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Heparin (unfractionated): Drug information

Heparin (unfractionated): Drug information
(For additional information see "Heparin (unfractionated): Patient drug information" and see "Heparin (unfractionated): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: Canada
  • Heparin Leo
Pharmacologic Category
  • Anticoagulant
Dosing: Adult

Note: Heparin may be given by continuous IV infusion or SubQ depending on the indication. For weight-based IV heparin, an institution-specific dosing nomogram may help to achieve therapeutic anticoagulation more rapidly (see example based on aPTT under "Venous thromboembolism treatment"). If unusually large doses of heparin are required to achieve therapeutic targets, consider possible heparin resistance (Hull 2022a). Safety: Many concentrations of heparin are available ranging from 1 to 20,000 units/mL. Carefully examine each prefilled syringe or vial to ensure the correct concentration is selected.

Antibiotic lock technique, adjunctive therapy

Antibiotic lock technique, adjunctive therapy (catheter-salvage strategy) (off-label use): Note: Antibiotic lock therapy is used in addition to systemic antibiotics for certain catheter-related infections when the catheter cannot be removed. Heparin is incompatible with ethanol and should not be used with ethanol lock therapy (Balestrino 2016; IDSA [Mermel 2009]). Heparin is also incompatible with certain antibiotics; confirm compatibility prior to use (Bookstaver 2013).

Intracatheter: 100 to 5,000 units/mL in combination with an appropriate antibiotic. Heparin concentration depends on compatibility with the selected antibiotic, antibiotic concentration, and catheter type, which may vary by institution (Bookstaver 2009; Bookstaver 2013; IDSA [Mermel 2009]). For patients with end-stage renal disease requiring hemodialysis, maximum final heparin concentration should not exceed 1,000 units/mL due to increased risk of bleeding (Yevzlin 2007). Instill into each lumen of the catheter access port using a sufficient volume to fill the catheter (eg, 2 to 5 mL) with a maximum dwell time of ≤72 hours, depending on frequency of catheter use. Withdraw lock solution prior to catheter use; replace with fresh lock solution after catheter use (Bookstaver 2009; IDSA [Mermel 2009]).

Atrial fibrillation

Atrial fibrillation (to prevent stroke and systemic embolism): Note: When admitted for short-term hospitalization (eg, admission for a procedure or surgery), ambulatory patients taking an oral anticoagulant and not at high risk of immediate thromboembolism typically do not require bridging anticoagulation. Patients at high risk of thromboembolism (eg, recent cardioversion, high CHA2DS2-VASc score, prior cardioembolic stroke, current intracardiac thrombus) may be considered for bridging with a parenteral anticoagulant (see Transitioning between anticoagulants below) (ACCP [You 2012]).

IV: Initial bolus of 60 to 80 units/kg (maximum: 5,000 units), followed by a continuous infusion of 12 to 18 units/kg/hour (maximum: 1,000 units/hour). Institutional dosing protocols may vary; adjust infusion rate to maintain anticoagulation target (ACCP [Garcia 2012]; ACCP [You 2012]; Dager 2018).

Frostbite

Frostbite (adjunctive agent) (off-label use): Note: Patients should be transferred to a facility that is familiar with managing patients with frostbite. Anticoagulation may be used in conjunction with thrombolytic therapy, either concurrently or following administration of the thrombolytic, but not as monotherapy (Hickey 2020; Nygaard 2017; WMS [McIntosh 2019]). Optimal regimens, administration routes, and doses, including the use of therapeutic or low-dose anticoagulation after thrombolytic therapy, have not been identified; refer to institutional protocols.

Example regimens include:

When thrombolytic is administered IV:

IV: 500 to 1,000 units/hour as a fixed dose or targeted to an aPTT 2× control for up to 6 hours (WMS [McIntosh 2019]; Zafren 2022); some centers extend the duration to up to 5 days (Johnson 2011) or transition to therapeutic low-molecular-weight heparin (LMWH) (eg, enoxaparin) (Nygaard 2017).

When thrombolytic is administered intra-arterial:

Intra-arterial: 500 units/hour administered through the intra-arterial catheter; targeted to a goal aPTT 50 to 70 seconds; after discontinuation of thrombolytic therapy, continue anticoagulation for 72 to 96 hours or transition to therapeutic LMWH (eg, enoxaparin) (Bruen 2007; Ibrahim 2015; Paine 2020). Instead of intra-arterial heparin, some suggest the use of IV heparin after intra-arterial thrombolytic (see IV dosing above) (Gonzaga 2016).

Hemodialysis, anticoagulation of circuit

Hemodialysis, anticoagulation of circuit:

Note: Standard dosing has not been established for intermittent hemodialysis or CRRT. Recommendations provided below are example regimens. Refer to institutional protocols. May need to individualize dose based on patient-specific needs.

Intermittent hemodialysis:

Standard risk for bleeding:

IV: Initial: Bolus 1,000 units or 2,000 units at the beginning of hemodialysis, followed by a continuous infusion of 500 units/hour; stop the infusion 60 minutes before the end of hemodialysis (Kovalik 2020; Shen 2012).

If clotting occurs during first half of hemodialysis session: Increase IV bolus by 500 units before each subsequent session (eg, administer 1,500 units or 2,500 units, depending on the previously attempted dose, at the beginning of hemodialysis) until clotting no longer occurs or up to a maximum of 4,000 units; administer continuous infusion as described above (Kovalik 2020; Shen 2012).

If clotting occurs during second half of hemodialysis session: Administer the same IV bolus dose, but increase continuous infusion by 100 units/hour for each subsequent session (eg, administer 600 units/hour) until clotting no longer occurs or up to a maximum of 1,000 units/hour; stop the infusion 30 minutes before the end of hemodialysis (Kovalik 2020; Shen 2012).

High risk for bleeding:

Note: There is no standard practice to prevent clotting of the hemodialysis circuit among patients who are at high risk for bleeding. Dialysis without heparin is preferred, but may consider heparin anticoagulation in patients who continue to have recurrent filter thrombosis (Kovalik 2020).

IV: Initial: Bolus 1,000 units at the beginning of hemodialysis; do not administer a continuous infusion during the procedure (Kovalik 2020; Shen 2012).

If clotting occurs during hemodialysis: IV: Bolus 1,000 units at the beginning of the subsequent hemodialysis session, followed by a continuous infusion of 500 units/hour; stop the infusion 60 minutes before the end of hemodialysis; if clotting continues, increase continuous infusion by 100 units/hour at each subsequent session (eg, administer 600 units/hour) until clotting no longer occurs or up to a maximum of 1,000 units/hour (Kovalik 2020; Shen 2012).

CRRT:

Note: For patients who require anticoagulation due to repeated clotting of hemofilter and when regional citrate anticoagulation is not feasible or unavailable (Davenport 2020).

IV: Initial: Bolus 500 to 1,000 units, followed by a continuous infusion of 500 units/hour; titrate to maintain an aPTT ~1.5 times the control or ~45 seconds (Davenport 2020; Tsujimoto 2020).

