Heparin

Dosage Forms

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

Solution, Intravenous:

Generic: 25,000 units (500 mL); 25,000 units/500 mL in NaCl 0.45% (500 mL)

Solution, Injection, as sodium:

Generic: 2000 units (1000 mL); 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, 500 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); 25,000 units/500 mL in Dextrose 5% (500 mL)

Solution, Intravenous, as sodium [preservative free]:

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

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

Generic: 5000 units/0.5 mL (0.5 mL)

Pharmacology

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/Pharmacodynamics

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)

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)

Onset of Action

Anticoagulation: IV: Immediate; SubQ: ~20 to 30 minutes

Half-Life Elimination

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

Premature neonates gestational age 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).

Use in Specific Populations

Special Populations: Renal Function Impairment

The half-life may be increased.

Special Populations: Hepatic Function Impairment

The half-life may be increased or decreased.

Special Populations: Elderly

Plasma levels may be higher.

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 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

Antibiotic lock technique, adjunctive therapy (catheter-salvage strategy)yes

Based on the 2009 Infectious Diseases Society of America clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection, antibiotic lock therapy may be used as salvage therapy for catheter-related infections in addition to systemic antibiotics when the catheter cannot be removed. Antibiotic lock solutions contain an appropriate antimicrobial and are usually mixed with heparin or NS at a sufficient volume to fill the catheter lumen.

Mechanical heart valve, bridging anticoagulation (for interruptions in warfarin therapy)yes

Based on the 2017 American Heart Association/American College of Cardiology (AHA/ACC) focused update of the 2014 guideline for the management of patients with valvular heart disease, heparin may be considered as bridge therapy during intervals of subtherapeutic anticoagulation for patients with mechanical mitral or tricuspid valve replacement. For patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or the patient has an older-generation mechanical aortic valve.

Mechanical heart valve, postsurgical management (to transition to warfarin)cyes

Data from a limited number of patients in case series and older randomized, controlled trials suggest that IV heparin may be beneficial after surgical placement of a mechanical heart valve when transitioning to warfarin Kulik 2006.

Based on the 2012 American College of Chest Physicians guideline on antithrombotic and thrombolytic therapy for valvular disease, IV heparin may be used in the postoperative period after surgical mechanical valve placement to reduce the risk of valve thrombosis. Clinical experience also suggests the utility of heparin for this use Gaasch 2019a.

Non-ST-elevation acute coronary syndromesyes

Based on the 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), heparin is effective and recommended for the treatment of patients presenting with NSTE-ACS undergoing an invasive strategy with percutaneous coronary intervention (PCI) or as an alternative to enoxaparin or fondaparinux in patients presenting with NSTE-ACS undergoing an ischemia-guided strategy.

Percutaneous coronary interventionyes

Based on the 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guidelines for PCI, heparin is effective and recommended to prevent thrombus formation during PCI.

Peripheral arterial occlusion, acuteyes

Based on the 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease, heparin is recommended and effective in the acute treatment of peripheral arterial occlusion to limit thrombus propagation while other interventions are considered. Clinical experience also suggests the utility of heparin for this use Braun 2019, Pearl 2019.

ST-elevation myocardial infarctionyes

Based on the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction (STEMI), heparin is effective and recommended for the treatment of patients presenting with STEMI managed by an invasive strategy with PCI, or by thrombolysis with fibrinolytic therapy.

Additional off-label uses

Ventricular assist device.

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; history of thrombocytopenia with pentosan polysulfate; uncontrolled active bleeding; cases where the administration of sodium or chloride could be clinically detrimental (applies to large volume heparin 2 unit/mL IV solutions only); 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.

Dosage and Administration

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 2019a). 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 (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]).

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 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 (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) 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).

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 2019).

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 2019a; 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 (ACCF/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]; AHA/ACC [Amsterdam 2014]; Cutlip 2019b).

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 (ACCF/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]; AHA/ACC [Amsterdam 2014]; Cutlip 2019b).

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 (ACCF/AHA/SCAI [Levine 2011]; Cutlip 2019b).

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 (ACCF/AHA/SCAI [Levine 2011]; Cutlip 2019b).

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 full-dose heparin; refer to recommendations above for PCI with no prior anticoagulant therapy (ACCF/AHA/SCAI [Levine 2011]).

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 (ACCF/AHA/SCAI [Levine 2011]; Cutlip 2019b; 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 (ACCF/AHA/SCAI [Levine 2011]; Cutlip 2019b; Steg 2010).

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 (AHA/ACC [Nishimura 2017]).

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]; Gaasch 2019b).

Mechanical heart valve, postsurgical management (to transition to warfarin) (off-label use): Note: Initiate postoperatively when risk of bleeding is acceptable (ACCP [Whitlock 2012]; Gaasch 2019a).

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 (Gaasch 2019a).

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 2019; Pearl 2019).

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 2019a).

