This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or standards of non-Merck sources.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(HEP a rin)

Generic Available (U.S.)

Yes

Index Terms

• Heparin Calcium
• Heparin Lock Flush
• Heparin Sodium

Brand Names: U.S.

• Hep-Lock
• Hep-Lock U/P
• HepFlush®-10

Brand Names: Canada

• Hepalean®
• Hepalean® Leo
• Hepalean®-LOK

Pharmacologic Category

• Anticoagulant

Use: Labeled Indications

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 I.V. devices and is not to be used for systemic anticoagulant therapy.

Use: Unlabeled

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Heparin does not cross the placenta. Some products contain benzyl alcohol as a preservative; their use in pregnant women is contraindicated by some manufacturers.

Lactation

Does not enter breast milk

Breast-Feeding Considerations

Some products contain benzyl alcohol as a preservative; their use in breast-feeding women is contraindicated by some manufacturers due to the association of gasping syndrome in premature infants.

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); 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.

Warnings/Precautions

Boxed warnings:

• Benzyl alcohol: See “Dosage form specific issues” below.

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.

• 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.

• 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: [U.S. Boxed Warning]: Some products contain benzyl alcohol as a preservative; use of these products is contraindicated in neonates. In neonates, large amounts of benzyl alcohol (>100 mg/kg/day) have been associated with fatal toxicity (gasping syndrome). 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.

Adverse Reactions

Note: 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, stroke, or MI).

Frequency not defined.

Cardiovascular: Allergic vasospastic reaction (possibly related to thrombosis), chest pain, hemorrhagic shock, shock, thrombosis

Central nervous system: Chills, fever, headache

Dermatologic: Alopecia (delayed, transient), bruising (unexplained), cutaneous necrosis, dysesthesia pedis, erythematous plaques (case reports), eczema, urticaria, purpura

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

Gastrointestinal: Constipation, hematemesis, nausea, tarry stools, vomiting

Genitourinary: Frequent or persistent erection

Hematologic: Bleeding from gums, epistaxis, hemorrhage, ovarian hemorrhage, retroperitoneal hemorrhage, thrombocytopenia (see note)

Hepatic: Liver enzymes increased

Local: Irritation, erythema, pain, hematoma, and ulceration have been rarely reported with deep SubQ injections; I.M. injection (not recommended) is associated with a high incidence of these effects

Neuromuscular & skeletal: Peripheral neuropathy, osteoporosis (chronic therapy effect)

Ocular: Conjunctivitis (allergic reaction), lacrimation

Renal: Hematuria

Respiratory: Asthma, bronchospasm (case reports), hemoptysis, pulmonary hemorrhage, rhinitis

Miscellaneous: Allergic reactions, anaphylactoid reactions, heparin resistance, hypersensitivity (including chills, fever, and urticaria)

Metabolism/Transport Effects

None known.

Drug Interactions

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

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

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

Aspirin: May enhance the anticoagulant effect of Heparin. 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

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

Drotrecogin Alfa (Activated): Heparin may enhance the adverse/toxic effect of Drotrecogin Alfa (Activated). Bleeding may occur. Management: Potential benefits of therapeutic heparin doses should be weighed against an increased risk of bleeding in patients who receive drotrecogin alfa. In patients receiving prophylactic heparin doses consider continuing this during drotrecogin. Risk D: Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification

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

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. Risk X: Avoid combination

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

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

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).

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.

Reconstitution

Standard concentration/diluent: 25,000 units/500 mL D₅W (premixed). If preparing solution, mix thoroughly prior to administration.

Minimum volume: 250 mL D₅W.

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; variable stability (consult detailed reference) in D₅NS, D₅W, D₁₀W, LR, peritoneal dialysis solutions, TPN.