Ischemic heart disease

Ischemic heart disease:

Acute coronary syndromes:

ST-elevation myocardial infarction (off-label use):

Adjunct to percutaneous coronary intervention: see Percutaneous coronary intervention for dosing guidance.

Adjunct to fibrinolysis: IV: Bolus 60 units/kg (maximum: 4,000 units), followed by 12 units/kg/hour (maximum: 1,000 units/hour); adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours or until revascularization (if performed) (ACCF/AHA [O’Gara 2013]; Antman 2006; Wallentin 2003).

No planned reperfusion: IV: Bolus 50 to 70 units/kg (maximum: 5,000 units), followed by 12 units/kg/hour; adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours (Lincoff 2020).

Non-ST-elevation acute coronary syndromes (off-label use):

Ischemia-guided (conservative) approach (alternative agent): IV: Bolus 60 units/kg (maximum: 5,000 units), followed by 12 units/kg/hour (maximum: 1,000 units/hour); adjust infusion rate to maintain anticoagulation target based on institutional protocol; continue for ≥48 hours or until management changes to an invasive strategy (eg, percutaneous coronary intervention [PCI]) (AHA/ACC [Amsterdam 2014]; Cohen 1997; Cutlip 2020a; Ferguson 2004; Stone 2006); if PCI is performed, see Percutaneous coronary intervention for dosing guidance.

Invasive approach (adjunct to percutaneous coronary intervention): see Percutaneous coronary intervention for dosing guidance.

Percutaneous coronary intervention (off-label use):

No prior anticoagulant therapy:

No planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 70 to 100 units/kg (maximum: 10,000 units) to achieve activated clotting time (ACT) of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (ACC/AHA [Lawton 2021]; Cutlip 2020b; Lincoff 2020).

Planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 50 to 70 units/kg (maximum: 7,000 units) to achieve ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (ACC/AHA [Lawton 2021]; Cutlip 2020b; Lincoff 2020).

Prior anticoagulant therapy:

Prior anticoagulation with heparin:

No planned glycoprotein IIb/IIIa inhibitor use: IV: Check ACT prior to PCI and administer heparin bolus as needed (eg, 2,000 to 5,000 units) to achieve ACT of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus (maximum: 10,000 units) as needed to maintain goal ACT throughout procedure (ACC/AHA [Lawton 2021]; Cutlip 2020a; Lincoff 2020).

Planned glycoprotein IIb/IIIa inhibitor use: IV: Check ACT prior to PCI and administer heparin bolus as needed (eg, 2,000 to 5,000 units) to achieve ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus (maximum 7,000 units) as needed to maintain goal ACT throughout procedure (ACC/AHA [Lawton 2021]; Cutlip 2020a; Lincoff 2020).

Prior anticoagulation with enoxaparin:

If percutaneous coronary intervention occurs ≤12 hours after the last SubQ dose of enoxaparin: Transition to unfractionated heparin is not recommended. Refer to enoxaparin monograph for dosing recommendations.

If percutaneous coronary intervention occurs >12 hours after the last SubQ dose of enoxaparin: May use unfractionated heparin; refer to recommendations above for PCI with no prior anticoagulant therapy (ACC/AHA [Lawton 2021]).

Prior anticoagulation with fondaparinux:

No planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 85 units/kg (maximum: 10,000 units) to achieve ACT of 250 to 300 seconds (goal ACT may vary depending on point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (ACC/AHA [Lawton 2021]; Cutlip 2020a; Steg 2010).

Planned glycoprotein IIb/IIIa inhibitor use: IV: Initial bolus of 60 units/kg (maximum: 7,000 units) to achieve ACT of 200 to 250 seconds (regardless of point-of-care device); repeat bolus as needed to maintain goal ACT throughout procedure (ACC/AHA [Lawton 2021]; Cutlip 2020a; Steg 2010).

Mechanical heart valve, bridging anticoagulation

Mechanical heart valve, bridging anticoagulation (for interruptions in warfarin therapy) (off-label use): Note: Bridging during intervals of subtherapeutic anticoagulation should be considered for patients with mechanical mitral or tricuspid valve replacement; however, for patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or patient has an older-generation mechanical aortic valve (ACC/AHA [Otto 2021]).

IV: Limited data available: Initial: 12 to 18 units/kg/hour (no bolus) starting when INR falls below the therapeutic range; adjust infusion rate to maintain anticoagulation target based on institutional protocol. If patient is to undergo an invasive procedure, discontinue heparin 4 to 6 hours prior to procedure; reinitiate heparin infusion as soon as possible after the procedure when bleeding risk is acceptable. Continue heparin until warfarin has been reinitiated and INR is within therapeutic range for 2 consecutive days (ACCP [Douketis 2012]; Konkle 2019b).

Mechanical heart valve, postsurgical management

Mechanical heart valve, postsurgical management (to transition to warfarin) (off-label use): Note: Initiate postoperatively when risk of bleeding is acceptable (ACCP [Whitlock 2012]; Konkle 2022).

IV: Limited data available: Initial: 12 to 18 units/kg/hour (no bolus); adjust infusion rate to maintain anticoagulation target based on institutional protocol. Overlap with warfarin until INR is stable and within therapeutic range for ≥2 consecutive days (Konkle 2022).

Peripheral arterial occlusion, acute

Peripheral arterial occlusion, acute (off-label use): Note: Specific dosing information is limited, but anticoagulation is commonly used at the time of diagnosis to limit thrombus propagation while the patient is evaluated for other possible interventions (AHA/ACC [Gerhard-Herman 2017]; Braun 2022; Pearl 2020).

IV: Initial bolus of 60 to 80 units/kg, followed by an initial continuous infusion of 12 to 18 units/kg/hour; adjust infusion rate to maintain anticoagulation target based on institutional protocol (ACCP [Garcia 2012]; Dager 2018; Hull 2022a).

Venous thromboembolism prophylaxis

Venous thromboembolism prophylaxis (alternative agent): Note: Low-weight patients (eg, <50 kg) may be more sensitive to routine prophylactic doses, increasing the potential for higher than intended levels of anticoagulation; consider adhering to every-12-hour dosing interval (Dager 2018).

Medical patients with acute illness at moderate to high risk for venous thromboembolism: SubQ: 5,000 units every 8 to 12 hours; continue for length of hospitalization or until fully ambulatory (ACCP [Kahn 2012]; ASCO [Key 2020]; Pai 2019a); extended prophylaxis beyond acute hospital stay is not routinely recommended (ACCP [Kahn 2012]; Osataphan 2021; Sharma 2012).

Nonorthopedic surgery:

Patients with active cancer:

SubQ: 5,000 units 2 to 4 hours prior to surgery, then 5,000 units every 8 hours thereafter (ASCO [Key 2020]) or 5,000 units every 8 to 12 hours started ~6 to 24 hours after surgery (Bauer 2021). Note: The optimal duration of prophylaxis has not been established, but it is usually given for a minimum of 7 to 10 days; extending for up to 4 weeks may be reasonable in those undergoing major abdominal or pelvic surgery (ASCO [Key 2020]).