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 2019]; Pai 2019a); extended prophylaxis beyond acute hospital stay is not routinely recommended (ACCP [Kahn 2012]; 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 2019]) or 5,000 units every 8 to 12 hours started ~6 to 24 hours after surgery (Bauer 2019a). 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 2019]).

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 2019b).

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 2019b).

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 2019b).

Venous thromboembolism treatment, deep vein thrombosis and/or pulmonary embolism: Note: Some experts prefer IV heparin 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 2019). If thrombolytics are used during inpatient treatment, some experts recommend discontinuing heparin during administration then resuming upon completion of the thrombolytic infusion (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).

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 2019).

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 2019a). Note: For the treatment of VTE, overlap IV heparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is usually 4 to 5 days) (ACCP [Ageno 2012]; Hull 2019b).

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).

Dosing: Geriatric

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: 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. 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]; 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.

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 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 and Children: 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 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])

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])

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: 50 to 100 units/kg, ongoing continuous infusion should be considered (AHA [Giglia 2013])

Administration

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.

Storage

Heparin solutions are colorless to slightly yellow. Minor color variations do not affect therapeutic efficacy. Heparin should be stored at room temperature. Protect from freezing and temperatures >40°C.

Stability at room temperature and refrigeration:

Prepared bag: Variable (specific to solution, concentration, and/or study conditions); also refer to manufacturer's labeling.

Premixed bag: After seal is broken, 4 days.

Out of overwrap stability: 30 days.

Drug Interactions

5-Aminosalicylic Acid Derivatives: May enhance the adverse/toxic effect of Heparin. Specifically, the risk for bleeding/bruising may be increased. Monitor therapy

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. 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. Consider therapy modification

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

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

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

Antithrombin: May enhance the anticoagulant effect of Heparin. 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. Avoid combination

Aspirin: May enhance the anticoagulant effect of Heparin. Monitor therapy

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

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

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

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

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Drospirenone: Heparin may enhance the hyperkalemic effect of Drospirenone. 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. Avoid combination

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

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

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

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

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification

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

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

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

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

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

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

Nitroglycerin: May diminish the anticoagulant effect of Heparin. Nitroglycerin may decrease the serum concentration of Heparin. 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. Consider therapy modification

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 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. Avoid combination

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

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

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

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

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

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. 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. Avoid combination

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

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

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

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. 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. Avoid combination

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

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

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

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

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

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

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

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

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

Test Interactions

Increased thyroxine (competitive protein-binding methods); increased PT.

Adverse Reactions

Thrombocytopenia has been reported to occur at an incidence between 0% and 30%. It is often of no clinical significance; however, immunologically mediated heparin-induced thrombocytopenia (HIT) has been estimated to occur in 1% to 2% of patients and is marked by a progressive fall in platelet counts and, in some cases, thromboembolic complications (skin necrosis, pulmonary embolism, gangrene of the extremities, cerebrovascular accident, or myocardial infarction).

>10%: Hematologic & oncologic: Thrombocytopenia (≤30%)

1% to 10%: Hematologic & oncologic: Heparin-induced thrombocytopenia (1% to 2%)

Frequency not defined: Miscellaneous: Drug tolerance

Postmarketing: Adrenal hemorrhage, anaphylactic shock, burning sensation of feet, cyanotic extremities, dermal ulcer, hematoma, hemorrhage, hypersensitivity reaction, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, limb pain, local irritation, localized erythema, local pain, nonimmune anaphylaxis, osteoporosis, ovarian hemorrhage, peripheral ischemia, priapism, pruritus (feet), retroperitoneal hemorrhage, skin necrosis, suppression of aldosterone synthesis, thrombosis in heparin-induced thrombocytopenia, transient alopecia

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. Monitor patient closely for signs or symptoms of bleeding. 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.
• Hyperkalemia: Monitor for hyperkalemia; can cause hyperkalemia by suppressing aldosterone production.
• Hypersensitivity reactions: May occur; 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: 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]). Monitor platelets closely; 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. HIT or HITT may be delayed and can occur up to several weeks after discontinuation of heparin. 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).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: 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.

Monitoring Parameters

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

Pregnancy

Pregnancy Considerations

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

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 females 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 women (ESC [Regitz-Zagrosek 2018]). UFH or LMWH may be used in pregnant patients with mechanical heart valves (ESC [Regitz-Zagrosek 2018]; Nishimura 2014).

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

Patient Education

What is this drug used for?

• It is used to thin the blood so that clots will not form.
• It is used to treat blood clots.
• It is used to keep blood from clotting in catheters.
• It may be given to you for other reasons. Talk with the doctor.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• DVT like edema, warmth, numbness, change in color, or pain in the extremities.
• Severe dizziness
• Passing out
• Confusion
• Severe headache
• Coughing up blood
• Groin or pelvic pain and swelling
• Chills
• Chest pain
• Back pain
• Shortness of breath
• Injection site skin discoloration or skin breakdown
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.