Y-site administration: Compatible: Acetaminophen, acyclovir, alcohol (ethyl), allopurinol, amifostine, aminophylline, ampicillin, ampicillin/sulbactam, anidulafungin, atracurium, atropine, aztreonam, betamethasone sodium phosphate, bivalirudin, bleomycin, caffeine citrate, calcium gluconate, cefazolin, cefotaxime, cefotetan, ceftazidime, chlorpromazine, cimetidine, cisplatin, cladribine, clindamycin, cyanocobalamin, cyclophosphamide, cytarabine, daptomycin, dexamethasone sodium phosphate, dexmedetomidine, digoxin, docetaxel, dopamine, doripenem, doxorubicin liposome, edrophonium, enalaprilat, epinephrine, eptifibatide, ertapenem, esmolol, estrogens (conjugated), ethacrynate, etoposide phosphate, famotidine, fenoldopam, fentanyl, fluconazole, fludarabine, fluorouracil, foscarnet, furosemide, gallium nitrate, gemcitabine, gold sodium thiosulfate, granisetron, hetastarch in lactate electrolyte injection (Hextend®), hydralazine, hydrocortisone sodium succinate, insulin (regular), isoproterenol, kanamycin, leucovorin calcium, lidocaine, linezolid, lorazepam, magnesium sulfate, melphalan, meperidine, meropenem, methotrexate, methyldopate, methylergonovine, metoclopramide, metronidazole, micafungin, midazolam, milrinone, minocycline, mitomycin, morphine, nafcillin, neostigmine, nitroprusside, norepinephrine, ondansetron, oxacillin, oxaliplatin, oxytocin, paclitaxel, palonosetron, pancuronium, pemetrexed, penicillin G potassium, pentazocine, phytonadione, piperacillin, piperacillin/tazobactam, potassium chloride, procainamide, prochlorperazine edisylate, propofol, propranolol, pyridostigmine, ranitidine, remifentanil, sargramostim, scopolamine, sodium bicarbonate, tacrolimus, teniposide, terbutaline, theophylline, thiotepa, ticarcillin/clavulanate, tigecycline, tirofiban, trimethobenzamide, vasopressin, vecuronium, vinblastine, vincristine, warfarin, zidovudine. Incompatible: Alteplase, amiodarone, amphotericin B cholesteryl sulfate complex, amsacrine, caspofungin, diazepam, doxycycline, ergotamine, filgrastim, haloperidol, idarubicin, levofloxacin, methotrimeprazine, nesiritide, phenytoin, reteplase. Variable (consult detailed reference): Aldesleukin, amikacin, antithymocyte globulin (rabbit), ceftriaxone, ciprofloxacin, cisatracurium, dacarbazine, diltiazem, diphenhydramine, dobutamine, doxapram, doxorubicin HCl, droperidol, drotrecogin alfa, erythromycin lactobionate, fentanyl, gentamicin, hydromorphone, labetalol, methylprednisolone sodium succinate, metoprolol, nicardipine, nitroglycerin, pantoprazole, promethazine, quinidine gluconate, succinylcholine, telavancin, tenecteplase, thiopental, tobramycin, TPN, vancomycin, vinorelbine.

Compatibility in syringe: Compatible: Aminophylline, amphotericin B, ampicillin, atropine, bleomycin, buprenorphine, caffeine citrate, cefazolin, cefotaxime, cefoxitin, chloramphenicol, cisplatin, clindamycin, clonidine, cyclophosphamide, digoxin, dobutamine, dopamine, epinephrine, etomidate, fentanyl, fluorouracil, furosemide, hyaluronidase, iohexol, iopamidol, iothalamate meglumine 60%, ioxaglate meglumine 39.3% and ioxaglate sodium 19.6%, leucovorin calcium, lidocaine, lincomycin, methotrexate, metoclopramide, mitomycin, nafcillin, naloxone, neostigmine, nitroglycerin, nitroprusside, pancuronium, phenobarbital, piperacillin, ranitidine, succinylcholine, sulfamethoxazole/trimethoprim, verapamil, vincristine. Incompatible: Amiodarone, diazepam, doxorubicin hydrochloride, droperidol, erythromycin lactobionate, gentamicin, haloperidol, hydromorphone, kanamycin, levofloxacin, meperidine, methotrimeprazine, midazolam, pantoprazole, pentazocine, promethazine, streptomycin, tobramycin, vancomycin, warfarin. Variable (consult detailed reference): Amikacin, ceftriaxone, chlorpromazine, cimetidine, dimenhydrinate, morphine, vinblastine.

Mechanism of Action

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)

Pharmacodynamics/Kinetics

Onset of action: Anticoagulation: I.V.: Immediate; SubQ: ~20-30 minutes

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

Distribution: Does not cross placenta; does not enter breast milk

Metabolism: Hepatic; may be partially metabolized in the reticuloendothelial system

Half-life elimination:

Dose-dependent: I.V. bolus: 25 units/kg: 30 minutes; 100 units/kg: 60 minutes; 400 units/kg: 150 minutes (Hirsh, 2008)

Mean: 1.5 hours; Range: 1-2 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 (Hirsh, 2008).

