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Pronunciation

(HEP a rin)

Index Terms

  • Heparin Calcium
  • Heparin Lock Flush
  • Heparin Sod/Sod Chloride
  • Heparin Sodium
  • Heparinized Saline

Dosage Forms

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

Solution, Injection, as sodium:

Generic: 1000 units (500 mL); 2000 units (1000 mL); 12,500 units (250 mL); 25,000 units (250 mL, 500 mL); 1000 units/mL (1 mL, 10 mL, 30 mL); 2500 units/mL (10 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/0.5 mL (0.5 mL)

Solution, Intravenous, as sodium:

Hep Flush-10: 10 units/mL (10 mL [DSC])

Generic: 10,000 units (250 mL); 12,500 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); 2 units/mL (3 mL); 10 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL, 30 mL [DSC]); 100 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL, 30 mL [DSC], 100 mL [DSC], 250 mL); 2000 units/mL (5 mL)

Solution, Intravenous, as sodium [preservative free]:

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

Brand Names: U.S.

  • Hep Flush-10 [DSC]

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Heparin

Pharmacology

Potentiates the action of antithrombin III and thereby inactivates thrombin (as well as activated coagulation factors IX, X, XI, XII, 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)

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 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

Hepatic; may be partially metabolized in the reticuloendothelial system

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 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).

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. As an anticoagulant for extracorporeal 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: Unlabeled

ST-elevation myocardial infarction (STEMI) as an adjunct to fibrinolytic therapy; unstable angina/non-STEMI (UA/NSTEMI); anticoagulant during percutaneous coronary intervention (PCI)

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; uncontrolled active bleeding except when due to disseminated intravascular coagulation (DIC); 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 nursing mothers is contraindicated by some manufacturers.

Dosing: Adult

Note: Many concentrations of heparin are available ranging from 1 unit/mL to 20,000 units/mL. Carefully examine each prefilled syringe or vial prior to use ensuring 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.

Acute coronary syndromes (off-label use): IV infusion (weight-based dosing per institutional nomogram recommended):

STEMI: Adjunct to fibrinolysis (full-dose alteplase, reteplase, or tenecteplase) (Antman, 2008): Initial bolus of 60 units/kg (maximum: 4000 units), then 12 units/kg/hour (maximum: 1000 units/hour) as continuous infusion. Check aPTT every 4 to 6 hours; adjust to target of 1.5 to 2 times the upper limit of control (50 to 70 seconds). Continue for a minimum of 48 hours, and preferably for the duration of hospitalization (up to 8 days) or until revascularization (if performed) (ACCF/AHA [O’Gara, 2013]).

Unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI): Initial bolus of 60 units/kg (maximum: 4000 units), followed by an initial infusion of 12 units/kg/hour (maximum: 1000 units/hour). Check aPTT every 4 to 6 hours; adjust to target of 1.5 to 2 times the upper limit of control (50 to 70 seconds). Optimal duration of therapy is unknown; however, most trials continued therapy for 2 to 5 days. Recommended duration is 48 hours or until percutaneous coronary intervention is performed (AHA/ACC [Amsterdam, 2014]).

Anticoagulation (Intermittent administration): IV: Initial: 10,000 units, then 50 to 70 units/kg (5000 to 10,000 units) every 4 to 6 hours

Atrial fibrillation (off-label use): Guidelines pertaining to peri-cardioversion use (ACCP [You, 2012]):

Patients with atrial fibrillation (for more than 48 hours or unknown duration) undergoing cardioversion: IV heparin to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 units/mL anti-Xa activity started at the time of transesophageal echocardiography (TEE) is recommended with cardioversion performed within 24 hours of the TEE if no thrombus is seen.

Patients with atrial fibrillation (for 48 hours or less) undergoing cardioversion: Cardioversion may be performed without prolonged anticoagulation. However, anticoagulation with IV heparin to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 units/mL anti-Xa activity should be started at presentation in patients with no contraindications to anticoagulation.

Emergency cardioversion in hemodynamically unstable patient: Cardioversion may be performed without prolonged anticoagulation. Anticoagulation with IV heparin to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 units/mL anti-Xa activity should be started prior to cardioversion in patients with no contraindications to anticoagulation.

