Generic Name: heparin

Brand Names: Heparin Sodium-Sodium Chloride, Hep-Pak CVC, Hep-Pak, Lok-Pak-N, Dextrose-Heparin Sodium, Heparin Lock Flush, Hep-Lock

Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Treatment of Venous Thrombosis and Pulmonary Embolism

Treatment of DVT and pulmonary embolism.

The American College of Chest Physicians (ACCP) recommends the use of low molecular weight heparin over unfractionated heparin for the treatment of venous thromboembolism, provided severe renal failure is not present. In patients with DVT and concurrent cancer, ACCP recommends use of a low molecular weight heparin over unfractionated heparin for initial treatment and long-term prophylaxis (at least the first 3–6 months) of venous thromboembolism.

In patients with suspected venous thromboembolism, ACCP recommends that IV or sub-Q unfractionated heparin or sub-Q low molecular weight heparin be initiated during confirmation of diagnosis unless contraindicated.

Follow-up anticoagulant (≥3 months) after initial treatment of venous thromboembolism when coumarin derivatives are contraindicated or inconvenient.

Short-term treatment of venous thromboembolism that occurs during pregnancy. After full-dose heparin therapy, may convert to sub-Q adjusted-dose heparin until term (immediately before delivery). For follow-up postpartum prophylaxis, overlap therapy with heparin and warfarin until adequate response to warfarin is obtained (as determined by the INR) and continue warfarin for at least 6 weeks.

Treatment of systemic venous thrombosis secondary to placement of central venous or umbilical vein catheters in neonates and/or the presence of underlying serious conditions such as cancer, trauma/surgery, congenital heart disease, or systemic lupus erythematosus.

Treatment of unilateral renal vein thrombosis in neonates in the absence of uremia or extension into the inferior vena cava as an alternative to supportive care and monitoring for extension of thrombus; data limited and use controversial.

Use suggested in neonates for unilateral renal vein thrombosis that extends into the inferior vena cava.

Conjunctive treatment with thrombolytic therapy for bilateral renal vein thrombosis in neonates and various degrees of renal failure; avoid use of low molecular weight heparin in such patients.

General Surgery Thromboprophylaxis

Prophylaxis of postoperative DVT and pulmonary embolism in patients undergoing general (e.g., abdominal, gynecologic, urologic) surgery who are at risk of thromboembolic disease.

Early ambulation without specific thromboprophylaxis recommended by ACCP in patients undergoing general surgery who are at low risk for venous thromboembolism (those undergoing minor operations who are <40 years of age and who have no clinical risk factors).

Recommended for prevention of thromboembolic events in surgical patients who are at moderate risk (e.g., patients undergoing nonmajor surgery who have risk factors, patients undergoing nonmajor surgery who are 40–60 years of age and have no other risk factors, patients undergoing major surgery who are <40 years of age and have no additional risk factors).

Recommended for thromboprophylaxis in patients at higher risk (e.g., patients undergoing major surgery who are >40 years of age or who have additional risk factors, patients undergoing nonmajor surgery who are >60 years of age or who have additional risk factors) for such events.

Use in combination with mechanical prophylaxis (e.g., graduated-compression elastic stockings or intermittent pneumatic compression [IPC]) in patients at high risk for venous thromboembolism who have multiple high-risk factors such as a history of previous venous thromboembolism, cancer, or a hypercoagulable state.

Thromboprophylaxis with low-dose unfractionated heparin or a low molecular weight heparin is recommended in patients with additional risk factors undergoing major vascular surgery.

Thromboprophylaxis with low-dose unfractionated heparin is one of several options in patients with additional risk factors undergoing gynecologic laparoscopic procedures.

Prevention of postoperative venous thromboembolism in patients undergoing extensive surgery for gynecologic cancer.

Use recommended for routine thromboprophylaxis in patients undergoing major, open urologic surgery (e.g., radical prostatectomy, cystectomy, nephrectomy).

Use in combination with IPC and/or graduated-compression elastic stockings in patients undergoing urologic surgery who have multiple risk factors.

Thromboprophylaxis recommended in patients undergoing laparoscopic procedures with additional risk factors.

Neurosurgery Thromboprophylaxis

Postoperative prophylaxis of DVT and pulmonary embolism after intracranial neurosurgery†, as an alternative to the use of IPC with or without graduated-compression elastic stockings.

In high-risk patients undergoing intracranial neurosurgery†, consider in combination with mechanical prophylaxis.

Postoperative thromboprophylaxis in patients undergoing elective spinal surgery† who have additional risk factors. Use in combination with graduated compression stockings and/or IPC in patients with multiple risk factors.

Use not recommended for prophylaxis in patients with acute spinal cord injury†. Instead, ACCP recommends anticoagulation with a low molecular weight heparin once primary hemostasis is evident. Alternatively, use combination ofIPC and unfractionated heparin or a low molecular weight heparin in patients with acute spinal cord injury.

Orthopedic Surgery

Prophylaxis of postoperative venous thromboembolism in patients undergoing hip-fracture surgery† as an alternative to fondaparinux. If surgery for repair of hip fracture likely to be delayed, may initiate prophylaxis with either low-dose unfractionated heparin or a low molecular weight heparin.

Use not recommended by ACCP for prophylaxis of postoperative venous thromboembolism in patients undergoing hip- or knee-replacement surgery.