Patients without cancer: Note: For patients with moderate or high risk of venous thromboembolism (VTE) and low risk of bleeding.

SubQ: 5,000 units every 8 to 12 hours, with initial dose given ≥2 hours prior to surgery. Alternatively, may postpone pharmacologic prophylaxis until after surgery (eg, high bleeding risk) when it is safe to initiate. Continue until fully ambulatory and risk of VTE has diminished (typically up to 10 days) (ACCP [Gould 2012]; Pai 2019b).

Orthopedic surgery (eg, hip fracture surgery, total hip arthroplasty, total knee arthroplasty): SubQ: 5,000 units every 8 to 12 hours, with initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved; optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days; some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty or higher end of the range (~30 days) for total hip arthroplasty (ACCP [Falck-Ytter 2012]; Pai 2019c). For extended duration of prophylaxis, may transition to an oral anticoagulant or alternative SubQ anticoagulant with less frequent dosing (Pai 2019c).

Pregnancy: Note: For patients at moderate or high VTE risk during antepartum and postpartum periods. Dose intensity is individualized based on risk of thrombosis and bleeding complications (ACOG 196 2018; Bauer 2022).

Prophylactic dose (also referred to as intermediate dose to account for weight gain during pregnancy):

First trimester: SubQ: 5,000 to 7,500 units every 12 hours (ACOG 196 2018).

Second trimester: SubQ: 7,500 to 10,000 units every 12 hours (ACOG 196 2018).

Third trimester: SubQ: 10,000 units every 12 hours (reduce dose if the aPTT becomes elevated) (ACOG 196 2018).

Adjusted dose (therapeutic): Note: Reserved for patients at the highest VTE risk (eg, history of recurrent thrombosis, severe thrombophilia).

SubQ: 10,000 units every 12 hours; adjust dose to target an aPTT of 1.5 to 2.5 times control, measured 6 hours after injection; monitor aPTT once daily until stable and within therapeutic range, then monitor every 1 to 2 weeks (ACCP [Bates 2012]; ACOG 196 2018; Bauer 2022).

Note: Discontinue heparin at the onset of spontaneous labor. Prior to planned induction of labor or cesarean delivery, discontinue heparin ≥12 hours before in patients receiving 7,500 to 10,000 units every 12 hours or ≥24 hours before in patients receiving >10,000 units/dose or >20,000 units/day. Consider checking coagulation parameters before delivery. Appropriate discontinuation is particularly important if neuraxial anesthesia is planned. May restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery, unless significant bleeding occurred or traumatic neuraxial catheter placement. Anticoagulation should continue for up to 6 weeks postpartum, but potentially longer (ACCP [Bates 2012]; ACOG 2018; Bauer 2022).

Venous thromboembolism treatment, deep vein thrombosis and/or pulmonary embolism

Venous thromboembolism treatment, deep vein thrombosis and/or pulmonary embolism: Note: IV heparin may be preferred for initial therapy in patients who are hemodynamically unstable, may need invasive procedures or thrombolysis due to extensive clot burden, are obese, have renal failure, or when rapid reversal of anticoagulation may be needed (Lip 2022). If thrombolytics are used, it is recommended to discontinue heparin during administration then resume upon completion of the thrombolytic infusion (ASH [Ortel 2020]); Tapson 2019).

Inpatient treatment: IV: Initial: 80 units/kg bolus followed by a continuous infusion of 18 units/kg/hour or 5,000 unit bolus followed by 1,333 units/hour; adjust infusion rate to maintain target laboratory values based on institutional protocol (ACCP [Garcia 2012]). Note: Weight-based dosing is more effective than fixed dosing at reaching therapeutic anticoagulation (ACCP [Garcia 2012]; AHA [Hirsh 1994]; Bates 2001; Dager 2018; Vandiver 2012).

Example Weight-Based IV Heparin Nomogram for Treatment of Venous Thromboembolisma,b

aHull 2022a

bThis is one example of a weight-based heparin dosing nomogram. Each institution should establish their own heparin dosing nomogram. Other heparin nomograms based on aPTT or anti-Factor Xa monitoring may be employed. Therapeutic range for aPTT must be established at each individual laboratory (Dager 2018).

cUse actual body weight for calculations.

Initial dose and monitoring

80 units/kg bolus (maximum dose: 10,000 units)c, then 18 units/kg/hour (maximum initial infusion: 2,000 units/hour)c

Obtain aPTT 6 hours after initial heparin bolus

Dosing adjustments and monitoring

If using anti-Factor Xa activity (units/mL)

Response

If using aPTT (seconds)

0 to 0.09

• Bolus 25 units/kg

• Increase infusion by 3 units/kg/hour

• Repeat assay in 6 hours

<40

0.1 to 0.19

• Increase infusion by 2 units/kg/hour

• Repeat assay in 6 hours

40 to 49

0.2 to 0.29

• Increase infusion by 1 unit/kg/hour

• Repeat assay in 6 hours

50 to 69

0.3 to 0.7

• No change (within therapeutic range)

• Repeat assay in 6 hours

• Once therapeutic for 2 consecutive assays, may change to once-daily assays

70 to 110

0.71 to 0.79

• Decrease infusion by 1 unit/kg/hour

• Repeat assay in 6 hours

111 to 120

0.8 to 0.89

• Stop infusion for 1 hour, then decrease by 2 units/kg/hour

• Repeat assay 6 hours after restarting the infusion

121 to 130

0.9 to 0.99

• Stop infusion for 1 hour, then decrease by 3 units/kg/hour

• Repeat assay 6 hours after restarting the infusion

131 to 140

1 to 1.09

• Stop infusion for 2 hours, then decrease by 4 units/kg/hour

• Repeat assay 6 hours after restarting the infusion

141 to 150

≥1.1

• Stop infusion for 2 hours, then decrease by 5 units/kg/hour and notify clinician

• Repeat assay 6 hours after restarting the infusion

>150

Outpatient treatment: Note: Alternative for patients who have a contraindication to other anticoagulants.

SubQ: Initial: 333 units/kg, followed by 250 units/kg every 12 hours (ACCP [Guyatt 2012]; ACCP [Holbrook 2012]; Lip 2022).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail.

Transitioning from another anticoagulant to IV heparin:

Transitioning from a therapeutic dose of SubQ low-molecular-weight heparin or SubQ fondaparinux to a therapeutic dose of IV heparin: Start IV heparin without a bolus dose (infusion rate depends on the indication) 1 to 2 hours before the next dose of low-molecular-weight heparin (LMWH) or fondaparinux would have been due (Dager 2018).

Transitioning from warfarin to a therapeutic dose of IV heparin: Stop warfarin and, when INR is as close as possible to the lower end of the targeted INR range, start IV heparin without a bolus dose (infusion rate depends on the indication) (Dager 2018).

Transitioning from a direct-acting oral anticoagulant to a therapeutic dose of IV heparin: Stop direct-acting oral anticoagulant (DOAC) and, when the next DOAC dose would have been due, start IV heparin without a bolus dose (infusion rate depends on the indication) (Dager 2018).