Excretion: Urine (small amounts as unchanged drug)

Dosage

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 I.V. devices and is not to be used for anticoagulant therapy.

Children >1 year:

Prophylaxis for cardiac catheterization (arterial approach): I.V.: Bolus: 100-150 units/kg (Monagle, 2008)

Systemic heparinization:

Intermittent I.V.: Initial: 50-100 units/kg, then 50-100 units/kg every 4 hours (Note: Continuous I.V. infusion is preferred)

I.V. infusion: Initial loading dose: 75 units/kg given over 10 minutes, then initial maintenance dose: 20 units/kg/hour; adjust dose to maintain aPTT of 60-85 seconds (assuming this reflects an antifactor Xa level of 0.35-0.7 units/mL); see table.

Pediatric Protocol For Systemic Heparin Adjustment

To be used after initial loading dose and maintenance I.V. infusion dose (see usual dosage listed above) to maintain aPTT of 60-85 seconds (assuming this reflects antifactor Xa level of 0.35-0.7 units/mL).

Obtain blood for aPTT 4 hours after heparin loading dose and 4 hours after every infusion rate change.

Obtain daily CBC and aPTT after aPTT is therapeutic.

Adults:

Thromboprophylaxis (low-dose heparin): SubQ: 5000 units every 8-12 hours

Intermittent I.V.: Initial: 10,000 units, then 50-70 units/kg (5000-10,000 units) every 4-6 hours

I.V. infusion (weight-based dosing per institutional nomogram recommended):

Acute coronary syndromes:

Percutaneous coronary intervention (Levine, 2011):

No prior anticoagulant therapy:

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

or

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

Prior anticoagulant therapy:

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

or

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

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 4-6 hours; adjust to target of 1.5-2 times the upper limit of control (50-70 seconds). Duration of heparin therapy depends on concurrent therapy and the specific patient risks for systemic or venous thromboembolism.

Unstable angina/non-ST-elevation myocardial infarction (NSTEMI) (Anderson, 2011): 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 4-6 hours; adjust to target of 1.5-2 times the upper limit of control (50-70 seconds). The American College of Chest Physicians consensus conference has recommended dosage adjustments to correspond to a therapeutic range equivalent to heparin levels of 0.3-0.7 units/mL by antifactor Xa determinations.

Treatment of venous thromboembolism:

DVT/PE: I.V.: 80 units/kg (or alternatively 5000 units) I.V. push followed by continuous infusion of 18 units/kg/hour (or alternatively 1300 units/hour). The American College of Chest Physicians consensus conference has recommended dosage adjustments to correspond to a therapeutic range equivalent to heparin levels of 0.3-0.7 units/mL by antifactor Xa determinations.

DVT/PE: SubQ:

Monitored dosing regimen: Initial: 17,500 units or 250 units/kg then 250 units/kg every 12 hours. The American College of Chest Physicians consensus conference has recommended dosage adjustments to correspond to a therapeutic range equivalent to heparin levels of 0.3-0.7 units/mL by antifactor Xa determinations.

Unmonitored dosing regimen: Initial: 333 units/kg then 250 units/kg every 12 hours

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 6-8 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.

Addition of heparin (0.5-3 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.

Dosing adjustments in the elderly: 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

Dosage adjustment in renal impairment: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity.

Dosage adjustment in hepatic impairment: No dosage adjustment required; adjust therapeutic heparin according to aPTT or anti-Xa activity.

Administration: I.M.

Do not administer I.M. due to pain, irritation, and hematoma formation.

Administration: I.V.

Continuous 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 I.V. devices and is not to be used for anticoagulant therapy.

Administration: Other

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).

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 when the risk of HIT is >0.1% (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 <0.1% (eg, medical/obstetrical patients receiving heparin flushes), routine platelet count monitoring is not recommended (Hirsh, 2008).

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

For SubQ injections, when used for treatment (eg, monitored dosing regimen), aPTT is measured 6 hours after injection.

Note: Continuous I.V. infusion is preferred over I.V. 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).