Interstitial cystitis (bladder pain syndrome) (off-label use): Intravesical: Note: Various dosage regimens of heparin (20,000 to 50,000 units) alone or with alkalinized lidocaine (1% to 4%) have been used. When lidocaine and heparin are mixed, there is a risk of precipitation if proper alkalinization does not occur. Lidocaine stability and pH should be determined after the components have been mixed, prior to administration.

Single-dose regimen: Instill the combination of 50,000 units of heparin, lidocaine 200 mg, and sodium bicarbonate 420 mg in 15 mL of sterile water into the bladder via catheter and allow to dwell for 30 minutes before draining (Parsons, 2012).

Once-weekly dosing regimen: Instill the combination of 20,000 units of heparin, lidocaine 4% (5 mL), and sodium bicarbonate 7% (25 mL) into an empty bladder via catheter once weekly for 12 weeks and allow to dwell for 30 minutes before draining (Nomiya, 2013).

Twice-weekly dosing regimen: Instill 25,000 units of heparin (diluted with 5 mL of sterile water) into bladder via catheter twice weekly for 3 months (Kuo, 2001).

Maintenance of catheter patency (continuous infusion): Using heparin 2 unit/mL large volume IV solutions, may administer at an infusion rate of 3 mL/hour (equivalent to 6 units/hour); however, rate of infusion dependent upon age, weight, clinical condition of patient, and procedure being employed. Do not use as a “catheter lock flush”.

Maintenance of line patency (line flushing): When using daily flushes of heparin to maintain patency of single and double lumen central catheters, 10 units/mL is commonly used for younger infants (eg, <10 kg) while 100 units/mL is used for older infants, children, and adults. Capped PVC 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). 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.

Parenteral nutrition: Addition of heparin (0.5 to 3 unit/mL) to peripheral and central parenteral nutrition has not been shown to decrease catheter-related thrombosis. The final concentration of heparin used for TPN solutions may need to be decreased to 0.5 units/mL in small infants receiving larger amounts of volume in order to avoid approaching therapeutic amounts. Arterial lines are heparinized with a final concentration of 1 unit/mL.

Percutaneous coronary intervention (off-label use; Levine, 2011): IV:

No prior anticoagulant therapy:

If no GPIIb/IIIa inhibitor use planned: Initial bolus of 70 to 100 units/kg (target ACT 250 to 300 seconds for HemoTec®, 300 to 350 seconds for Hemochron®)

or

If planning GPIIb/IIIa inhibitor use: Initial bolus of 50 to 70 units/kg (target ACT 200 to 250 seconds regardless of device)

Prior anticoagulant therapy:

If no GPIIb/IIIa inhibitor use planned: Additional heparin as needed (eg, 2000 to 5000 units) (target ACT 250 to 300 seconds for HemoTec®, 300 to 350 seconds for Hemochron®)

or

If planning GPIIb/IIIa inhibitor use: Additional heparin as needed (eg, 2000 to 5000 units) (target ACT 200 to 250 seconds regardless of device)

Thromboprophylaxis (low-dose heparin): SubQ: 5000 units every 8 to 12 hours. Note: The American College of Chest Physicians recommends a minimum of 10 to 14 days for patients undergoing total hip arthroplasty, total knee arthroplasty, or hip fracture surgery (Guyatt, 2012).

Venous thromboembolism (treatment): Note: Start warfarin on the first or second treatment day and continue heparin until INR is ≥2 for at least 24 hours (usually 5 to 7 days) (Guyatt, 2012).

DVT/PE (off-label dosing): IV: 80 units/kg (or alternatively 5000 units) IV push followed by continuous infusion of 18 units/kg/hour (or alternatively 1000 units/hour) (Guyatt, 2012)

or

DVT/PE (off-label dosing): SubQ: Unmonitored dosing regimen: Initial: 333 units/kg then 250 units/kg every 12 hours (Guyatt, 2012; Kearon, 2006)

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 ranging from 1 unit/mL to 20,000 units/mL. Carefully examine each prefilled syringe or vial prior to use ensuring 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.