Transitioning from IV heparin to another anticoagulant:

Transitioning from a therapeutic dose of IV heparin to therapeutic SubQ low-molecular-weight heparin or SubQ fondaparinux: Stop IV heparin and within 1 hour start SubQ LMWH or SubQ fondaparinux. Note: If aPTT is not within therapeutic range at the time heparin is stopped, consult local protocol (Dager 2018).

Transitioning from a therapeutic dose of IV heparin to warfarin: Start warfarin and continue IV heparin until INR is within therapeutic range (Dager 2018; Hull 2022a). Note: Overlap IV heparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is ~5 days) (ACCP [Ageno 2012]; Hull 2022b).

Transitioning from a therapeutic dose of IV heparin to a direct-acting oral anticoagulant: Start DOAC when the heparin infusion is stopped (consult local protocol if the aPTT is above the target range) (Dager 2018).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: IV, SubQ: Mild to severe impairment: No initial dosage adjustment necessary; adjust to maintain anticoagulation target based on institutional protocol (Dager 2010; Estes 1980).

Renal replacement therapies: Poorly dialyzed (Nemecek 2019): IV, SubQ: No supplemental dose or initial dosage adjustment necessary in patients receiving renal replacement therapies (eg, hemodialysis, peritoneal dialysis, CRRT, PIRRT); adjust to maintain anticoagulation target based on institutional protocol (Dager 2015; expert opinion).

Dosing: Hepatic Impairment: Adult

No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Factor Xa activity.

Dosing: Pediatric

(For additional information see "Heparin (unfractionated): Pediatric drug information")

Note: Many concentrations of heparin are available and range from 1 to 20,000 units/mL. Carefully examine each prefilled syringe, bag, or vial prior to use to ensure that the correct concentration is chosen. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.

Prophylaxis:

Central line flush; patency (intermittent doses): Limited data available (ACCP [Monagle 2012]; Bradford 2016; Conway 2014; Lee 2005): Infants, Children, and Adolescents: When using intermittent flushes of heparin to maintain patency of single and double lumen central catheters, various recommendations exist; refer to institution specific protocols. Capped polyvinyl chloride catheters and peripheral heparin locks require flushing more frequently (eg, every 6 to 8 hours). Volume of heparin flush is usually similar to volume of catheter (or slightly greater). Dose of heparin flush used should not approach therapeutic unit per kg dose. Additional flushes should be given when stagnant blood is observed in catheter, after catheter is used for drug or blood administration, and after blood withdrawal from catheter.

Extracorporeal membrane oxygenation (ECMO) (venoarterial [VA]/cardiac), anticoagulation: Note: While used to prevent thrombosis, full anticoagulation dosing is necessary; Infants, Children, and Adolescents: IV: 100 units/kg prior to ECMO cannulation followed by continuous IV heparin infusion to maintain the activated clotting time (ACT) between 180 and 220 seconds; ACT should be checked hourly while patient is on ECMO; additional monitoring targets for heparin therapy are prolongation of the PTT to 1.5 to 2.5 times the control value or an anti-Xa level of 0.3 to 0.7 units/mL (AHA [Giglia 2013]).

Parenteral nutrition (PN) additive, venous access patency: Infants, Children, and Adolescents: 1 unit/mL (final heparin concentration in PN), both central and peripheral. The final concentration of heparin used for PN solutions may need to be decreased to 0.5 units/mL in small infants receiving larger PN volumes in order to avoid approaching therapeutic amounts (Corkin 2015).

Peripheral arterial catheters in situ: Infants, Children, and Adolescents: Intra-arterial (via arterial catheter): Continuous infusion of heparin at a final concentration of 5 units/mL at 1 mL/hour (ACCP [Monagle 2012]; Butt 1987).

Thromboprophylaxis in congenital heart defect (CHD) patients with systemic to pulmonary artery shunts (eg, Sano shunt, Blalock-Taussig shunt, central shunt) or central venous lines in certain CHD patients (eg, previous thrombosis or hypercoagulable states): Infants, Children, and Adolescents: Low Dose: Continuous IV infusion: 10 to 15 units/kg/hour (AHA [Giglia 2013]).

Thrombosis, treatment:

Systemic heparinization:

Infants: IV: Initial loading dose: 75 units/kg over 10 minutes; then initial continuous maintenance infusion at: 28 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (ACCP [Monagle 2012]; Hepponstall 2017).

Children and Adolescents: IV: Initial loading dose: 75 units/kg over 10 minutes, then initial continuous maintenance infusion at: 20 units/kg/hour; adjust dose to maintain an anti-Xa activity of 0.35 to 0.7 units/mL or an aPTT range that correlates to this anti-Xa range or a protamine titration range of 0.2 to 0.4 units/mL (ACCP [Monagle 2012]; Hepponstall 2017). Note: A lower initial continuous maintenance infusion dose of 18 units/kg/hour in older patients has also been suggested (Hepponstall 2017).

Note: Because of variation among hospitals with reagents (lot numbers) and corresponding control of aPTT values, individual institutions should establish unique, institution-specific nomograms based on current reagent. Due to extensive variability within reagents and anti-Xa levels with corresponding aPTTs, a specific nomogram has not been provided; refer to guidelines for a specific nomogram (ACCP [Monagle 2012]).

Systemic to pulmonary artery shunt thrombosis (eg, Sano shunt, Blalock-Taussig shunt, central shunt); treatment in CHD patients: Infants, Children, and Adolescents: IV: Bolus: 50 to 100 units/kg, ongoing continuous infusion should be considered (AHA [Giglia 2013]; PALS [Topjian 2020]).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

All patients: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity

Dosing: Hepatic Impairment: Pediatric

All patients: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity

Dosing: Older Adult

Patients >60 years of age may have higher serum levels and clinical response (longer aPTTs) as compared to younger patients receiving similar dosages. Lower dosages may be required.

Dosing: Obesity: Adult

The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Venous thromboembolism prophylaxis:

Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):

SUBQ: 5,000 to 7,500 units every 8 hours (expert opinion). Note: Until large prospective studies are available evaluating dosing and outcomes, it is reasonable to use 5,000 units every 8 hours. In patients with a BMI >50 kg/m2, consider 7,500 units every 8 hours (expert opinion).

Therapeutic anticoagulation, treatment:

Class 1 or 2 obesity (BMI 30 to 39 kg/m2):

IV: Use actual body weight for dosing calculation; adjust infusion rate to maintain target laboratory values based on institutional protocol (Shlensky 2020). Refer to indication-specific dosing recommendations.

Class 3 obesity (BMI ≥40 kg/m2):

IV: Use adjusted body weight for dosing calculation; adjust infusion rate to maintain target laboratory values based on institutional protocol (Barletta 2008; Hosch 2017; expert opinion). Alternatively, dosing based on actual body weight (with or without a bolus) may be considered with an initial reduced maintenance dose (eg, 12 units/kg/hour for VTE treatment) (Gerlach 2013; Riney 2010; Shin 2015; expert opinion). Refer to indication-specific dosing recommendations.

