Heparin (Heparin)

HEPARIN: UNFRACTIONATED

General Monograph

Heparin Sodium

Anticoagulant

Action And Clinical Pharmacology: Heparin is a heterogeneous preparation of sulfated mucopolysaccharide polymers whose molecular weights range from 3 000 to 30 000 daltons, averaging between 12 000 and 15 000 daltons. Heparin exerts its anticoagulant activity by reversibly binding to antithrombin III (AT III), accelerating the ability of AT III to neutralize thrombin and activated coagulation factor X (Xa). The heparin-AT III complex also inactivates activated coagulation factors IX, XI, XII and plasmin. Thrombin and factor Xa are the most sensitive to inactivation by the heparin-AT III complex.

Heparin is not a thrombolytic agent. It does not directly cause clot lysis, but prevents progression of the existing clot by inhibiting any further clotting processes, allowing naturally occurring thrombolytics to slowly effect clot lysis.

At therapeutic doses, heparin prolongs several coagulation tests including activated coagulation time, activated partial thromboplastin time (APTT, used clinically), plasma recalcification time, prothrombin time (minimally), thrombin time and whole blood clotting time.

Pharmacokinetics: Heparin is not absorbed through the gastrointestinal mucosa and must be given parenterally, usually by i.v. infusion or deep s.c. injection. The onset of action is immediate after i.v. injection but can be delayed 20 to 60 minutes following s.c. injection. Heparin is extensively bound to plasma proteins. Heparin does not cross the placental barrier and is not distributed into breast milk. Heparin is not removed by hemodialysis.

The dose-response relationship of heparin is not linear. Anticoagulant effect increases disproportionately in intensity and duration as the dose is increased. The plasma half-life of heparin increases from approximately 60 minutes with a 100 unit/kg dose to about 150 minutes with a 400 unit/kg dose. Clinically a half-life of approximately 90 minutes is used.

Heparin is cleared via a dual mechanism. At low doses, clearance is predominantly through a saturable mechanism by the reticuloendothelial system. At higher doses, renal clearance through a nonsaturable mechanism also occurs. The rapid saturable mechanism predominates at therapeutic heparin concentrations.

The clearance of heparin from plasma is accelerated in patients with pulmonary embolism and may be reduced in patients with cirrhosis or severe renal impairment.

There is no definitive evidence that the pharmacokinetic or anticoagulant properties of the forms of heparin derived from porcine or bovine sources or prepared as sodium or calcium salts are different (see Adverse Effects).

Indications And Clinical Uses: Heparin is used in the treatment of acute deep venous thrombosis and pulmonary embolism. It is effective when used prophylactically in low doses to prevent the occurrence of venous thromboembolism in moderate risk patients.

Heparin is used to prevent clotting during dialysis and to prevent intravascular coagulation during open heart surgical procedures.

The use of heparin in the treatment of cerebral and coronary thrombosis is controversial. If used during stroke, heparin should only be used if hemorrhage has been ruled out and there are major, progressing neurological deficits. In patients with acute MI who are also receiving thrombolytics, i.v. heparin therapy in conjunction with low dose oral ASA is recommended. In patients with unstable angina, continous i.v. heparin can reduce the incidence of acute MI and recurrent angina, but it is not known if mortality is reduced.

Dilute concentrations of heparin are used to maintain the patency of i.v. injection devices; however, in the case of peripheral devices, heparin is no more effective than 0.9% sodium chloride for injection.

Contra-Indications: Patients with a generalized hemostatic abnormality 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 neurosurgery or spinal surgery; hypersensitivity to heparin, including thrombocytopenia; severe liver damage; shock.

Manufacturers’ Warnings In Clinical States: Administration of large doses of heparin should be delayed at least 4 hours postoperatively.

Precautions: Anticoagulants are thought to be of no value in completed stroke and may even increase the risk of fatal cerebral bleeding. When considered for use in any of the following conditions, the advantages of heparin therapy must be carefully weighed against the risks:

Cardiovascular: subacute bacterial endocarditis; increased capillary permeability; dissecting aneurysm; severe hypertension; during and immediately following major surgery, especially of the brain, spinal cord and eye.

Hematologic: conditions associated with increased bleeding tendencies such as hemophilia, some purpuras and thrombocytopenia. In patients with a history of heparin-induced thrombocytopenia (HIT), danaparoid and ancrod are considered alternatives.

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 (see Overdose). Monitoring can be effectively performed using a weight-based heparin dose adjustment nomogram.

Heparin can prolong the prothrombin time.

Apparent resistance to heparin may be encountered in patients with acquired or familial AT III deficiency, since 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. Some of these disease states have been reported to be: febrile illness, infections associated with thrombosing tendencies, pulmonary embolism, myocardial infarction, extensive thrombotic disorders especially those associated with neoplastic disease and following surgery.

