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Pronunciation

(leh puh ROO din)

Generic Available (U.S.)

No

Index Terms

• Lepirudin (rDNA)
• Recombinant Hirudin

Brand Names: U.S.

• Refludan®

Brand Names: Canada

• Refludan®

Pharmacologic Category

• Anticoagulant, Thrombin Inhibitor

Pharmacologic Category Synonyms

• Direct Thrombin Inhibitor
• DTI
• Thrombin Inhibitor

Use: Labeled Indications

Indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications

Pregnancy Risk Factor

B

Pregnancy Considerations

Lepirudin crosses the placenta in pregnant rats; however, it is not known if lepirudin crosses the placenta in humans.

Lactation

Enters breast milk/consult prescriber

Contraindications

Hypersensitivity to hirudins or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Allergic and hypersensitivity reactions, including anaphylaxis have been reported. Be cautious in re-exposing patients (anaphylaxis has been reported).

• Bleeding: The most common complication is bleeding. Certain patients are at increased risk of bleeding; risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; recent puncture of large vessels or organ biopsy; recent CVA, stroke, intracerebral surgery, or other neuraxial procedure; severe uncontrolled hypertension; renal impairment; recent major surgery; recent major bleeding (intracranial, GI, intraocular, or pulmonary). Monitor for signs and symptoms of bleeding.

Disease-related concerns:

• Cirrhosis: Use with caution in patients with cirrhosis.

• Renal impairment: Use with caution in patients with renal impairment, relative overdose might occur even with standard dosage regimen. The bolus dose and rate of infusion must be reduced in patients with known or suspected renal insufficiency.

• Thrombolytic episode: Cautiously administer after a thrombolytic episode; risk of intracranial bleeding.

Concurrent drug therapy issues:

• Streptokinase: Allergic reactions may occur frequently in patients treated concomitantly with streptokinase.

Special populations:

• Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions:

• Monitoring: Strict monitoring of aPTT is required; formation of antihirudin antibodies can increase the anticoagulant effect of lepirudin.

Adverse Reactions

As with all anticoagulants, bleeding is the most common adverse event associated with lepirudin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables.

HIT patients:

>10%: Hematologic: Anemia (12%), bleeding from puncture sites (11%), hematoma (11%)

1% to 10%:

Cardiovascular: Heart failure (3%), pericardial effusion (1%), ventricular fibrillation (1%)

Central nervous system: Fever (7%)

Dermatologic: Maculopapular rash (4%), eczema (3%)

Gastrointestinal: GI bleeding/rectal bleeding (5%)

Genitourinary: Vaginal bleeding (2%)

Hepatic: Transaminases increased (6%)

Renal: Hematuria (4%)

Respiratory: Epistaxis (4%)

<1% (Limited to important or life-threatening): Allergic reactions, anaphylaxis, hemoperitoneum, hemoptysis, intracranial bleeding, liver bleeding, pulmonary bleeding, retroperitoneal bleeding, mouth bleeding, pruritus, urticaria, injection site reactions, thrombocytopenia

Non-HIT populations (including those receiving thrombolytics and/or contrast media):

1% to 10%: Respiratory: Bronchospasm/stridor/dyspnea/cough

<1% (Limited to important or life-threatening): Angioedema, laryngeal edema, tongue edema, intracranial bleeding (0.6%), allergic reactions (unspecified), anaphylactoid reactions, anaphylaxis, thrombocytopenia

Metabolism/Transport Effects

None known.

Drug Interactions

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

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

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

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

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

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, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity)

Storage

Intact vials should be stored at 2°C to 25°C (36°F to 77°F). Manufacturer recommends using reconstituted solution immediately after preparation. Reconstituted solutions of lepirudin are stable for 24 hours at room temperature.

Reconstitution

Intravenous bolus: Use a solution with a concentration of 5 mg/mL: Reconstitute one vial (50 mg) of lepirudin with 1 mL of sterile water for injection or 0.9% sodium chloride injection. The final concentration of 5 mg/mL is obtained by transferring the contents of the vial into a sterile, single-use syringe (of at least 10 mL capacity) and diluting the solution to a total volume of 10 mL using sterile water for injection, 0.9% sodium chloride, or 5% dextrose in water.