Thromboprophylaxis in Selected Medical Conditions

Prophylaxis of venous thromboembolism in medical patients who have severely restricted mobility during acute illness (e.g., bedrest, heart failure, severe lung disease) and have one or more additional risk factors (e.g., previous venous thromboembolism, sepsis, acute neurologic disease, inflammatory bowel disease).

Prophylaxis with low-dose unfractionated heparin or a low molecular weight heparin recommended in critically ill patients who are at moderate risk for thromboembolism (e.g., active medical or general surgical condition).

Prophylaxis with a low molecular weight heparin recommended in critically ill patients who are at higher risk for thromboembolism, such as those with major trauma or who are undergoing orthopedic surgery.

Thromboembolism During Pregnancy

Primary prevention of thromboembolism in pregnant women with inherited causes of thrombophilia (e.g., deficiencies of antithrombin III, heterozygous genetic deficiency of both prothrombin G20210A and factor V Leiden, or homozygous genetic deficiency for factor V Leiden or prothrombin G20210A).

Secondary prophylaxis of venous thromboembolism (e.g., women with inherited thrombophilias, ≥1 episodes of idiopathic venous thromboembolism) during pregnancy.

Prevention of complications of pregnancy† (e.g., pregnancy loss in women with a history of antiphospholipid syndrome and recurrent fetal loss, thrombophilic deficit, preeclampsia, intrauterine growth retardation, abruption) when used alone or in combination with low-dose aspirin.

Has been used to prevent early pregnancy loss in women who have undergone in vitro fertilization†.

Embolism Associated with Atrial Fibrillation/Flutter

Treatment and secondary prevention of thromboembolism in patients with atrial fibrillation and embolization.

Used acutely with follow-up oral anticoagulation (e.g., warfarin) to reduce incidence of thromboembolic episodes in selected patients with atrial fibrillation or atrial flutter†. ACC, AHA, and European Society of Cardiology (ESC) recommend heparin or a low molecular weight heparin in all patients with atrial fibrillation, except those with lone atrial fibrillation or unless contraindicated.

Base choice of antithrombotic agent on absolute risks of stroke and bleeding and relative risk and benefits in individual patients.

In pregnant women with atrial fibrillation and risk factors for thromboembolism†, ACC/AHA/ESC suggest use during the first trimester and last month of pregnancy.

May be substituted for oral anticoagulant (e.g., warfarin) therapy in patients with atrial fibrillation who require a series of diagnostic or surgical procedures that necessitate interruption of oral anticoagulation† for >1 week or in selected high-risk patients who require interruption of oral anticoagulant therapy† for shorter periods.

Antithrombotic therapy in patients with atrial flutter† generally should be managed as in patients with atrial fibrillation.

Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter

Has been used with follow-up oral anticoagulation (e.g., warfarin) in patients undergoing electrical or pharmacologic cardioversion† for atrial fibrillation or atrial flutter.

Thromboembolism Associated with Prosthetic Heart Valves

Treatment of valve thrombosis† when used with follow-up oral anticoagulation (e.g., warfarin).

Reduction of the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or bioprosthetic heart valves†.

In pregnant women with prosthetic mechanical heart valves, ACCP states that aggressive, adjusted-dose therapy with low molecular weight heparin or high-dose unfractionated heparin therapy appears reasonable despite lack of definitive data on optimal therapy because of risks of withholding anticoagulation.

Arterial Thromboembolism

Prophylaxis and treatment of peripheral arterial embolism. Use immediately in patients with evidence of arterial emboli or thrombosis to prevent thrombotic propagation.

No evidence of efficacy in the treatment of chronic peripheral arterial disease.

Prophylaxis during cardiac catheterization via an artery in neonates and children. Use following cardiac catheterization if femoral artery thrombosis occurs.

Treatment of aortic thrombosis in neonates with umbilical artery catheters. In neonates experiencing spontaneous aortic thrombosis with evidence of renal ischemia, ACCP suggests urgent, aggressive use of thrombolytic or surgical therapy supported by anticoagulation with unfractionated heparin or a low molecular weight heparin.

Thromboembolism Associated with Cardiac and Arterial Vascular Surgery

Prevention of activation of the coagulation mechanism as blood passes through an extracorporeal circuit in dialysis procedures and during arterial and cardiac surgery.

Prevention of recurrent embolism in patients undergoing thrombolectomy.

Postoperative prevention of thrombosis in neonates undergoing the Norwood procedure for a hypoplastic left heart.

Perioperative prevention of thrombosis in children receiving endovascular stents.

Intraoperative prevention of thrombosis in neonates undergoing placement of Blalock-Taussig shunts.

Disseminated Intravascular Coagulation

Diagnosis and treatment of acute and chronic consumptive coagulopathies, including disseminated intravascular coagulation.

Treatment of aseptic vegetations on cardiac valves in patients with disseminated neoplasms or debilitating disease suggested.

Thrombosis Associated with Indwelling Venous or Arterial Devices

Maintenance of patency of indwelling peripheral or central venipuncture devices designed for intermittent injections and/or blood sampling.

Thromboprophylaxis and treatment of arterial catheter thrombosis in children with peripheral arterial catheters and in neonates with umbilical artery catheters.

Acute Ischemic Complications Following ST-Segment Elevation AMI

Used in combination with platelet-aggregation inhibitors (e.g., aspirin) during and after successful coronary artery reperfusion (e.g., with thrombolytic agents) for prevention of ischemic complications of AMI† (e.g., death, reinfarction, stroke).

