heparin sodium in 0.45% sodium chloride injection Warnings and Precautions

5 WARNINGS AND PRECAUTIONS

     

5.1 Fatal Medication Errors

Do not use this product as a "catheter lock flush" product. Heparin is supplied in various strengths. Fatal hemorrhages have occurred due to medication errors. Carefully examine all heparin products to confirm the correct container choice prior to administration of the drug.

5.2 Hemorrhage

Hemorrhage, including fatal events, has occurred in patients receiving heparin sodium. Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks.

Hemorrhage can occur at virtually any site in patients receiving heparin. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1)]. A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3)]. These patients may require a lower dose. An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a hemorrhagic event.

Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including:

Cardiovascular — Subacute bacterial endocarditis. Severe hypertension.
Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye.
Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.
Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin dose during concomitant treatment with antithrombin III (human).
Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine.
Other — Menstruation, liver disease with impaired hemostasis.

5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)

HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition known as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes.

Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided.

Thrombocytopenia of any degree should be monitored closely.If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation.

Delayed Onset of HIT (With or Without Thrombosis): Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT (With or Without Thrombosis).

5.4 Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered [see Warnings and Precautions (5.3)].

5.5 Coagulation Testing and Monitoring

When heparin sodium is administered in therapeutic amounts, its dosage should be monitored by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly [see Overdosage (10)]. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy [see Dosage and Administration (2.2)].

5.6 Heparin Resistance

Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.

5.7 Hypersensitivity Reactions

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [see Adverse Reactions (6.1)].

Because heparin sodium is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.

5.8 Hyperkalemia

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin.

Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

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Warnings and Precautions

5 WARNINGS AND PRECAUTIONS

     

5.1 Fatal Medication Errors

Do not use this product as a "catheter lock flush" product. Heparin is supplied in various strengths. Fatal hemorrhages have occurred due to medication errors. Carefully examine all heparin products to confirm the correct container choice prior to administration of the drug.

5.2 Hemorrhage

Hemorrhage, including fatal events, has occurred in patients receiving heparin sodium. Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks.

Hemorrhage can occur at virtually any site in patients receiving heparin. Adrenal hemorrhage (with resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1)]. A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical Pharmacology (12.3)]. These patients may require a lower dose. An unexplained fall in hematocrit or fall in blood pressure should lead to serious consideration of a hemorrhagic event.

Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including:

Cardiovascular — Subacute bacterial endocarditis. Severe hypertension.
Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye.
Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.
Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin dose during concomitant treatment with antithrombin III (human).
Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine.
Other — Menstruation, liver disease with impaired hemostasis.

5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)

HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition known as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and fatal outcomes.

Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided.

Thrombocytopenia of any degree should be monitored closely.If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation.

Delayed Onset of HIT (With or Without Thrombosis): Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT (With or Without Thrombosis).

5.4 Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered [see Warnings and Precautions (5.3)].

5.5 Coagulation Testing and Monitoring

When heparin sodium is administered in therapeutic amounts, its dosage should be monitored by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly [see Overdosage (10)]. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy [see Dosage and Administration (2.2)].

5.6 Heparin Resistance

Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.

5.7 Hypersensitivity Reactions

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [see Adverse Reactions (6.1)].

Because heparin sodium is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.

5.8 Hyperkalemia

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin.

Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

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