Reference Range

Venous thromboembolism: Heparin: 0.3-0.7 unit/mL anti-Xa activity (by chromogenic assay) or 0.2-0.4 unit/mL (by protamine titration); aPTT: 1.5-2.5 times control (usually reflects an aPTT of 60-85 seconds) (Hirsh, 2008; Kearon, 2008)

When used with thrombolytic therapy in patients with acute MI, a lower therapeutic range corresponding to an antiXa level of 0.2-0.5 units/mL by chromogenic assay; aPTT: 1.5-2 times control (or approximately an aPTT of 50-70 seconds) is recommended (Goodman, 2008).

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.

Patient Education

This drug can only be administered by infusion or injection. You may have a tendency to bleed easily while taking this drug (brush teeth with soft brush, floss with waxed floss, use electric razor, avoid scissors or sharp knives and potentially harmful activities). Report immediately any chest pain; difficulty breathing or unusual cough; bleeding or bruising (bleeding gums, nosebleed, blood in urine, dark stool); pain in joints or back; CNS changes (fever, confusion); unusual fever; persistent nausea or GI upset; change in vision, or swelling, pain, or redness at injection site.

Geriatric Considerations

In the clinical setting, age has not been shown to be a reliable predictor of a patient's anticoagulant response to heparin. However, it is common for the elderly to have a “standard” response for the first 24-48 hours after a loading dose (5000 units) and a maintenance infusion of 800-1000 units/hour. After this period, they then have an exaggerated response (ie, elevated aPTT), requiring a lower infusion rate. Hence, monitor closely during this period of therapy. Elderly women are more likely to have bleeding complications and osteoporosis may be a problem when used >3 months or total daily dose exceeds 30,000 units.

Anesthesia and Critical Care Concerns/Other Considerations

Evidence-Based Information: Management of Intracerebral Hemorrhage (ICH) Due to Unfractionated Heparin (UFH): Overall management of ICH is similar regardless of cause; however, iatrogenic spontaneous ICH may have specific treatments. According to the 2007 ACC/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, UFH-related ICH should be treated with I.V. protamine given by slow I.V. injection (not to exceed 5 mg/minute) with a maximum dose of 50 mg (Class I recommendation). Faster infusions of protamine can result in cardiovascular collapse. The use of protamine for reversal of low molecular weight heparins (eg, enoxaparin) is significantly less effective.

Cardiovascular Considerations

Heparin-Induced Thrombocytopenia: Heparin-associated thrombocytopenia commonly occurs within 48-72 hours of initiation. Platelet counts usually fall below 100,000 cells/mm³ and return to normal within 4 days with continued heparin therapy. Heparin-induced thrombocytopenia (HIT) is a more serious, immunoglobulin-mediated reaction with a high risk for thromboembolic events. In HIT, thrombocytopenia usually begins 5-10 days following heparin initiation; HIT can begin within ~10 hours in patients who have received heparin within the previous 100 days (Warkentin, 2001). It can also occur up to several weeks after heparin has been discontinued. There are many misconceptions regarding the treatment of patient's with suspected or actual heparin-induced thrombocytopenia (HIT). It is well known that the diagnosis of HIT is based on clinical context and aided by serologic testing. In the right context, development of thrombocytopenia in patients receiving heparin therapy leads one to consider the diagnosis of HIT. A standardized patient evaluation should be adopted to optimally treat patients. Patients should be evaluated for heparin exposure and all forms of heparin discontinued. Next, initiation of an appropriate alternative form of anticoagulation is essential to prevent morbidity and mortality related to HIT. Finally, issues regarding long-term anticoagulation need to be considered.

The development of HIT can occur with the administration of either unfractionated or low molecular weight heparin and is not necessarily dependent on the dose administered. An evaluation for HIT should occur when the platelet count falls by ≥50% and/or a thrombotic event occurs between 5 and 14 days after heparin is initiated or received. Of note, patients who undergo cardiac surgery are at high risk of developing anti-PF4/heparin antibodies due to the amount of heparin exposure. HIT/HITT may even occur several weeks after heparin has been discontinued. It is important to recognize and evaluate patients for all sources of heparin they may be receiving. This includes subcutaneous heparin product administration, heparin flushes, heparin in admixtures such as parenteral nutrition, heparin use during dialysis, flushes for central and peripheral catheters, and implanted devices that may have heparin impregnated on the surface (heparin-coated pulmonary artery catheters). All forms of heparin must be discontinued and an appropriate alternate form of anticoagulation be initiated in patients with HIT regardless of documented thrombosis. Also, patients with suspected HIT or definite HIT should have this documented as an allergy in their medical record and signs indicating "No Heparin" should be placed above the patient's bed and documented in the pharmacy system.