ACC and AHA recommend unfractionated heparin or a low molecular weight heparin for prevention of systemic embolism following AMI in patients at high risk for such events (e.g., large or anterior MI, atrial fibrillation, previous embolus, left ventricular thrombus, cardiogenic shock).

Used IV in conjunction with fibrin-selective thrombolytic therapy (e.g., alteplase, reteplase, tenecteplase) and low-dose aspirin therapy in patients with ST-segment AMI.

Also recommended in conjunction with non-fibrin-selective thrombolytic therapy in patients at high risk for systemic embolism.

Use suggested in patients not receiving thrombolytic therapy who do not have a contraindication for anticoagulation.

Acute Ischemic Complications of Percutaneous Coronary Interventions

Reduction in the risk of complications in patients undergoing percutaneous coronary intervention (PCI) or surgical coronary revascularization. Used in conjunction with aspirin, a GP IIb/IIIa-receptor inhibitor, and/or clopidogrel in such patients.

A direct thrombin inhibitor (e.g., argatroban, bivalirudin) recommended over unfractionated heparin in patients with acute heparin-induced thrombocytopenia (HIT) or a history of HIT who are undergoing PCI or cardiac catheterization.

In patients undergoing PCI at high risk for bleeding, ACCP recommends use of bivalirudin over heparin as an adjunct to therapy with GP IIb/IIIa-receptor inhibitors. In patients at low risk for complications, ACC, AHA, ACCP, and other clinicians consider bivalirudin a reasonable alternative to the combination of unfractionated heparin and a GP IIb/IIIa-receptor inhibitor.Bivalirudin recommended over heparin in patients undergoing PCI without a GP IIb/IIIA-receptor inhibitor.

ACC and AHA consider a low molecular weight heparin a reasonable alternative to unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes undergoing PCI .

Acute Ischemic Complications of Unstable Angina or Non-ST-Segment Elevation MI

Reduction in the risk of acute cardiac ischemic events (death and/or MI) in intermediate- and high-risk patients with unstable angina or non-ST-segment elevation MI†. Patients at intermediate risk for death or nonfatal MI include hospitalized patients with prolonged rest angina relieved with rest or sublingual nitroglycerin, nocturnal angina, dynamic T-wave changes, resting ST-segment depression of <1 mm in multiple leads, or those >65 years of age. High-risk patients include those who have unstable angina with prolonged ischemic pain at rest, elevated troponin I or T concentrations, or rest angina with dynamic ST changes >1 mm.

ACCP recommends a low molecular weight heparin over unfractionated heparin for the short-term treatment in such patients.

Used concurrently with aspirin and/or other standard therapy (e.g., nitrates, β-adrenergic blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors).

Cerebral Thromboembolism

Prophylaxis of venous thromboembolism in patients with ischemic stroke† and impaired mobility who do not have contraindications to such therapy.

Short-term (3 months) prophylaxis of thromboembolism in cardioembolic ischemic stroke in neonates†.

Treatment of arterial ischemic stroke in children†.

Treatment of acute cerebral venous sinus thrombosis† in adults, even in the presence of hemorrhagic venous infarcts. Some experts do not recommend heparin for patients with large hemorrhagic venous infarcts with associated hematomas. Treatment of cerebral venous sinus thrombosis without large ischemic infarctions or intracranial hemorrhage in neonates.

Anticoagulant in Blood Transfusions and Blood Samples

In vitro anticoagulant in blood transfusions and in blood samples drawn for laboratory purposes.

Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Laboratory Monitoring of Therapy

• Individualize dosage carefully based on patient’s weight and clinical and laboratory findings. The generally accepted therapeutic range for the aPTT during full-dose IV or sub-Q heparin therapy is 1.5–2.5 times the control value in seconds. The generally accepted therapeutic range for the activated clotting time (ACT) is 2–3 times the control value in seconds. Alternatively, because commercial reagents in the aPTT assay vary in responsiveness, some clinicians recommend correlating the aPTT with plasma heparin concentrations in patients with acute thrombosis, using an aPTT that corresponds to therapeutic plasma heparin concentrations of 0.2–0.4 units/mL (as measured by protamine sulfate titration) or 0.3–0.7 units/mL (as measured by an amidolytic assay).
• Laboratory monitoring of coagulation tests usually not performed with fixed low-dose sub-Q heparin therapy because such tests are generally unaffected or only minimally prolonged.
• With continuous IV infusion, perform coagulation tests prior to initiation of therapy, approximately every 4 hours during the early stages of therapy, and daily thereafter.
• With intermittent IV injection, perform coagulation tests prior to initiation of therapy, prior to each injection during the early stages of therapy, and daily thereafter.
• With deep sub-Q injection, perform coagulation tests prior to initiation of therapy, 4–6 hours following injection during the early stages of therapy, and daily thereafter.
• Perform periodic platelet counts, hematocrit, and tests for occult blood in stool during the entire course of therapy.

Conversion to Oral Anticoagulation

• Warfarin is generally administered for follow-up treatment after full-dose heparin. Usually overlap therapy for 4–5 days or until an adequate response to warfarin is obtained (e.g., as indicated by INR >2 on two consecutive days).
• Some manufacturers recommend abrupt discontinuance of heparin therapy after confirmation of adequate response to warfarin. However, some clinicians recommend gradual discontinuance of heparin infusions (e.g., reducing the rate by 50% over 6 hours and then discontinuing over the next 12 hours) because of concern about possible rebound thrombosis.