Rationale for recommendations:

Heparin is extensively bound to plasma proteins and has a low Vd, which is similar to blood volume. However, increased blood volume is expected with increasing body weight, resulting in increased dosing requirements for patients with obesity (Estes 1980; Hirsh 1995).

Venous thromboembolism prophylaxis: Due to increases in blood volume and likely decreased bioavailability of SUBQ heparin in patients with obesity, higher dosing (7,500 units every 8 hours) has been recommended in those who require venous thromboembolism prophylaxis (Kroon 1991; Samuel 2015; Streiff 2015). However, a large retrospective cohort study suggests similar occurrence of venous thromboembolism and major bleeding in patients without obesity and those with obesity (BMI ≥30 kg/m2) when administered prophylactic unfractionated heparin at 5,000 units every 8 hours (Patanwala 2018). Data are lacking in patients with a BMI >50 kg/m2.

Therapeutic anticoagulation, treatment: Retrospective studies show no difference in time to achievement of therapeutic aPTT or bleeding rates when actual body weight was used for bolus and maintenance treatment dosing without dose capping in the following weight classifications: BMI <30 kg/m2, BMI 30 to 39.9 kg/m2, or BMI ≥40 kg/m2 (Bauer 2009; Shlensky 2020). In patients with a BMI ≥40 kg/m2, a retrospective study using actual body weight for weight-based dosing showed higher likelihood of supratherapeutic aPTT values compared to patients with a BMI <40 kg/m2 (Barletta 2008).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Generic: 2000 units (1000 mL); 25,000 units (500 mL); 2000 units in 0.9% NaCl per liter (1000 mL); 25,000 units/500 mL (500 mL); 25,000 units/500 mL in NaCl 0.45% (500 mL)

Solution, Injection, as sodium:

Generic: 12,500 units (250 mL); 25,000 units (250 mL); 1000 units/mL (1 mL, 10 mL, 30 mL); 5000 units/mL (1 mL, 10 mL); 10,000 units/mL (1 mL, 4 mL, 5 mL); 20,000 units/mL (1 mL)

Solution, Injection, as sodium [preservative free]:

Generic: 1000 units/mL (2 mL); 5000 units/mL (1 mL); 5000 units/0.5 mL (0.5 mL)

Solution, Intravenous, as sodium:

Generic: 1000 units (500 mL); 10,000 units (250 mL); 20,000 units (500 mL); 25,000 units (250 mL); 1 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL); 10 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL); 100 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL); 1000 units/500 mL in NaCl 0.9% (500 mL); 25,000 units/250 mL in Dextrose 5% (250 mL); 25,000 units/250 mL in NaCl 0.45% (250 mL)

Solution, Intravenous, as sodium [preservative free]:

Generic: 10 units/mL (1 mL [DSC], 3 mL [DSC], 5 mL [DSC]); 100 units/mL (1 mL [DSC], 3 mL [DSC], 5 mL [DSC])

Solution Prefilled Syringe, Injection, as sodium [preservative free]:

Generic: 5000 units/0.5 mL (0.5 mL)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Generic: 25,000 units/500 mL (500 mL)

Solution, Injection, as sodium:

Generic: 1000 units/mL (1 mL, 2 mL, 10 mL, 30 mL); 10,000 units/mL (0.5 mL, 1 mL, 5 mL); 1000 units (500 mL, 1000 mL)

Solution, Intravenous, as sodium:

Generic: 20,000 units/500 mL in Dextrose 5% (500 mL); 10 units/mL ([DSC]); 100 units/mL (2 mL, 10 mL); 25,000 units/250 mL in Dextrose 5% (250 mL)

Solution Prefilled Syringe, Subcutaneous:

Generic: 5000 units/0.5 mL (0.5 mL)

Administration: Adult

SubQ: Inject in subcutaneous tissue only (not muscle tissue). Injection sites should be rotated (usually left and right portions of the abdomen, above iliac crest).

IM: Do not administer IM due to pain, irritation, and hematoma formation.

Continuous IV infusion: Infuse via infusion pump. If preparing solution, mix thoroughly prior to administration.

Heparin lock: Inject via injection cap using positive pressure flushing technique. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.

Central venous catheters: Must be flushed with heparin solution when newly inserted, daily (at the time of tubing change), after blood withdrawal or transfusion, and after an intermittent infusion through an injectable cap. A volume of at least 10 mL of blood should be removed and discarded from a heparinized line before blood samples are sent for coagulation testing.

Intravesical (off-label use): Various dosage regimens of heparin (20,000 to 50,000 units) alone or with alkalinized lidocaine (1% to 4%) have been instilled into the bladder.

Intra-arterial (off-label use): Infuse via infusion pump. If preparing solution, mix thoroughly prior to administration (Bruen 2007).

Administration: Pediatric

Note: Many concentrations of heparin are available and range from 1 to 20,000 units/mL. Carefully examine each prefilled syringe, bag, or vial prior to use to ensure that the correct concentration is chosen.

Parenteral: Do not administer IM due to pain, irritation, and hematoma formation.

IV:

IV bolus: Administered over 10 minutes (ACCP [Monagle 2012]).

Continuous IV infusion: Infuse via infusion pump.

Heparin lock: Inject via injection cap using positive pressure flushing technique. Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.

Central venous catheters: Must be flushed with heparin solution when newly inserted, daily (at the time of tubing change), after blood withdrawal or transfusion, and after an intermittent infusion through an injectable cap.

SubQ: Not all preparation intended for SubQ administration, verify product selection. Inject in subcutaneous tissue only (not muscle tissue). Injection sites should be rotated (usually left and right portions of the abdomen, above iliac crest).

Usual Infusion Concentrations: Adult

Note: Premixed solutions available

IV infusion: 25,000 units in 250 mL (concentration: 100 units/mL) of D5W, 1/2NS, or NS

Usual Infusion Concentrations: Pediatric

Note: Premixed solutions available

IV infusion: 100 units/mL

Use: Labeled Indications

Anticoagulation: Prophylaxis and treatment of thromboembolic disorders (eg, venous thromboembolism, pulmonary embolism) and thromboembolic complications associated with atrial fibrillation; prevention of clotting in arterial and cardiac surgery; as an anticoagulant for blood transfusions, extracorporeal circulation, and dialysis procedures.

Note: Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for systemic anticoagulant therapy.

Use: Off-Label: Adult

Antibiotic lock technique, adjunctive therapy (catheter-salvage strategy); Frostbite; Mechanical heart valve, bridging anticoagulation (for interruptions in warfarin therapy); Mechanical heart valve, postsurgical management (to transition to warfarin); Non-ST-elevation acute coronary syndromes; Percutaneous coronary intervention; Peripheral arterial occlusion, acute; ST-elevation myocardial infarction

Medication Safety Issues
Sound-alike/look-alike issues:

Heparin may be confused with Hespan

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

National Patient Safety Goals:

The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).