Gastrointestinal: inaccessible ulcerative lesions; ulcerative colitis; continuous tube drainage of stomach or small intestine.

Obstetric: threatened abortion; menstruation.

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.

Patients on long-term daily administration of heparin should be observed for the possible development of osteoporosis and spontaneous fracture of ribs and/or vertebrae.

Drug Interactions: 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 (see Precautions).

Heparin is often started with or several hours after thrombolytic therapy with alteplase or streptokinase, to increase patency of coronary vessels after coronary thrombolysis. The APTT should be monitored closely, starting 4 to 6 hours after initiation of heparin therapy. Close patient monitoring for clinical signs of bleeding is indicated.

Salicylates, other nonsteroidal anti-inflammatory agents, dextran, dipyridamole and ticlopidine interfere with platelet aggregation which increases the risk of bleeding. Use with caution and monitor patients for signs of hemorrhage.

Cefamandole, cefotetan, methimazole, propylthiouracil and valproic acid may cause hypoprothrombinemia and increase the risk of bleeding; monitor patient for signs of bleeding.

Probenecid may increase and prolong the anticoagulant action of heparin.

Nitroglycerin, i.v., may reduce heparin’s anticoagulant effect and necessitate higher doses. This interaction has been reported to occur regardless of whether or not propylene glycol is used as a solvent for the nitroglycerin. The mechanism has not been conclusively documented. When i.v. nitroclycerin therapy is initiated, monitor patients closely to ensure anticoagulation remains adequate. Likewise, when nitroglycerin therapy is stopped, a decrease in heparin dosage may be necessary and patients should be monitored for signs of excessive anticoagulation.

Digitalis, quinine, ACTH, insulin, corticosteroids, antihistamines and nicotine have been reported to interfere with the anticoagulant effect of heparin; however, there is no substantial literature support to document these interactions.

I.M. 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.).

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. While this appears high, 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% unfavorable 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 on this type of therapy. Like heparin, low molecular weight heparins (LMWHs) do not cross the placenta and may be considered in pregnant patients with osteoporosis (see Adverse Effects). 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 or to an inherent limitation in these patients. If used in this group, heparin should be administered in high doses with careful laboratory monitoring.

Lactation: Heparin is not excreted in breast milk because of its high molecular weight.

Adverse Reactions: Hematologic: Bleeding is the most common side effect of heparin and is an extension of its pharmacological effect. 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 ecchymoses 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, i.e., 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 (see Overdose).

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 to 10%) than from porcine gut (2 to 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´10L, 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
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.

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 (see Adverse Effects, Hematologic). 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. Vasopasm 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 production, hyperkalemia (due to aldosterone suppression), priapism and rebound hyperlipidemia have also been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: If the APTT is excessive but bleeding is not apparent or minor, heparin infusion may be stopped temporarily and then restarted if desired, at a reduced rate. The heparin antagonist, protamine sulfate, can be considered for severe bleeding, especially if the APTT is greater than 3 times control.

If immediate reversal of heparinization is desired, 1 mg of protamine sulfate can be used to neutralize approximately 90 units of bovine lung source heparin and 115 units of porcine intestinal mucosa source heparin. The amount of heparin neutralized by protamine not only varies with the organ from which it is derived but also with the method of manufacture and the specific activity of heparin. The amount of protamine required to neutralize 1 000 units of an individual lot of heparin can be determined and may be listed on individual product labels.

Too rapid administration of protamine can cause severe hypotensive and anaphylactoid-like 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.

Due to the relatively short half-life of heparin (approximately 90 minutes), decreasing amounts of protamine sulfate are required as time from the last heparin injection increases.

If heparin is given by continuous infusion, 25 to 50 mg of protamine sulfate may be given slowly after stopping the infusion. If heparin was given by deep s.c. injection, protamine dosage should be determined according to the amount given.

Dosage And Administration: Heparin may be given by intermittent or continuous i.v. infusion or by deep (intrafat) s.c. injection, depending upon the situation and the prescriber’s choice. Avoid i.m. injection of heparin. Continuous infusion is the preferred method for administration of full-dose heparin therapy, but requires the use of a constant rate infusion pump. Intermittent infusions are not recommended, having been associated with a higher incidence of bleeding, likely due to higher total dosages required. Undesirable fluctuations of over- and under-coagulation also occur with intermittent infusions due to the short half-life of heparin. The s.c. route is usually reserved for prophylactic administration of heparin; however, it can also be given in dosages sufficient to treat thromboembolism. Ideally, the dose of heparin should be adjusted to prolong the APTT to a targeted therapeutic range based on a “gold standard” heparin assay (0.2 to 0.4 units/mL by protamine sulfate titration).