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Administer by IV infusion, intermittent IV injection, or deep sub-Q (intrafat) injection. Do not administer IM because of frequency of hematoma at injection site.

Heparin lock flush solution: Administer by intracatheter instillation into an indwelling IV injection device. Not intended for systemic anticoagulation or injection by any parenteral route of administration.

IV Administration

For solution and drug compatibility information, see Compatibility Under Stability.

Use of a controlled-infusion device (e.g., infusion pump) is recommended to ensure precise control of flow rate during continuous IV infusion.

If an infusion pump is used with flexible plastic containers (Viaflex^®) of heparin solution, discontinue pumping action before the container is empty to prevent air embolism.

Do not use flexible containers (e.g., Viaflex^®) containing drug solutions in series connections.

Dilution

When adding heparin to a solution for continuous IV infusion, invert the container at least 6 times to ensure adequate mixing and to prevent pooling of the drug in solution.

Dilute intermittent IV injections in ADD-Vantage^® vials with 50–100 mL of 0.9% sodium chloride or 5% dextrose injection.

Rate of Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

For maintaining catheter patency, a rate of 3 mL/hour of heparin sodium IV solution (2 units/mL in 0.9% sodium chloride injection) appears satisfactory.

Sub-Q Administration

Inject with a 25- or 26-gauge needle sub-Q deeply above the iliac crest or into the abdominal fat layer, or arm to minimize tissue trauma.

Intracatheter Instillation

Instill a quantity of heparin lock flush solution (e.g., containing 10 or 100 units/mL) sufficient to fill the indwelling venipuncture device into the lumen of the device following the initial placement of the device in the vein and after each use.

When the indwelling venipuncture device is used for repeated withdrawal of blood samples for laboratory analysis and the presence of heparin or 0.9% sodium chloride is likely to alter results of the analysis, aspirate and discard heparin lock flush solution (1 mL) from the device before withdrawing the blood sample. After the blood sample is drawn, inject another dose (e.g., 1 mL of 10 units/mL) of heparin lock flush solution into the device.

Following injection of heparin lock flush solution from a prefilled syringe (Ansyr^®, Abboject^®-PA), single-dose vial, or cartridge (Carpuject^®) into an indwelling venipuncture device, discard unused portions of the solutions. A multiple-dose vial is available for repeated use.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Available as heparin sodium; dosage is expressed in terms of heparin sodium in USP units.

Dosage requirements for full-dose therapy vary greatly among individuals; carefully individualize dosage based on the patient’s weight and clinical and laboratory findings.

Pediatric Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Treatment of Venous Thrombosis and Pulmonary Embolism

IV

Neonates: Weight-based dosage sufficient to prolong the aPTT to a range that corresponds to an anti-factor X_a concentration of 0.35–0.7 units/mL. Initial treatment with unfractionated heparin sodium or low molecular weight heparin may be continued for 5–10 days; ACCP states that data are insufficient to make strong recommendations and that treatment should be individualized considering risks versus benefits. Follow-up with low molecular weight heparin for 10 days to 3 months. Convert to oral anticoagulation or initiate or resume therapy with a low molecular weight heparin if thrombus extends following discontinuance of IV heparin sodium. (See Conversion to Oral Anticoagulation under Dosage and Administration.)

Neonates with unilateral renal vein thrombosis that extends into the inferior vena cava: Adjust dosage adjusted to prolong the aPTT to a range corresponding to an anti-factor X_a concentration of 0.35–0.7 unit/mL for 6 weeks to 3 months.

Children >2 months of age with a first thromboembolic event: Adjust maintenance dosage to prolong the aPTT to a range corresponding to an anti-factor X_a concentration of 0.35–0.7 units/mL for 5–10 days. Massive or extensive venous thromboembolism may require a longer initial treatment period. Convert to warfarin therapy for follow-up oral anticoagulation. (See Conversion to Oral Anticoagulation under Dosage and Administration.)

For full-dose IV heparin sodium therapy in children, some manufacturers recommend an initial loading dose of 50 units/kg followed by 100 units/kg every 4 hours by intermittent infusion or 20,000 units/m² per 24 hours by continuous IV infusion.

For full-dose IV heparin sodium therapy in children, ACCP recommends a loading dose of 75–100 units/kg given over 10 minutes.

Infants <1 year of age: An initial maintenance dosage of 28 units/kg per hour recommended by ACCP, with dosage adjusted to maintain an aPTT of 60–85 seconds (assuming this corresponds to an anti-factor X_a concentration of 0.35–0.7 units/mL).

Children >1 year of age: An initial maintenance dosage of 20 units/kg per hour recommended by ACCP, with dosage adjusted to maintain an aPTT of 60–85 seconds (assuming this corresponds to an anti-factor X_a concentration of 0.35–0.7 units/mL).

Weight-adjusted dosage required for older children is similar to that for adults (18 units/kg per hour).

Arterial Thromboembolism

IV

For neonates and children requiring cardiac catheterization via an artery: 100–150 units/kg by direct injection suggested; multiple doses may be required in prolonged procedures (>60 minutes).