Administration issues:

The 100 unit/mL concentration should not be used to flush heparin locks, IV lines, or intra-arterial lines in neonates or infants <10 kg (systemic anticoagulation may occur). The 10 unit/mL flush concentration may inadvertently cause systemic anticoagulation in infants <1 kg who receive frequent flushes.

Other safety concerns:

Heparin sodium injection 10,000 units/mL and Hep-Lock U/P 10 units/mL have been confused with each other. Fatal medication errors have occurred between the two whose labels are both blue. Never rely on color as a sole indicator to differentiate product identity.

Labeling changes: Effective May 1, 2013, heparin labeling is required to include the total amount of heparin per vial (rather than only including the amount of heparin per mL). During the transition, hospitals should consider only stocking the newly labeled heparin to avoid potential errors and confusion with the older labeling.

Heparin lock flush solution is intended only to maintain patency of IV devices and is not to be used for anticoagulant therapy.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Postmarketing:

Cardiovascular: Vasospasm (including cyanotic extremities, limb ischemia, and limb pain)

Dermatologic: Skin ulceration at injections site (SUBQ), transient alopecia

Endocrine & metabolic: Acute adrenocortical insufficiency, adrenal hemorrhage, hyperkalemia, ovarian hemorrhage, suppression of aldosterone synthesis

Genitourinary: Priapism

Hematologic & oncologic: Bruise, hemorrhage, heparin-induced thrombocytopenia retroperitoneal hemorrhage, thrombocytopenia (often of no clinical significance with continued therapy), thrombosis in heparin-induced thrombocytopenia (including acute myocardial infarction, cerebrovascular accident, deep vein thrombosis, gangrene of the extremities, pulmonary embolism, skin necrosis)

Hepatic: Increased serum alanine aminotransferase, increased serum aspartate aminotransferase

Hypersensitivity: Anaphylactic shock, hypersensitivity reaction, nonimmune anaphylaxis, severe infusion related reaction (skin necrosis)

Local: Erythema at injection site (SUBQ), hematoma at injection site (SUBQ), irritation at injection site (SUBQ), pain at injection site (SUBQ), tissue necrosis at injection site (SUBQ)

Neuromuscular & skeletal: Osteoporosis (with long-term use)

Contraindications

Hypersensitivity to heparin or any component of the formulation (unless a life-threatening situation necessitates use and use of an alternative anticoagulant is not possible); severe thrombocytopenia; history of heparin-induced thrombocytopenia; history of heparin-induced thrombocytopenia with thrombosis; uncontrolled active bleeding; not for use when appropriate blood coagulation tests cannot be obtained at appropriate intervals (applies to full-dose heparin only).

Note: Some products contain benzyl alcohol as a preservative; their use in neonates, infants, or pregnant or breastfeeding women is contraindicated by some manufacturers.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May occur, including fatal events. Use with caution in patients with an increased risk of bleeding, including subacute bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; continuous GI tube drainage; severe uncontrolled hypertension; history of hemorrhagic stroke; use shortly after brain, spinal, or ophthalmologic surgery or other invasive procedures including spinal tap or spinal anesthesia; concomitant treatment with platelet inhibitors; recent GI bleeding; impaired hemostasis; thrombocytopenia or platelet defects; patients with hereditary antithrombin deficiency receiving concurrent antithrombin replacement therapy; severe liver disease; hypertensive or diabetic retinopathy; renal failure; or in patients (especially women) >60 years of age. Discontinue if bleeding occurs; severe hemorrhage or overdosage may require protamine (consult Protamine monograph for dosing recommendations).

• Heparin resistance: Dose requirements >35,000 units/24 hours to maintain a therapeutic aPTT may occur in patients with antithrombin deficiency, increased heparin clearance, elevations in heparin-binding proteins, and elevations in factor VIII and/or fibrinogen; frequently encountered in patients with fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, and in postsurgical patients; measurement of anticoagulant effects using anti-Factor Xa levels may be of benefit.

• Hepatic effects: Elevations in serum aminotransferases have been observed during therapy. These elevations should be evaluated with caution as they may occur and resolve in the setting of the underlying condition for which heparin is being used.

• Hyperkalemia: Hyperkalemia may occur, especially in patients with diabetes, renal impairment, history of metabolic acidosis, history of hyperkalemia, or taking concomitant potassium-sparing medication; may suppress aldosterone production.

• Hypersensitivity reactions: Hypersensitivity reactions, including fever, chills, urticaria, asthma, rhinitis, lacrimation, and anaphylaxis, have been reported. In patients with a documented hypersensitivity reaction, heparin should only be considered in life-threatening situations when use of an alternative anticoagulant is not possible. Some products are derived from animal tissue and may be contraindicated in patients with animal allergies (ie, pork); consult individual prescribing information.

• Osteoporosis: May occur with prolonged use (>6 months) due to a reduction in bone mineral density.

• Thrombocytopenia: Mild thrombocytopenia (platelet count >100,000/m3) may occur during therapy. Heparin-induced thrombocytopenia (HIT), a serious antibody-mediated reaction resulting from irreversible aggregation of platelets, may occur. Patients who develop HIT may be at risk of developing a new thrombus (heparin-induced thrombocytopenia with thrombosis [HITT]). Discontinue therapy and consider alternatives if platelet count falls below 100,000/mm3, there is a >50% reduction in platelet count from baseline, and/or thrombosis develops while on heparin therapy. Onset of HIT or HITT is usually delayed (5 to 10 days after exposure in heparin-naive individuals) and can occur up to several weeks after discontinuation of heparin. “Rapid onset” HIT can occur within 24 hours of heparin initiation, especially in patients with recent heparin exposure within the previous 100 days. Use with extreme caution (for a limited duration) or avoid use in patients with history of HIT, especially if administered within 100 days of a HIT episode (Dager 2007; Warkentin 2001).

Special populations:

• Older adult: Use with caution in patients >60 years of age, particularly women; older adults can be more sensitive to heparin and a higher incidence of bleeding has been reported in these patients. May require lower doses.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol as a preservative. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome"); the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling. Use in neonates, infants, or pregnant or nursing mothers is contraindicated by some manufacturers; the use of preservative-free heparin is, therefore, recommended in these populations.

• Sulfites: Some preparations contain sulfite which may cause allergic reactions.

Other warnings/precautions:

• Fatal medications errors: Many concentrations of heparin are available ranging from 1 unit/mL to 20,000 units/mL. Clinicians must carefully examine each prefilled syringe or vial prior to use ensuring that the correct concentration is chosen; fatal hemorrhages have occurred related to heparin overdose especially in pediatric patients.

Warnings: Additional Pediatric Considerations

Confirm the concentration of all heparin injection vials prior to administration; do not use heparin injection as a "catheter lock flush" as the injection is supplied in various concentrations including highly concentrated strengths. Fatal hemorrhages have occurred in pediatric patients when higher concentrations of heparin injection were confused with lower concentrations of heparin lock flush.