Dosage requirements for full-dose heparin therapy vary widely between individuals. Body weight is a relatively good predictor of heparin dose and initial dosages may be calculated on a unit/kg basis.

An initial APTT should be obtained 6 hours after commencement of heparin therapy and after every change in infusion rate. In children, an APTT should be obtained 4 hours after the loading dose and every 4 hours following each change in infusion rate. It is desirable to obtain 2 or 3 APTT determinations in the first 24 hours to stabilize the dose, and then one each day for the remainder of heparin therapy. Further dosage changes should reflect both laboratory and clinical findings.

The duration of heparin therapy ranges from 5 to 14 days. The 5-day course has been reported to be as effective as 7- to 10-day courses for proximal venous thrombosis and submassive pulmonary embolism. For patients with recurrent thrombotic events, massive pulmonary embolism or massive iliofemoral venous thrombosis, a 7- to 10-day course may be more effective.

Treatment of Venous Thrombosis and Pulmonary Embolism (Full-Dose Therapy): The following regimens have been recommended: I.V.: a) Initial bolus of 5 000 units, followed by 30 000 to 40 000 units by continuous infusion over 24 hours. b) Initial bolus of 80 units/kg, followed by continuous infusion of 18 units/kg/h.

Children: Initial bolus of 75 to 100 units/kg followed by continuous infusion of 28 units/kg/h for infants, 20 units/kg/h for children older than 1 year of age and 18 units/kg/h for older children.

S.C.: Initial i.v. bolus of 5 000 units. Starting dose should be 17 500 units s.c. every 12 hours but ranges from 15 000 to 20 000 units s.c. every 12 hours. The APTT should be taken at 6 hours postdose (midpoint of dosing interval) and dosage adjusted to maintain APTT between 1.5 and 2 times control.

Prevention of Venous Thromboembolism (Fixed-Dose Therapy): The usual prophylactic dose for general surgical and medical patients at risk for thromboembolism is 5 000 units s.c. every 12 hours, starting 2 hours preoperatively and continuing for 5 to 7 days or until the patient is fully ambulatory, whichever is longer. The APTT is usually not prolonged by this dose and it is not necessary to monitor the APTT. The patient must still be clinically assessed for signs of thrombotic events (i.e., failure of prophylaxis) and full-dose heparin initiated if this occurs.

Certain groups of patients at high risk for thromboembolic events, i.e., those undergoing major orthopedic surgery or those with a previous history of venous thrombosis, should receive an adjusted low dose of heparin s.c. that maintains the APTT at the upper end of the normal range.

Long-term Therapy: Low dose s.c. heparin has been used for prevention of venous thrombosis or for follow-up treatment of deep vein thrombosis in patients in whom the use of oral anticoagulants is not feasible (i.e., pregnancy). Dosages have ranged from 5 000 units every 8 to 12 hours over 6 weeks to 6 months.

Disseminated Intravascular Coagulation: Heparin therapy for the treatment of DIC is controversial. For adults, 50 to 100 units/kg and for children 25 to 50 units/kg by i.v. infusion over 4 hours or by i.v. injection every 4 hours has been recommended. If no improvement is apparent by 4 to 8 hours, heparin should be discontinued.

Hemodialysis: For patients with multiple trauma or chronic renal failure, follow the equipment manufacturers operating instructions carefully.

Coronary Surgery: Heparin (10 000 units as an i.v. bolus) should be commenced immediately prior to angioplasty or coronary stent placement and followed by repeated boluses or continuous infusion of heparin to maintain the activated clotting time greater than 300 seconds with the Hemotec and greater than 300 seconds with the Hemochron. Alternatively, a weight adjusted regimen of 100 to 175 units/kg followed by 10 to 15 units/kg/h may be used. Heparin should be stopped after 2 to 4 hours in uncomplicated cases, but may be continued for up to 24 hours in complicated cases.

Peripheral Arterial Surgery: Heparin in doses of 100 to 150 units/kg i.v. is usually administered prior to cross clamping and supplemented with doses of 50 units/kg i.v. every 40 minutes until flow is restored. Protamine sulfate should be administered at the end of the procedure.

Heparin Lock Flush: Heparin lock flush solution in a concentration of 10 to 100 units/mL can be used to maintain the patency of indwelling venipuncture devices. However, recent literature indicates that the use of heparin-containing solutions to maintain catheter patency of peripheral indwelling infusion devices is not necessary and that normal saline for injection is equally effective.

HEPARIN: UNFRACTIONATED General MonographHeparin Sodium Anticoagulant

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