Neonates or children with femoral artery thrombosis associated with cardiac catheterization: 75–100 units/kg by direct injection, then 20–28 units/kg per hour depending on age for 5–7 days suggested; optimal duration unknown.

Neonates with aortic thrombosis associated with umbilical artery catheters: 75–100 units/kg by direct injection, then 28 units/kg per hour for 5–7 days suggested; optimal duration unknown.

Disseminated Intravascular Coagulation

IV

25–50 units/kg given by IV infusion or IV injection every 4 hours. Discontinue after 4–8 hours if there is no improvement.

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Treatment of Venous Thrombosis and Pulmonary Embolism

IV, then Sub-Q

Full-dose intermittent therapy (68-kg adult): 5000 units IV then 10,000–20,000 units sub-Q initially, followed by 8000–10,000 units sub-Q every 8 hours or 15,000–20,000 units sub-Q every 12 hours.

Adjusted-dose therapy: 5000 units IV initially as a loading dose followed by 17,500 units sub-Q twice daily, with dosage adjusted to prolong the aPTT to 1.5–2.5 times the control value at the mid-dose interval recommended by some clinicians.

IV

Full-dose continuous therapy (68-kg adult): 5000 units initial loading dose, then 20,000–40,000 units in 1 L of 0.9% sodium chloride injection or other compatible IV solution infused over 24 hours recommended by some manufacturers. ACCP recommends an initial loading dose of 5000 units, then ≥30,000 units infused over the first 24 hours.

Full-dose intermittent therapy (68-kg adult): 10,000 units initial loading dose, then 5000–10,000 units every 4–6 hours recommended by some manufacturers. ACCP states that intermittent IV regimens are associated with a higher risk of bleeding than continuous IV infusion and are not recommended.

Adjusted-dose continuous therapy: ACCP recommends 80 units/kg loading dose, then 18 units/kg per hour for 24 hours.

After 24 hours, adjust dosage to prolong the aPTT to a level corresponding with a plasma heparin concentration of 0.3–0.7 units/mL (amidolytic anti-factor X_a assay) for ≥5 days.

Pregnant women: 5000 units by direct injection followed by a continuous infusion to maintain aPTT in the therapeutic range) for ≥5 days. (See ThromboembolismDuring Pregnancy under Dosage and Administration for information on secondary prophylaxis).

General Surgery Thromboprophylaxis

Sub-Q

Moderate-risk general surgery patients: 5000 units 1–2 hours prior to surgery, then every 12 hours after surgery until patient is ambulatory or discharged from the hospital. (See General Surgery Prophylaxis under Uses for explanation of risk factors.)

High-risk general surgery patients: 5000 units administered 1–2 hours prior to surgery, then every 8 hours; for patients with multiple risk factors, combine pharmacologic therapy with intermittent pneumatic compression (IPC) or graduated-compression stockings.

Gynecologic laparoscopic surgery patients with additional risk factors: 5000 units 2–3 times daily recommended by ACCP.

Major gynecologic surgery for benign disease: 5000 units twice daily until hospital discharge.

Major gynecologic surgery with additional risk factors: 5000 units 3 times daily until hospital discharge.

Major gynecologic surgery for cancer: 5000 units 3 times daily until hospital discharge.

Major gynecologic surgery at particularly high-risk patients (e.g., >60 years of age, cancer surgery, history of venous thromboembolism): Continue prophylaxis for 2–4 weeks after hospital discharge.

Major open urologic surgery: 5000 units 2–3 times daily.

Urologic surgical patients with multiple risk factors: 5000 units 2–3 times daily in combination with IPC or graduated-compression stockings.

Neurosurgery Thromboprophylaxis

Sub-Q

Intracranial neurosurgery†: 5000 units administered 1–2 hours preoperatively, then every 8–12 hours is recommended.

Elective spinal surgery with additional risk factors: 5000 units 2–3 times daily initiated postoperatively alone or in combination with IPC or graded compression stockings.

Hip-fracture surgery: 5000 units administered 1-2 hours preoperatively, then every 8–12 hours.

Thromboprophylaxis in Selected Medical Conditions

Sub-Q

Hospitalized patients with CHF, severe respiratory disease, or impaired mobility and additional risk factors: 5000 units twice daily.

Critically ill patients at moderate risk: 5000 units twice daily. (See Medical Conditions Associated with Thromboembolism under Uses.)

Thromboembolism During Pregnancy

Sub-Q

Primary prevention in women with antithrombin deficiency, heterozygous genetic mutation for factor V Leiden and prothrombin G20210A or homozygous gene mutation for factor V Leiden or prothrombin G20210A : 5000 units every 12 hours with dosage adjusted to maintain an anti-factor X_a concentration of 0.1–0.3 units/mL, followed by postpartum oral anticoagulation (e.g., with warfarin).

Primary prevention in women with confirmed thrombophilia: 5000 units every 12 hours suggested.

Secondary prevention after a single episode of idiopathic venous thromboembolism with or without thrombophilia with no long-term anticoagulation: 5000 units every 12 hours with or without adjustment of dosage to maintain an anti-factor X_a concentration of 0.1–0.3 units/mL, followed by postpartum oral anticoagulation.

Secondary prevention after a single episode of venous thromboembolism and confirmed thrombophilia or family history of thrombosis not receiving long-term anticoagulation: 5000 units every 12 hours with or without adjustment of dosage to maintain an anti-factor X_a concentration of 0.1–0.3 units/mL, followed by postpartum oral anticoagulation.