Heparin-induced thrombocytopenia (HIT) has been reported in pediatric patients; incidence and risk factors are not well-defined due to variability related to patient inclusion and laboratory techniques; incidence rates up to 2.3% in PICU patients have been reported, and cases observed at both low and high levels of heparin exposure (eg, venous access device line flushes and supratherapeutic doses associated with hemodialysis and during cardiopulmonary bypass). Monitor platelet count closely; if HIT develops, consider alternate anticoagulation therapy (eg, danaparoid, argatroban) (ACCP [Monagle 2012]).

Heparin resistance should be suspected in pediatric patients if unable to achieve an activated clotting time (ACT) >300 seconds after administration of >600 units/kg (ACCP [Giglia 2013]).

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification

Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Aliskiren: Heparin may enhance the hyperkalemic effect of Aliskiren. Risk C: Monitor therapy

Andexanet Alfa (Coagulation Factor Xa [Recombinant], Inactivated): May diminish the therapeutic effect of Heparin. Risk X: Avoid combination

Angiotensin II Receptor Blockers: Heparin may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Heparin may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

Antithrombin: May enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Corticorelin: Heparin may enhance the adverse/toxic effect of Corticorelin. Significant hypotension and bradycardia have been previously attributed to this combination. Risk X: Avoid combination

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modification

Drospirenone-Containing Products: May enhance the hyperkalemic effect of Heparin. Risk C: Monitor therapy

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination

Eplerenone: Heparin may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy

Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Nitroglycerin: May diminish the anticoagulant effect of Heparin. Nitroglycerin may decrease the serum concentration of Heparin. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Oritavancin: May diminish the therapeutic effect of Heparin. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor IV heparin effectiveness, which could lead to incorrect decisions to decrease heparin doses. Risk X: Avoid combination

Palifermin: Heparin may increase the serum concentration of Palifermin. Management: If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after palifermin administration. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy

Potassium Salts: Heparin may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Heparin may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Streptokinase: May enhance the anticoagulant effect of Heparin. Risk X: Avoid combination

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Telavancin: May diminish the therapeutic effect of Heparin. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor IV heparin effectiveness, which could lead to incorrect decisions to decrease heparin doses. Risk X: Avoid combination

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tobacco (Smoked): May decrease the serum concentration of Heparin. Risk C: Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Pregnancy Considerations

Heparin does not cross the placenta (ESC [Regitz-Zagrosek 2018]).

Due to pregnancy-induced physiologic changes, the risk of thromboembolism is increased during pregnancy and the immediate postpartum period. Heparin may be used for anticoagulation in pregnancy (ACOG 196 2018). Due to a better safety profile and ease of administration, the use of low molecular weight heparin (LMWH) is generally preferred over heparin (unfractionated heparin [UFH]) in pregnancy (ACOG 196 2018; Bates 2018; ESC [Regitz-Zagrosek 2018]). Anticoagulant therapy for the prevention and treatment of thromboembolism in pregnant patients can be discontinued prior to induction of labor or a planned cesarean delivery (Bates 2018) or LMWH can be converted to UFH in higher risk patients (ESC [Regitz-Zagrosek 2018]). Consult current recommendations for appropriate use in pregnancy.

Patients with mechanical heart valves have an increased risk of adverse maternal and fetal outcomes and these risks are greater without appropriate anticoagulation. UFH or LMWH may be used in pregnant patients with mechanical heart valves. Increased monitoring is required to maintain adequate therapeutic concentrations during pregnancy (consult current recommendations for details) (ESC [Regitz-Zagrosek 2018]; ACC/AHA [Otto 2021]).

Some products contain benzyl alcohol as a preservative; their use in pregnant patients is contraindicated by some manufacturers; use of a preservative-free formulation is recommended.

Breastfeeding Considerations

Heparin is not present in breast milk (Bates 2018).

Heparin is considered acceptable for use in patients who are breastfeeding (Bates 2018; ESC [Regitz-Zagrosek 2018]). However, some products contain benzyl alcohol as a preservative; their use in breastfeeding patients is contraindicated by some manufacturers due to the association of gasping syndrome in premature infants.

Monitoring Parameters

Hemoglobin, hematocrit, platelet count, PT, aPTT, signs/symptoms of bleeding, risk factors for bleeding, fecal occult blood test (if clinically indicated); potassium.

Level of anticoagulation can be monitored by anti-Factor Xa activity or aPTT (calibrated by anti-Factor Xa activity or by protamine titration assay) or activated clotting time depending upon the indication (ACCP [Garcia 2012]; ACCP [You 2012]; Bates 2001; Hirsh 1994; Vandiver 2012).

Patients with antiphospholipid syndrome may have a prolonged aPTT at baseline due to effects of the antiphospholipid antibodies. In order to prevent a prolonged value from being mistaken for therapeutic anticoagulation, aPTT should be measured at baseline. In this situation, anti-Factor Xa monitoring may be preferred (Hull 2019a).

Platelet count should be routinely monitored when the risk of heparin-induced thrombocytopenia (HIT) is >1%. If the patient experienced HIT within the past 100 days after receiving heparin or low-molecular-weight heparin, risk of recurrence is higher. Monitor closely if pre-exposure history is uncertain. When the risk of HIT is <1%, routine platelet count monitoring is not necessary (ACCP [Guyatt 2012]).

Reference Range

Adult:

Treatment of venous thromboembolism and atrial fibrillation:

Anti-Factor Xa activity: 0.3 to 0.7 unit/mL.

Protamine titration: 0.2 to 0.4 unit/mL.

aPTT: Therapeutic range must be established in individual laboratories to target an aPTT prolongation that corresponds to anti-Factor Xa activity or protamine titration values (ACCP [Garcia 2012]; ACCP [You 2012]; Bates 2001; Hirsh 1994; Vandiver 2012).

ST-elevation myocardial infarction as adjunct to fibrinolysis or when no reperfusion is planned: aPTT of 1.5 to 2 times control (or an aPTT of ~50 to 70 seconds) is recommended (ACCF/AHA [O’Gara 2013]; Lincoff 2020). Note: An anti-Factor Xa target has not been established for this indication.

Non-ST-elevation acute coronary syndrome: aPTT of 1.5 to 2 times control (or an aPTT of ~50 to 70 seconds) is recommended (ACCF/AHA [Amsterdam 2014]; Cutlip 2020a). Note: An anti-Factor Xa target has not been established for this indication.

Postmechanical heart valve replacement surgery (to transition to warfarin therapy): Some experts recommend an aPTT of 1.5 to 2 times control when bleeding risk is acceptable postoperatively and heparin is initiated (ACCP [Douketis 2012]; Konkle 2019b). Note: An anti-Factor Xa target has not been established for this indication.

Mechanism of Action

Potentiates the action of antithrombin III and thereby inactivates thrombin (as well as other coagulation factors IXa, Xa, XIa, XIIa, and plasmin) and prevents the conversion of fibrinogen to fibrin; heparin also stimulates release of lipoprotein lipase (lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids)

Pharmacokinetics

Note: Increased interpatient variability of pharmacokinetic parameters in pediatric patients compared to adults; however, age-related decreases in volume of distribution and clearance with increasing pediatric patient age have been reported (ACCP [Monagle 2012]; McDonald 1981).

