The risk of developing HIT may be lower with LMWHs, but cannot be reliably estimated until more patients have been exposed. It is thought to be more common with heparin derived from bovine lung (5-10%) than from porcine gut (2-5%). Two types of acute, reversible thrombocytopenia have been described. Mild thrombocytopenia most commonly occurs between 5 and 12 days after initiation of full dose therapy. Platelet count usually remains above 100 x 109/L, and heparin therapy does not necessarily have to be withdrawn. Platelet count may remain stable or even increase despite continued therapy; however, it should still be monitored. The more severe, delayed form of thrombocytopenia (platelets <100 x 109/L), is much less frequent, usually appearing 5 to 12 days after starting heparin therapy and recurs rapidly on rechallenge. It has occurred with low dosages and is not dose-related. It is generally reversible; platelet counts usually begin to return to normal within 4 days of stopping heparin. Paradoxically, patients may develop thrombotic complications including arterial thrombosis, gangrene, stroke, myocardial infarction and disseminated intravascular coagulation. Thrombosis is due to "white clots" composed of platelets and fibrin that result from marked in vivo platelet aggregation. Patients receiving heparin acutely should have platelet counts monitored at least every 2 or 3 days.
Hepatic: Heparin has been reported to cause elevations of AST and ALT in approximately 27 and 59% of patients, respectively. Transient increases in serum LDH levels have also occurred. No clinical signs of liver dysfunction have been reported and the significance is not known, except that interpretation of liver enzymes for other purposes (i.e., liver disease) must take into consideration the possible contribution of heparin.
Hypersensitivity: Heparin-induced thrombocytopenia. Other allergic reactions to heparin are rare. The most common manifestations of hypersensitivity are chills, fever and urticaria. Asthma, rhinitis, tearing, headache, nausea, vomiting, shock and anaphylactoid reactions have also occurred. Vasospasm has been reported 6 to 10 days after starting heparin; the etiology is thought to be allergic. Vasospasm often appears in a limb where an artery has recently been catheterized. The affected limb is usually painful, ischemic and cyanotic.
Protamine sulfate is of no use in hypersensitivity reactions.
Miscellaneous: Alopecia, affecting the entire scalp or confined to the temple, may occur. Itching and burning of the plantar surfaces of the feet, suppression of aldosterone product, hyperkalemia (due to aldosterone suppression), priapism and rebound hyperlipidemia have also been reported. Heparin Neutralization with Protamine Bleeding which may occur during therapy with heparin can usually be corrected by withdrawal. Clotting time should then return to normal in 30 to 60 minutes provided venous clotting time is not longer than 15 minutes when the infusion is interrupted. Should withdrawal of heparin sodium fail to control bleeding, fresh, matched blood (not more than three days old) may be administered in quantities of 250 to 500 mL.
The most rapid means of counteracting the effects of heparin is intravenous administration of protamine sulfate injection. However, protamine is by itself an anticoagulant and therefore excess must be avoided. A dosing ratio of 1 milligram protamine for every 100 units of heparin remaining in the patient is the usual rule. It is recommended that protamine doses be guided by blood coagulation studies to determine if additional doses are required. The activated partial thromboplastin time (APTT) or activated clotting time (ACT) are adequate for this purpose.
Allowance should be made for the rapid removal of heparin from circulation. The rate of heparin removal from plasma is dose-dependent.
However, it may be assumed that about 30 minutes after an intravenous injection, about 50% of the heparin is removed from circulation. So the amount of protamine sulfate required to neutralize the heparin will be that of approximately half of that required for the original dose. For example, if 1,000 units required 10 mg of protamine sulfate for neutralization, half an hour after intravenous administration of a 5,000 unit dose, the amount of protamine sulfate required will only be approximately: 5/2 x 10=25 mg. Too rapid administration of protamine can cause severe hypotensive and anaphylactoid reactions. Facilities to treat shock should be readily available when administering protamine. The rate of protamine administration should not exceed 20 mg/min and no more than 50 mg should be given in any 10-minute period. Doses exceeding 100 mg in a short period of time should be avoided, unless there is certain knowledge of larger protamine requirements. Any excess protamine sulfate, not complexed to heparin, has its own intrinsic anticoagulant effect. However, one study found overdose of protamine up to 600 to 800 mg I.V. to have only minor, transient effects on blood coagulation.
ADR Reporting Statement: Seek medical attention immediately at the first sign of any adverse drug reaction.

Oral anticoagulants (i.e., warfarin) can contribute to a small extent to an increase in APTT. Heparin can contribute to an increase in PT. While these two drugs are given together, the fact that each may contribute to an increase in PT and APTT should be taken into account. Heparin is often started with or several hours after thrombolytic therapy. Close patient monitoring for clinical signs of bleeding is indicated. The APTT should also be monitored closely. Salicylates, other nonsteroidal anti-inflammatory agents, dextran, dipyridamole, clopidogrel, ticlopidine and GPIIb-IIIa antagonists interfere with platelet aggregation which increases the risk of bleeding. They should be used cautiously with monitoring for signs of hemorrhage. In addition, in some situations, when heparin is used in conjunction with GPIIb-IIIa antagonists, the dose of heparin may need to be modified.
Ethacrynic Acid: Intravenously administered ethacrynic acid can cause GI bleeding. However, a significantly higher incidence of GI bleeding has been attributed to the concurrent use of intravenous ethacrynic acid and heparin. Furosemide may be a safer alternative when diuretic therapy is indicated in the patient receiving heparin.
Acetylsalicylic Acid: In a review article of heparin therapy, it was advocated that concurrent acetylsalicylic acid administration be "scrupulously avoided". While documentation to support this interaction is incomplete, it would be prudent to avoid concurrent therapy. Acetylsalicylic acid impairs the platelet release reaction and this platelet function defect combined with the anticoagulant effect of heparin may produce a hemorrhagic tendency.
Dextran: Limited data suggest that dextran and heparin may act synergistically when administered concurrently. Although the data are inadequate to document the clinical significance of this interaction, baseline laboratory measurements of anticoagulant activity should be obtained upon initiation of concurrent therapy as well as at frequent intervals during such therapy.

Directions for Use: The dosage of heparin sodium should be adjusted according to the patient's coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every 4 hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. Remaining portion should be discarded.

Store at temperatures not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AB01 - heparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.

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