Secondary prevention after ≥2 episodes of venous thromboembolism and/or who are receiving long-term anticoagulation: Administer every 12 hours with dosage adjusted to maintain the mid-interval aPTT in the therapeutic range, followed by resumption of postpartum long-term oral anticoagulation.

Primary or secondary prevention in women with antiphospholipid syndrome and a history of multiple pregnancy losses, preeclampsia, intrauterine growth retardation, or abruption: 5000 units twice daily or moderate twice-daily dosage adjusted to maintain an anti-factor X_a concentration of 0.1–0.3 units/mL and low-dose aspirin.

Atrial fibrillation with risk factors: 10,000–20,000 units every 12 hours with dosage adjusted to maintain the mid-interval aPTT (6 hours after dose) at 1.5 times the control value during the first trimester and last month of pregnancy.

IV

Atrial fibrillation with risk factors: Adjusted dose continuous therapy suggested to maintain the aPTT ≥1.5–2 times control value during first trimester and last month of pregnancy.

Embolism Associated with Atrial Fibrillation/Flutter

IV

Atrial fibrillation with AMI: 60 units/kg loading dose followed by 12 units/kg per hour to maintain an aPTT of approximately 1.5–2 times the control value.

Thromboembolism Associated with Prosthetic Heart Valves

Sub-Q

Pregnant women: Initially, 17,500–20,000 units every 12 hours and adjusted to maintain the mid-interval aPTT at least twice the control value or anti-factor X_a concentration of 0.35–0.7 units/mL throughout pregnancy suggested.

Alternatively, 17,500–20,000 units every 12 hours adjusted to maintain the mid-interval aPTT ≥twice the control value or an anti-factor X_a concentration of 0.35–0.7 units/mL until week 13 of pregnancy, then transfer to warfarin until the middle of the third trimester, followed by adjusted-dose heparin until close to term.

Disseminated Intravascular Coagulation

IV

50–100 units/kg by IV infusion or IV injection every 4 hours. Discontinue after 4–8 hours if there is no improvement.

Thrombosis Associated with Indwelling Venipuncture Devices

Intracatheter Instillation

Inject a quantity of heparin lock flush solution (e.g., containing 10 or 100 units/mL) sufficient to fill the device after each use. (See Intracatheter Instillation under Dosage and Administration: Administration.)

Acute Ischemic Complications of ST-Segment Elevation AMI

IV

Conjunctive therapy with fibrin-selective thrombolytic agents: Initially, 60 units/kg (maximum 4000 units) loading dose.

Maintenance dosage: 12 units/kg per hour (maximum 1000 units/hour in patients weighing >70 kg), adjusted to maintain a therapeutic aPTT for 48 hours. Follow-up therapy with oral anticoagulation (e.g., warfarin).

Conjunctive therapy with non-fibrin-selective thrombolytic agents in patients who are at high risk for thromboembolism: 5000 units by direct injection followed by 800 units/hr for patients weighing ≤80 kg or 1000 units/hr for patients weighing >80 kg for 48 hours. After 48 hours, change to sub-Q heparin.

Discontinue after 48 hours in patients at low risk for thromboembolism, convert to sub-Q therapy in patients at high risk of systemic embolization, and continue IV therapy in patients at high risk for coronary reocclusion.

Sub-Q

Conjunctive therapy with non-fibrin-selective thrombolytic agents in patients who are at high risk for thromboembolism: 12,500 units every 12 hours for 48 hours.

Patients who did not receive thrombolytic therapy: 7500–12,500 units every 12 hours for 48 hours. Continue therapy until patient is ambulatory in patients with impaired mobility.

Cardiac and Vascular Surgery Thromboprophylaxis

IV

Total body perfusion for open-heart surgery: Initially, ≥150 units/kg. Administer 300 units/kg for procedures estimated to last <1 hour. Administer 400 units/kg for those procedures estimated to last >1 hour.

Vascular surgery patients with additional risk factors: 5000 or 7500 units twice daily recommended by ACCP.

Acute Ischemic Complications of PCI

IV

PCI without concurrent antiplatelet therapy with a GP IIb/IIIa-receptor inhibitor: Dosage adjusted to maintain an activated clotting time (ACT) of 250–300 seconds with the HemoTec device or 300–350 seconds with the Hemochron device.

PCI with concurrent GP IIb/IIIa-receptor inhibitors: A loading dose of 50–70 units/kg targeted to an ACT of ≥200 seconds (using either the HemoTec or Hemochron device) recommended. Discontinue therapy immediately upon completion of an uncomplicated procedure.

Acute Ischemic Complications of Unstable Angina and Non-ST-Segment Elevation MI

IV

Adjusted-dose continuous therapy:70–80 units/kg loading dose followed by continuous IV infusion to maintain the aPTT between 1.5–2 times the control value for ≥48 hours in addition to aspirin and/or clopidogrel. Continue for ≥48 hours or until anginal pain resolves with pharmacologic therapy or with cardiac intervention (e.g., revascularization). Early treatment initiation appears to be necessary for beneficial effects.

Anticoagulant in Blood Transfusions and Blood Samples

In vitro

In blood transfusions, add 7500 units to 100 mL of 0.9% sodium chloride injection and then add 6–8 mL of this solution to each 100 mL of whole blood.