Onset of action: Anticoagulation: IV: Immediate; SubQ: ~20 to 30 minutes.

Absorption: Oral, rectal: Erratic at best from these routes of administration; SubQ absorption is also erratic, but considered acceptable for prophylactic use.

Distribution:

Premature neonates (data based on single dose of 100 units/kg within 4 hours of birth) (McDonald 1981): Inversely proportional to gestational age (GA).

GA 25 to 28 weeks: 81 ± 41 mL/kg.

GA 29 to 32 weeks: 73.3 ± 24.8 mL/kg.

GA 33 to 36 weeks: 57.8 ± 32.2 mL/kg.

Adults: Following a single 75 unit/kg dose: 36.6 ± 7.4 mL/kg (McDonald 1981).

Metabolism: Complex; thought to occur by depolymerization and desulphation via the reticuloendothelial system primarily in the liver and spleen (ACCP [Garcia 2012]; Dawes 1979; Estes 1980; Kandrotas 1992).

Half-life elimination:

Age-related: Shorter half-life reported in premature neonates compared to adult patients.

Premature neonates GA 25 to 36 weeks (data based on single dose of 100 units/kg within 4 hours of birth): Mean range: 35.5 to 41.6 minutes (McDonald 1981).

Dose-dependent: IV bolus: 25 units/kg: 30 minutes (Bjornsson 1982); 100 units/kg: 60 minutes (de Swart 1982); 400 units/kg: 150 minutes (Olsson 1963).

Mean: 1.5 hours; Range: 1 to 2 hours; affected by obesity, renal function, malignancy, presence of pulmonary embolism, and infections.

Note: At therapeutic doses, elimination occurs rapidly via nonrenal mechanisms. With very high doses, renal elimination may play more of a role; however, dosage adjustment remains unnecessary for patients with renal impairment (Kandrotas 1992).

Excretion: Urine (small amounts as unchanged drug); Note: At therapeutic doses, elimination occurs rapidly via nonrenal mechanisms. With very high doses, renal elimination may play more of a role; however, dosage adjustment remains unnecessary for patients with renal impairment (Kandrotas 1992).

Clearance: Age-related changes; within neonatal population, slower clearance with lower GA; however, when compared to adults, the overall clearance in neonatal and pediatric patients is faster than adults (ACCP [Monagle 2012 ]; McDonald 1981).

Pharmacokinetics: Additional Considerations

Altered kidney function: The half-life may be increased.

Hepatic function impairment: The half-life may be increased or decreased.

Older adult: Plasma levels may be higher.

Pricing: US

Solution (Heparin (Porcine) in NaCl Intravenous)

1000UT/500ML 0.9% (per mL): $0.01

2000UNIT/L 0.9% (per mL): $0.01

12500UT/250ML 0.45% (per mL): $0.04

25000UT/250ML 0.45% (per mL): $0.04 - $0.05

25000UT/500ML 0.45% (per mL): $0.02

Solution (Heparin Sod (Porcine) in D5W Intravenous)

40UNIT/ML 5% (per mL): $0.03

100 units/mL (per mL): $0.04 - $0.07

25000UT/500ML 5% (per mL): $0.02 - $0.04

Solution (Heparin Sod (Pork) Lock Flush Intravenous)

1 units/mL (per mL): $1.16 - $1.25

10 units/mL (per mL): $0.13 - $0.72

100 units/mL (per mL): $0.19 - $0.74

Solution (Heparin Sodium (Porcine) Injection)

1000 units/mL (per mL): $0.27 - $0.91

5000 units/mL (per mL): $1.45 - $5.20

10000 units/mL (per mL): $2.52 - $9.16

20000 units/mL (per mL): $12.00 - $20.95

Solution (Heparin Sodium (Porcine) PF Injection)

5000 units/0.5 mL (per 0.5 mL): $2.58 - $7.20

5000 units/mL (per mL): $7.20

Solution Prefilled Syringe (Heparin Sodium (Porcine) Injection)

5000 units/0.5 mL (per 0.5 mL): $6.84 - $6.84

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Agglutek (TW);
  • Anticlot (VN);
  • Caprin (IN);
  • Coaparin (PL);
  • Haidyparin (EG);
  • Hemastat (PH);
  • Hemonor (PE);
  • Hepaflex (FI, NO);
  • Hepagusan (ID);
  • Heparen (LK);
  • Heparil (UA);
  • Heparin (AT, BF, BG, BJ, CH, CI, CZ, DE, ET, FI, GB, GH, GM, GN, GR, IL, KE, LR, MA, ML, MR, MU, MW, NE, NG, NO, SC, SD, SE, SL, SN, TN, TZ, UG, ZA, ZM, ZW);
  • Heparin Injection B.P. (AU);
  • Heparin Leo (DK, HK, ID, MY, PH, TW);
  • Heparin Novo (TW);
  • Heparin Sodium B Braun (ID, MY);
  • Heparina (ES);
  • Heparine (BE, NL);
  • Heparine Choay (FR);
  • Heparine Novo (BE, NL);
  • Heprin (PH);
  • Hepsal (MT, SA, SG);
  • Heptin (PH);
  • Inhepar (CR, DO, GT, HN, NI, PA, SV);
  • Inviclot (ID);
  • Kabihep (PH);
  • Lioton (HR, RU, UA);
  • Lioton Gel (RO);
  • Liquemin (DE, IT);
  • Liquemine (BE, TR);
  • Lyogel (UA);
  • Minihep (AE, QA);
  • Monoparin (QA, SA);
  • Multiparin (NZ, PK);
  • Nuparin (PH);
  • Pharepa (LB);
  • Proparin (CR, DO, GT, HN, MX, NI, PA, SV);
  • Rhoneparina (PY);
  • Sakarin (PH);
  • Thrombophob (DE);
  • Thrombophob-S (EG);
  • Thromboreduct (DE);
  • Unihep (AE, QA);
  • Wellparin (VN)


For country abbreviations used in Lexicomp (show table)
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  57. Heparin sodium in 0.9% sodium chloride [prescribing information]. New York, NY: Pfizer Labs; September 2019.
  58. Heparin sodium in dextrose injection [prescribing information]. Lake Forest, IL: Hospira, Inc; August 2019.
  59. Heparin sodium in dextrose injection [prescribing information]. Lake Forest, IL: Hospira, Inc; September 2019.
  60. Heparin sodium in sodium chloride 2 units/mL [prescribing information]. Deerfield, IL: Baxter Healthcare Corporation; January 2022.
  61. Heparin sodium injection (single- and multi-dose vials) [prescribing information]. Lake Zurich, IL: Fesenius Kabi; June 2021.
  62. Heparin sodium injection (single- and multi-dose vials) [prescribing information]. Lake Zurich, IL: Fesenius Kabi; July 2021.
  63. Heparin sodium injection [prescribing information]. Rockford, IL: Mylan; September 2019.
  64. Heparin Sodium (Porcine) Lock Flush [prescribing information]. Glendale Heights, IL: Medefil Inc; December 2016.
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