Alternative anticoagulants such as direct thrombin inhibitors (argatroban, lepirudin, and bivalirudin) are the best approach in the United States (Greinacher, 1999; Greinacher, 1999; Greinacher, 2000). In Canada and other countries, one could also consider the initiation of full dose danaparoid. Alternative anticoagulation is necessary in order to treat and/or prevent new thromboembolic complications. During the subsequent days following the cessation of heparin in patients with isolated HIT, there is a high degree of thrombin generation increasing the likelihood of the development of thrombosis.

Low-molecular weight heparins should be avoided in the treatment of HIT because of the high degree of antibody cross reactivity (Warkentin, 1999). Also, in patients with isolated HIT or HIT with thrombosis (HITT), the use of vitamin K antagonists may lead to the development of venous limb gangrene when initiated as the treatment of HIT or if initiated without adequate anticoagulation from an appropriate alternative anticoagulant. Initiation of warfarin (maximum dose of 5 mg) or other vitamin K antagonists should be postponed until the platelet count has reached >150,000 x 10⁹ cells/L. The patient should remain on the appropriate alternative anticoagulant, in the therapeutic range, while warfarin is being initiated. Since the effects of coumarin anticoagulants are delayed upon initiation, anticoagulation with an alternative anticoagulant should be continued for five days and the patient should have a therapeutic INR for at least two consecutive days before the alternative anticoagulant is discontinued (Hirsh, 2008).

Finally, there has been increasing interest in the use of specific factor Xa inhibitors, such as fondaparinux, for the treatment of HIT. Currently there is limited data for using fondaparinux for treating patients with HIT. Recent laboratory data suggests that fondaparinux is not reactive with HIT antibody positive serum (Savi, 2005). As more data becomes available, these agents may be suitable alternatives in the treatment of HIT.

ST-Elevation Myocardial Infarction (STEMI): In patients with STEMI, the use of I.V. unfractionated heparin (UFH) or LMWH should be used when patients are at high risk for systemic emboli (eg, large or anterior MI, atrial fibrillation, previous embolus, known LV thrombus, or cardiogenic shock) (Class I indication).

Unlike earlier nonspecific thrombolytics (eg, streptokinase, urokinase), fibrin-specific thrombolytics (eg, alteplase, reteplase, or tenecteplase) do not decrease levels of coagulation factors (eg, factors V and VIII) instead they increase thrombin generation which may propagate further thrombus formation. Therefore, the concomitant use of weight-adjusted unfractionated heparin or enoxaparin (if renal function is preserved) is recommended (Class I indication).

Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI): In patients with UA/NSTEMI, the 2011 ACCF/AHA Guidelines recommend anticoagulation with enoxaparin, fondaparinux, or intravenous UFH in addition to dual antiplatelet therapy (ie, aspirin and clopidogrel) for those patients who are to be managed medically (Class I recommendation; level of evidence: A; Anderson, 2011). For patients who are managed with an early invasive strategy, bivalirudin, enoxaparin, fondaparinux (in combination with another factor IIa inhibitor [eg, UFH or bivalirudin] at the time of PCI), or intravenous UFH may be administered prior to or during PCI (Anderson, 2011; Levine, 2011).

Clinical trials have indicated that UFH should be weight-adjusted which would provide a more predictable response. The ACCF/AHA UA/STEMI and STEMI Guidelines recommend an initial dose of 60 units/kg and an initial infusion of 12 units/kg/hour with a goal to maintain activated partial thromboplastin time (aPTT) between 50-70 seconds (approximately 1.5-2 times control). Monitor aPTT at baseline and every 4-6 hours. Daily platelet counts may help in early identification of heparin-induced thrombocytopenia (HIT).