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. 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]).

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

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.

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D51/4NS, D51/2NS, D25W, fat emulsion 10%, 1/2NS, NS, Ringer’s injection.

Y-site administration: Incompatible with alteplase, amiodarone, amphotericin B cholesteryl sulfate complex, amsacrine, caspofungin, diazepam, doxycycline, ergotamine, filgrastim, haloperidol, idarubicin, levofloxacin calcium, methotrimeprazine, nesiritide, nicardipine, phenytoin, reteplase.

Compatibility in syringe: Incompatible with amiodarone, diazepam, doxorubicin hydrochloride, droperidol, erythromycin lactobionate, gentamicin, haloperidol, kanamycin, levofloxacin, meperidine, methotrimeprazine, midazolam, pantoprazole, pentazocine, promethazine, streptomycin, tobramycin, vancomycin, warfarin.

Storage

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

Stability at room temperature and refrigeration:

Prepared bag: 24-72 hours (specific to solution, concentration, and/or study conditions)

Premixed bag: After seal is broken, 4 days.

Out of overwrap stability: 30 days.

Drug Interactions

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

ACE Inhibitors: Heparin may enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

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

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

Canagliflozin: Heparin may enhance the hyperkalemic effect of Canagliflozin. 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

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

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. Consider therapy modification

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

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

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

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 Anticoagulants. Monitor therapy

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

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

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

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

Vitamin E: May enhance the anticoagulant effect of Anticoagulants. Vitamin E may also increase the overall risk for bleeding. Monitor therapy

Vitamin E (Oral): 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

Test Interactions

Increased thyroxine (competitive protein binding methods); increased PT

Aprotinin significantly increases aPTT and celite Activated Clotting Time (ACT) which may not reflect the actual degree of anticoagulation by heparin. Kaolin-based ACTs are not affected by aprotinin to the same degree as celite ACTs. While institutional protocols may vary, a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds is recommended in the presence of aprotinin. Consult the manufacturer’s information on specific ACT test interpretation in the presence of aprotinin.

Adverse Reactions

Frequency not defined. 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).

Cardiovascular: Chest pain, hemorrhagic shock, shock, thrombosis, vasospasm (allergic; possibly related to thrombosis)

Central nervous system: Chills, headache, local dysesthesia (feet), peripheral neuropathy

Dermatologic: Dermal ulcer (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this effect), eczema, erythematous plaques (case reports), localized erythema (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this effect), skin necrosis, transient alopecia (delayed), urticaria

Endocrine & metabolic: Adrenal hemorrhage, hyperkalemia (suppression of aldosterone synthesis), hyperlipidemia (rebound; on discontinuation), ovarian hemorrhage

Gastrointestinal: Constipation, hematemesis, melena, nausea, vomiting

Genitourinary: Erectile dysfunction (frequent or persistent erection), hematuria

Hematologic & oncologic: Bruise (unexplained), gingival hemorrhage, hematoma (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a higher incidence of this effect), hemorrhage, pulmonary hemorrhage, purpura, retroperitoneal hemorrhage, thrombocytopenia (see note)

Hepatic: Increased liver enzymes

Hypersensitivity: Anaphylactoid reaction, hypersensitivity reaction

Local: Local irritation and local pain (rarely reported with deep subcutaneous injections; intramuscular injection [not recommended] is associated with a high incidence of these effects)

Neuromuscular & skeletal: Osteoporosis (chronic therapy effect)

Ophthalmic: Allergic conjunctivitis, lacrimation

Respiratory: Asthma, bronchospasm (case reports), epistaxis, hemoptysis, rhinitis

Miscellaneous: Fever, heparin resistance

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding; risk factors include 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; or 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; thrombocytopenia or platelet defects; 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-induced thrombocytopenia (HIT): May cause thrombocytopenia; monitor platelet count closely. Patients who develop HIT may be at risk of developing a new thrombus (heparin-induced thrombocytopenia and thrombosis [HITT]). Discontinue therapy and consider alternatives if platelets are <100,000/mm3 and/or thrombosis develops. 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 in patients with history of HIT, especially if administered within 100 days of HIT episode (Dager, 2007; Warkentin, 2001); monitor platelet count closely.