Intravenous infusion: For continuous intravenous infusion, solutions with concentrations of 0.2 or 0.4 mg/mL may be used. Reconstitute 2 vials (50 mg each) of lepirudin with 1 mL each using either sterile water for injection or 0.9% sodium chloride injection. The final concentration of 0.2 mg/mL or 0.4 mg/mL is obtained by transferring the contents of both vials into an infusion bag containing 500 mL or 250 mL of 0.9% sodium chloride injection or 5% dextrose injection.

Compatibility

Stable in D₅W, NS.

Y-site administration: Visually compatible (Chalmers, 2001): Amiodarone.

Mechanism of Action

Lepirudin is a highly specific direct inhibitor of thrombin; lepirudin is a recombinant hirudin derived from yeast cells

Pharmacodynamics/Kinetics

Distribution: Two-compartment model; confined to extracellular fluids

Metabolism: Via release of amino acids via catabolic hydrolysis of parent drug

Half-life elimination: Initial: ~10 minutes: Terminal: Healthy volunteers: 1.3 hours; Marked renal impairment (Cl_cr <15 mL/minute and on hemodialysis): ≤2 days

Excretion: Urine (~48%, 35% as unchanged drug and unchanged drug fragments of parent drug); systemic clearance is proportional to glomerular filtration rate or creatinine clearance

Dosage

Note: Maximum infusion dose: Do not exceed 0.21 mg/kg/hour unless an evaluation of coagulation abnormalities limiting response has been completed. Bolus doses may increase the risk of bleeding; consider omitting or reducing dose in certain populations.

Heparin-induced thrombocytopenia: Bolus dose: 0.4 mg/kg IVP (over 15-20 seconds), followed by continuous infusion at 0.15 mg/kg/hour (maximum initial bolus dose: 44 mg; maximum initial infusion dose: 16.5 mg/hour); bolus and infusion must be reduced in renal insufficiency

or

Alternate dosing regimen (unlabeled dose; Selleng, 2007; Warkentin, 2008): Bolus dose: 0.2 mg/kg (use only if life- or limb-threatening thrombosis present) followed by continuous infusion of 0.05-0.1 mg/kg/hour. Further dosage reduction may be required in patients with renal dysfunction. This alternate dosing regimen has been recommended due to higher rates of bleeding associated with the FDA-approved dosing regimen.

Concomitant use with thrombolytic therapy: Bolus dose: 0.2 mg/kg IVP (over 15-20 seconds), followed by continuous infusion at 0.1 mg/kg/hour

Dosing adjustments during infusions: Monitor first aPTT 4 hours after the start of the infusion. Subsequent determinations of aPTT should be obtained at least once daily during treatment. More frequent monitoring is recommended in renally- or hepatically-impaired patients. Any aPTT ratio measurement out of range (1.5-2.5) should be confirmed prior to adjusting dose, unless a clinical need for immediate reaction exists. If the aPTT is below target range, increase infusion by 20%. If the aPTT is in excess of the target range, stop infusion for 2 hours and when restarted the infusion rate should be decreased by 50%. A repeat aPTT should be obtained 4 hours after any dosing change.

Use in patients scheduled for switch to oral anticoagulants: Once platelets normalize, reduce lepirudin dose gradually to reach aPTT ratio just above 1.5 before starting warfarin therapy. Monitor PT/INR closely until results stabilize in therapeutic range. When lepirudin is discontinued, there may be a small reduction in INR.

Dosing adjustment in renal impairment: All patients with a creatinine clearance of <60 mL/minute or a serum creatinine of >1.5 mg/dL require dosage reduction. An alternate dosing regimen has also been recommended for patients with serum creatinine >1 mg/dL (Warkentin, 2008). There is only limited information on the therapeutic use of lepirudin in patients with HIT and significant renal impairment; the following dosage recommendations are mainly based on single-dose studies in a small number of patients with renal impairment.

Initial: Bolus dose: 0.2 mg/kg IVP (over 15-20 seconds), followed by adjusted infusion based on renal function; refer to the following infusion rate adjustments based on creatinine clearance (mL/minute) and serum creatinine (mg/dL):

Note: Acute renal failure or hemodialysis: Infusion is to be avoided or stopped. Following the bolus dose, additional bolus doses of 0.1 mg/kg may be administered every other day only if aPTT falls below lower therapeutic limit (1.5-times patient baseline [or mean laboratory] aPTT).

Lepirudin infusion rates in patients with renal impairment: See tables.

Administration: Oral

Administer only intravenously

Administration: I.V.

I.V. bolus: Inject slowly for continuous infusion; solutions with 0.2 or 0.4 mg/mL may be used.