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Bleeding from the gums. See Effects on Bleeding.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

None reported

Nursing: Physical Assessment/Monitoring

Assess for risk factors for increased bleeding prior to starting therapy. Note specific infusion directions in Administration. Bleeding precautions should be observed at all times during heparin therapy. Monitor for hypersensitivity reaction, bleeding, chest pain, hyperkalemia, and peripheral neuropathy. For I.V. bolus administration, emergency treatment for hypersensitivity reactions should be immediately available. Teach patient bleeding precautions.

Dosage Forms

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

Infusion, premixed in 1/2 NS, as sodium [porcine intestinal mucosa source]: 25,000 units (250 mL, 500 mL)

Infusion, premixed in D₅W, as sodium [porcine intestinal mucosa source]: 10,000 units (250 mL); 12,500 units (250 mL); 20,000 units (500 mL); 25,000 units (250 mL, 500 mL)

Infusion, premixed in NS, as sodium [porcine intestinal mucosa source]: 1000 units (500 mL); 2000 units (1000 mL)

Infusion, premixed in NS, as sodium [porcine intestinal mucosa source, preservative free]: 1000 units (500 mL); 2000 units (1000 mL)

Injection, solution, as sodium [lock flush preparation; porcine intestinal mucosa source]: 10 units/mL (1 mL, 2 mL, 3 mL, 5 mL, 10 mL, 30 mL [DSC]); 100 units/mL (1 mL, 2 mL, 3 mL, 5 mL, 10 mL, 30 mL)

Hep-Lock: 10 units/mL (1 mL, 2 mL, 10 mL, 30 mL); 100 units/mL (1 mL, 2 mL, 10 mL, 30 mL) [contains benzyl alcohol]

Injection, solution, as sodium [lock flush preparation; porcine intestinal mucosa source, preservative free]: 1 units/mL (2 mL, 3 mL, 5 mL); 2 units/mL (3 mL); 10 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 6 mL, 10 mL); 100 units/mL (1 mL, 2 mL, 2.5 mL, 3 mL, 5 mL, 10 mL)

Hep-Lock U/P: 10 units/mL (1 mL); 100 units/mL (1 mL)

HepFlush®-10: 10 units/mL (10 mL)

Injection, solution, as sodium [porcine intestinal mucosa source]: 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)

Injection, solution, as sodium [porcine intestinal mucosa source, preservative free]: 1000 units/mL (2 mL); 5000 units/mL (0.5 mL); 10,000 units/mL (0.5 mL)

Pricing: U.S. (www.drugstore.com)

Solution (Heparin Sodium (Porcine))

1000 units/mL (10): $188.99

10000 units/mL (5): $29.99

10000 units/mL (25): $259.20

References

Anderson JL, Adams CD, Antman EM, et al, "2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines," Circulation, 2011, 123(18):e426-579.

Antman EM, Anbe DT, Armstrong PW, et al,“ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction),” Circulation, 2004, 110(9):e82-292.

Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.

Broderick J, Connolly S, Feldmann E, et al, “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group,” Stroke, 2007, 38(6):2001-23. Available at http://stroke.ahajournals.org/cgi/content/short/STROKEAHA.107.183689

Cruickshank MK, Levine MN, Hirsh J, et al, “A Standard Heparin Nomogram for the Management of Heparin Therapy,” Arch Intern Med, 1991, 151(2):333-7.

Dager WE and White RH, “Pharmacotherapy of Heparin-Induced Thrombocytopenia,” Expert Opin Pharmacother, 2003, 4(6):919-40.

Decousus HA, Croze M, Levi FA, et al, “Circadian Changes in Anticoagulant Effect of Heparin Infused at a Constant Rate,” Br Med J (Clin Res Ed), 1985, 290(6465):341-4.

Flaker GC, Bartolozzi J, Davis V, et al, “Use of a Standardized Heparin Nomogram to Achieve Therapeutic Anticoagulation after Thrombolytic Therapy in Myocardial Infarction. TIMI 4 investigators. Thrombolysis in Myocardial Infarction,” Arch Intern Med, 1994, 154(13):1492-6.

Francis JL, Groce JB 3rd, and the Heparin Consensus Group, “Challenges in Variation and Response of Unfractionated Heparin,” Pharmacotherapy, 2004, 24(8 Pt 2), 108-19.

Goodman SG, Menon V, Cannon CP, et al, “Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice,” Chest, 2008, 133(6 Suppl):708-75.