When used as an in vitro anticoagulant for blood samples, add 70–150 units to each 10–20 mL of whole blood.

Prescribing Limits

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Acute Ischemic Complications of ST-Segment Elevation AMI

IV:

Conjunctive therapy with fibrin-selective thrombolytic agents: Maximum 4000 units loading dose.

Maintenance dosage: Maximum 1000 units/hour in patients weighing >70 kg, adjusted to maintain a therapeutic aPTT for 48 hours.

Special Populations

Geriatric Patients

Patients >60 years of age may require a lower dosage. Consider lower dosages in geriatric patients undergoing PCI, particularly when combined with GP IIb/IIIa-receptor inhibitors.

Women

Consider lower dosages in women undergoing PCI, particularly when combined with GP IIb/IIIa-receptor inhibitors.

Cautions

Contraindications

• Uncontrollable bleeding, unless such bleeding is secondary to disseminated intravascular coagulation.
• Severe thrombocytopenia.
• Inability to perform suitable blood coagulation tests at required intervals in patients receiving full-dose therapy. Lack of such tests generally is not a contraindication for fixed low-dose therapy, since monitoring of coagulation tests usually is not required.
• Known hypersensitivity to heparin or bisulfites (in certain IV solutions). Hypersensitivity to corn products (solutions containing dextrose). (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Hematologic Effects

Hemorrhage can range from minor local ecchymoses to major hemorrhagic complications. Bleeding may occur at any site; some hemorrhagic complications may be difficult to detect.

Use with extreme caution in patients with an increased risk of hemorrhage. Such patients include those with subacute bacterial endocarditis; ulcerative GI lesions; hemorrhagic blood dyscrasias (e.g., hemophilia, some vascular purpuras, thrombocytopenia); menstruation; hepatic disease with impaired hemostasis; severe hypertension; major surgery, especially involving the eye, brain, or spinal cord; continuous tube drainage of the stomach or small intestine; and spinal tap or spinal anesthesia. Screen patients prior to treatment initiation to rule out bleeding disorders.

Monitor patients with appropriate coagulation tests just prior to surgery. Discontinue therapy immediately if hemorrhage occurs or if coagulation tests are unduly prolonged. Nosebleed, hematuria, or tarry stools may be noted as the first sign of bleeding or overdosage. Easy bruising or petechiae may precede frank bleeding. If severe hemorrhage or overdosage occurs, administer protamine sulfate immediately. Blood transfusions may also be required following massive blood loss.

If signs and symptoms of acute adrenal hemorrhage and insufficiency occur, measure plasma cortisol concentrations. Initiate vigorous therapy with IV corticosteroids after discontinuance. Do not delay initiation of corticosteroid until laboratory confirmation of the diagnosis, since any delay may be fatal.

Perform periodic hematocrit and tests for occult blood in stool during the entire course of therapy.

Obtain baseline APTT value prior to insertion of an indwelling venipuncture device (e.g., heparin lock) since repeated injections of small doses of heparin sodium can alter APTT results.

Monitor platelet counts before and during therapy since 2 forms of acute, reversible thrombocytopenia (direct, nonimmunologic effect on circulating platelets or related to the presence of a heparin-dependent IgG platelet-aggregating antibody) have occurred with heparin therapy. Monitor closely thrombocytopenia of any degree. Mild thrombocytopenia (platelet count >100,000/mm³) may remain stable or reverse with continued therapy. If clinically important heparin-induced thrombocytopenia (HIT) occurs, discontinue the drug immediately and substitute a direct thrombin inhibitor (e.g., bivalirudin, lepirudin) if necessary. HIT with or without thrombosis also may occur up to several weeks following treatment discontinuance. Evaluate patients who develop thrombocytopenia or thrombosis after treatment discontinuance for HIT and HIT with thrombosis.

Sensitivity Reactions

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

Hypersensitivity

Generally contraindicated in patients who are hypersensitive to the drug. Patients with documented hypersensitivity should be given the drug only in clearly life-threatening situations.

Use with caution in individuals with a history of allergy since heparin is derived from animal tissue.

Major Toxicities

White Clot Syndrome

New thrombus formation (usually arterial) has been associated with HIT resulting in irreversible platelet aggregation (“white clot syndrome”). May lead to severe thromboembolic complications including DVT, cerebral vein thrombosis, limb ischemia, mesenteric thrombosis, renal artery thrombosis, skin necrosis, gangrene of the extremities (possibly requiring amputation), MI, pulmonary embolism, stroke, and possibly, death.

General Precautions

Hematologic Effects

Discontinue promptly when new thrombosis develops in association with a reduction in platelet count or thrombocytopenia. (See White Clot Syndrome under Cautions.)

Heparin Resistance

Increased resistance to the antithrombotic effects of heparin reported; associated with fever, MI, thrombophlebitis, infections with thrombosing tendencies, thrombosis, antithrombin III deficiency, malignant neoplasms, and surgery (i.e., postoperatively).

Dispensing and Administration Precautions

Ensure accuracy of dispensing; similarity in product packaging color of heparin sodium injection 10,000 units/mL (deep blue background), and HEP-LOCK^® U/P 10 units/mL (light blue background) may result in life-threatening medication errors. Do not rely upon color as sole means of identification of correct drug. Use drug name, dosage strength, and other measures (e.g., bar code, color photographs, review of medication identification and administration procedures) to carefully distinguish between heparin formulations when dispensing. Report dispensing errors to manufacturers or directly to FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-1078), or internet (https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm).