• 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, elevations in factor VIII and/or fibrinogen; frequently encountered in patients with fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, MI, cancer, and in postsurgical patients; measurement of anticoagulant effects using antifactor Xa levels may be of benefit.

• Hyperkalemia: Monitor for hyperkalemia; can cause hyperkalemia by suppressing aldosterone production.

• Hypersensitivity reactions: May occur; only in life-threatening situations when use of an alternative anticoagulant is not possible should heparin be cautiously used in patients with a documented hypersensitivity reaction.

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

Special populations:

• Elderly: Use with caution in patients >60 years of age, particularly women; they are also more sensitive to the dose 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, signs of bleeding; fecal occult blood test; aPTT (or antifactor Xa activity levels) or ACT depending upon indication

Platelet counts should be routinely monitored (eg, every 2-3 days on days 4-14 of heparin therapy) when the risk of HIT is >1% (eg, receiving therapeutic dose heparin, postoperative antithrombotic prophylaxis), if the patient has received heparin or low molecular weight heparin (eg, enoxaparin) within the past 100 days, if pre-exposure history is uncertain, or if anaphylactoid reaction to heparin occurs. When the risk of HIT is <1% (eg, medical/obstetrical patients receiving heparin flushes), routine platelet count monitoring is not recommended (Guyatt, 2012).

For intermittent IV injections, aPTT is measured 3.5-4 hours after IV injection.

Note: Continuous IV infusion is preferred over IV intermittent injections. For full-dose heparin (ie, nonlow-dose), the dose should be titrated according to aPTT results. For anticoagulation, an aPTT 1.5-2.5 times normal is usually desired. Because of variation among hospitals in the control aPTT values, nomograms should be established at each institution, designed to achieve aPTT values in the target range (eg, for a control aPTT of 30 seconds, the target range [1.5-2.5 times control] would be 45-75 seconds). Measurements should be made prior to heparin therapy, 6 hours (pediatric: 4 hours) after initiation, and 6 hours (pediatric: 4 hours) after any dosage change, and should be used to adjust the heparin infusion until the aPTT exhibits a therapeutic level. When two consecutive aPTT values are therapeutic, subsequent measurements may be made every 24 hours, and if necessary, dose adjustment carried out. In addition, a significant change in the patient's clinical condition (eg, recurrent ischemia, bleeding, hypotension) should prompt an immediate aPTT determination, followed by dose adjustment if necessary. In general, may increase or decrease infusion by 2-4 units/kg/hour dependent upon aPTT.

Heparin infusion dose adjustment: A number of dose-adjustment nomograms have been developed which target an aPTT range of 1.5-2.5 times control (Cruickshank, 1991; Flaker, 1994; Hull, 1992; Raschke, 1993). However, institution-specific and indication-specific nomograms should be consulted for dose adjustment. Note: aPTT values vary throughout the day with maximum values occurring during the night (Decousus, 1985).

Pregnancy Risk Factor

C

Pregnancy Considerations

Increased resorptions were observed in some animal reproduction studies. Heparin does not cross the placenta. Heparin may be used for the prevention and treatment of thromboembolism in pregnant women; however the use of low molecular weight heparin (LMWH) is preferred. Twice-daily heparin should be discontinued prior to induction of labor or a planned cesarean delivery. In pregnant women with mechanical heart valves, adjusted-dose LMWH or adjusted-dose heparin may be used throughout pregnancy or until week 13 of gestation when therapy can be changed to warfarin. LMWH or heparin should be resumed close to delivery. In women who are at a very high risk for thromboembolism (older generation prosthesis in mitral position or history of thromboembolism), warfarin can be used throughout pregnancy and replaced with LMWH or heparin near term; the use of low-dose aspirin is also recommended. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (Guyatt, 2012).

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (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 bleeding that is very bad or that will not stop), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), severe dizziness, passing out, fall or crash hitting head, confusion, severe headache, chills, angina, back pain, skin discoloration, shortness of breath, or injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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