Greinacher A, Janssens U, Berg G, et al, “Lepirudin (Recombinant Hirudin) for Parenteral Anticoagulation in Patients With Heparin-Induced Thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) Investigators,” Circulation, 1999, 100(6):587-93.

Greinacher A, Volpel H, Janssens U, et al, “Recombinant Hirudin (Lepirudin) Provides Safe and Effective Anticoagulation in Patients With Heparin-Induced Thrombocytopenia: A Prospective Study,” Circulation, 1999, 99(1):73-80.

Hirsh J, Bauer KA, Donati MB, et al, “Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):141-59.

Hirsh J, Guyatt G, Albers GW, et al, “Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):71-109.

Hull RD, Raskob GE, Rosenbloom D, et al, “Optimal Therapeutic Level of Heparin Therapy in Patients with Venous Thromboembolism,” Arch Intern Med, 1992, 152(8):1589-95.

Jaff MR, McMurtry MS, Archer SL, et al, “Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement from the American Heart Association,” Circulation, 2011, 123(16):1788-830.

Kearon C, Kahn SR, Agnelli G, et al, “Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 33(6 Suppl):454-545.

Klerk CP, Smorenburg SM, and Buller HR, “Thrombosis Prophylaxis in Patient Populations With a Central Venous Catheter: A Systematic Review,” Arch Intern Med, 2003, 163(16):1913-21.

Levine GN, Bates ER, Blankenship JC, et al, “2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions,” Circulation, 2011, 124(23):e574-651.

Monagle P, Chalmers E, Chan A, et al, “Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):887-968.

Raschke RA, Reilly BM, Guidry JR, et al, “The Weight-Based Heparin Dosing Nomogram Compared With a “Standard Care” Nomogram: A Randomized Controlled Trial,” Ann Intern Med, 1993, 119(9):874-81.

Savi P, Chong BH, Greinacher A, et al, “Effect of Fondaparinux on Platelet Activation in the Presence of Heparin-Dependent Antibodies: A Blinded Comparative Multicenter Study With Unfractionated Heparin,” Blood, 2005, 105(1):139-44.

Sinnaeve PR, Alexander JH, Bogaerts K, et al,“Efficacy of Tenecteplase in Combination With Enoxaparin, Abciximab, or Unfractionated Heparin: One-Year Follow-Up Results of the Assessment of the Safety of a New Thrombolytic-3 (ASSENT-3) Randomized Trial in Acute Myocardial Infarction,” Am Heart J, 2004, 147(6):993-8.

Verma AK, Levine M, Shalansky SJ, et al, “Frequency of Heparin-Induced Thrombocytopenia in Critical Care Patients,” Pharmacotherapy, 2003, 23(6):745-53.

Warkentin TE, Greinacher A, Koster A, et al, “Treatment and Prevention of Heparin-induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):340-80.

Warkentin TE and Kelton JG, “Temporal Aspects of Heparin-Induced Thrombocytopenia,” N Engl J Med, 2001, 344(17):1286-92.

Warkentin TE, "Heparin-Induced Thrombocytopenia: A Clinicopathologic Syndrome," Thromb Haemost, 1999, 82(2):439-47.

Warkentin TE, Levine MN, Hirsch J, et al, “Heparin-Induced Thrombocytopenia in Patients Treated With Low-Molecular Weight Heparin or Unfractionated Heparin,” N Engl J Med, 1995, 332(20):1330-5.

International Brand Names

• Agglutek (TW)
• Caprin (IN)
• Coaparin (PL)
• Hemastat (PH)
• Hepaflex (FI, NO)
• Heparin (AT, BF, BG, BJ, CH, CI, CZ, DE, ET, FI, GB, GH, GM, GN, GR, HN, 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)
• Heparine (BE, NL)
• Heparine Choay (FR)
• Heparine Novo (BE, NL)
• Heprin (PH)
• Heptin (PH)
• Inviclot (ID)
• Lioton (RU)
• Liquemin (DE, IT)
• Liquemine (BE, BR, TR, UY, VE)
• Meparin (PH)
• Multiparin (NZ, PK)
• Nuparin (PH)
• Parinix (AR)
• Proparin (MX)
• Thrombophob (DE)
• Thromboreduct (DE)
• Unihepa (MY)

Lexi-Comp.com

Last full review/revision March 2012