Specific Populations

Pregnancy

Category C.

Lactation

Not distributed into milk.

Pediatric Use

Some heparin sodium injections and heparin lock flush solutions contain benzyl alcohol as a preservative. Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates. Several manufacturers of heparin lock flush solution and heparin sodium injection do not recommend use in neonates. AAP states that presence of small amounts of this preservative in a commercially available injection should not proscribe its use when indicated in neonates.

Because of the potential risk of bleeding, heparin lock flush solutions containing 100 units/mL should be avoided in neonates, particularly low birthweight neonates. Some manufacturers of heparin lock flush solutions recommend use with extreme caution in infants with concomitant conditions associated with an increased risk of hemorrhage.

Geriatric Use

Manufacturers state that risk of hemorrhage may be higher in patients >60 years of age, particularly women. (See Geriatric Patients and see Women under Dosage and Administration.)

Renal Impairment

Patients with renal failure may be at increased risk of bleeding complications.

Common Adverse Effects

Hemorrhage.

Interactions

Drugs Affecting Platelet Function

Potential pharmacodynamic interaction (increased risk of bleeding complications). Use with caution.

Specific Drugs and Laboratory Tests

Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration achieved 2–4 hours following sub-Q administration.

Onset

Immediate following direct IV injection or IV infusion of full doses.

Within 20–60 minutes following deep sub-Q injection.

Duration

Heparin lock flush solutions: Anticoagulation maintained within the device for 4–24 hours.

Special Populations

Plasma heparin concentrations may be increased and aPTTs more prolonged in geriatric (>60 years of age) patients compared with younger adults.

Distribution

Extent

Does not cross the placenta and is not distributed into milk.

Plasma Protein Binding

Extensively bound to LDL, globulins, and fibrinogen. May contribute to the lack of relationship between duration of anticoagulant effect and blood concentration half-life.

Elimination

Metabolism

Cleared from the circulation mainly by the reticuloendothelial system. May be partially metabolized in the liver to uroheparin, which is partially desulfated heparin.

Elimination Route

Small fraction excreted in urine as unchanged drug.

Half-life

1–2 hours in healthy adults. Half-life increases with increasing doses. Plasma half-life averages 56, 96, and 152 minutes following IV heparin sodium doses of 100, 200, or 400 units/kg, respectively. Shorter plasma half-life in patients with pulmonary embolism than in healthy individuals or patients with other thrombotic disorders.

Special Populations

Decreased plasma half-life in patients with liver impairment; half-life may be prolonged in patients with cirrhosis.

Half-life may be slightly prolonged in anephric patients or patients with severe renal impairment.

Stability

Storage

Parenteral

Solution for Injection

Heparin lock flush solutions: 15–30°C or 25°C (may be exposed to 15–30°C). Do not freeze.

Heparin sodium injections derived from beef lung: 20–25°C.

Heparin sodium injections derived from porcine intestinal mucosa: 20–25°C.

Heparin sodium injection in 5% dextrose or in 0.45 or 0.9% sodium chloride injection: 20–25°C (may be exposed to up to 40°C).

Heparin sodium injection in water for injection: 15–30°C. Certain commercially available heparin sodium in 5% dextrose injection: 15–30°C.

Premixed heparin sodium injection in Viaflex^® Plus containers: 25°C (may be exposed to up to 40°C).

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

When administered in a venipuncture device with an incompatible drug, flush the entire device with 0.9% sodium chloride injection, a compatible isotonic injection, or sterile water prior to and immediately after administration of the incompatible drug. Inject another dose of heparin lock flush solution (e.g., 1 mL of 10 units/mL) into the device after the second flush. A cartridge (Carpuject^®) containing 2 mL of 0.9% sodium chloride injection is supplied by one manufacturer for flushing before and after administration of a drug incompatible with heparin.

Drug Compatibility

Actions

• Acts as a catalyst to markedly accelerate the rate at which antithrombin III (heparin cofactor) neutralizes thrombin and activated coagulation factor X (X_a). Low-dose therapy neutralizes X_a which prevents the conversion of prothrombin to thrombin. Low doses of heparin have very little effect on thrombin and exert a measurable antithrombogenic effect only if thrombin formation has not already occurred.
• Full-dose therapy neutralizes thrombin, which prevents the conversion of fibrinogen to fibrin. Also prevents the formation of a stable fibrin clot by inhibiting activation of fibrin stabilizing factor. Low-dose or full-dose therapy inhibits thrombus formation when stasis is induced. Full-dose therapy may prevent extension of existing thrombi.
• Full-dose therapy prolongs several coagulation assays including the ACT, aPTT, plasma recalcification time, PT, thrombin time, and whole blood clotting time. Clotting time is generally unaffected or only minimally prolonged by low-dose therapy. A single dose of heparin lock flush solution at a concentration of 10 units/mL does not induce systemic anticoagulant effects. However, repeated flushing of a catheter device with a heparin lock flush solution may result in a systemic anticoagulant effect.

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.

• Importance of reporting any unexplained bleeding or bruising to clinician.
• Importance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary and herbal supplements, and any concomitant illnesses.
• Importance of women informing clinician if they are or plan to become pregnant or to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 11/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions November 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.