Monitoring Parameters

Monitor aPTT levels; obtain baseline aPTT, then monitor first aPTT 4 hours after the start of the infusion and every 4 hours until steady state is reached (2 consecutive aPTTs in the same range) (Warkentin, 2008). Subsequent determinations of aPTT should be obtained at least once daily during treatment. More frequent monitoring is recommended in renally- or hepatically-impaired patients. Any aPTT ratio measurement out of range (1.5-2.5) should be confirmed prior to adjusting dose, unless a clinical need for immediate reaction exists

Reference Range

aPTT 1.5 to 2.5 times the control value

Test Interactions

PT/INR levels may become elevated in the absence of warfarin. If warfarin is initiated, initial PT/INR goals while on lepirudin may require modification.

Patient Education

This drug can only be administered by infusion. Report immediately any pain, swelling, burning, or bleeding at infusion site. 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 avoid potentially harmful activities). Report unusual 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, or swelling or pain at injection site.

Anesthesia and Critical Care Concerns/Other Considerations

Evidence-Based Information: Heparin-Induced Thrombocytopenia (HIT): In a case series of 9 patients with HIT, the combination of lepirudin and a GP IIb/IIIa inhibitor was safe and effective during PCI (Pinto, 2003). Another case report describes use in patients with HIT during cardiopulmonary bypass (Liu, 2002). During prolonged treatment (>5 days) in HIT patients, anticoagulant activity should be monitored daily (Eichler, 2000). Antihirudin antibodies develop frequently and may enhance lepirudin's activity. In this trial, about half of the patients who developed antihirudin antibodies required a 45% (range: 17% to 90%) decrease in dose.

The American College of Chest Physicians Evidence Based Clinical Practice Guidelines (8th Edition, 2008) recommend reducing the initial lepirudin dose based on serum creatinine concentrations for the treatment of heparin-induced thrombocytopenia (see Dosing: Renal Impairment).

Cardiovascular Considerations

Subcutaneous Administration of Lepirudin: Initial data for the subcutaneous administration of lepirudin shows promise. A multicenter, prospective, dose-ranging trial of lepirudin for the treatment of deep venous thrombosis demonstrated that a dose of lepirudin 1.25 mg/kg every 12 hours was safe and effective at reducing the incidence of subsequent thromboembolic events when compared to heparin; however, this trial was small with only 155 patients enrolled (Schiele F, 1997). Another small trial of 19 patients with either heparin-induced thrombocytopenia (HIT) and thromboembolism, isolated HIT, or history of HIT and needing interruption of oral anticoagulation, evaluated the subcutaneous administration of lepirudin at a dose of 25 mg twice daily (Hule G, 2000). Patients with HIT and thromboembolic complications were administered continuous intravenous lepirudin to maintain a therapeutic aPTT for the first 10 days of therapy then switch to subcutaneous lepirudin. The authors found that administration of subcutaneous lepirudin was safe and effective. One important observation was 63% of patients developed antibodies to lepirudin prolonging the peak and trough aPTTs when compared to the group without antibodies to lepirudin. The duration of administration ranged from 20-26 days. Based on these trials, there is emerging evidence that subcutaneous administration of lepirudin may be safe and effective; however, large trials are needed to fully describe how to utilize this therapy.

Anaphylaxis: Fatal anaphylactic reactions have been reported in patients re-exposed to lepirudin in a second or subsequent treatment course. Consider alternative treatment options. Since these reactions are immune-mediated, patient with recent exposure to hirudins may be at increased risk.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Bleeding is the major adverse effect of lepirudin. 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

Contraindicated in patients with a recent stroke

Nursing: Physical Assessment/Monitoring

Note Administration for infusion specifics. Bleeding precautions should be observed. Monitor for hypersensitivity reaction, bleeding, chest pain, and rash. Teach patient bleeding precautions.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution:

Refludan®: 50 mg

References

Chalmers JR, Bobek MB, and Militello MA, “Visual Compatibility of Amiodarone Hydrochloride Injection With Various Intravenous Drugs,” Am J Health Syst Pharm, 2001, 58(6):504-6.

Eichler P, Friesen HJ, Lubenow N, et al, “Antihirudin Antibodies in Patients With Heparin-Induced Thrombocytopenia Treated With Lepirudin: Incidence, Effects on aPTT, and Clinical Relevance,” Blood, 2000, 96(7):2373-8.

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.

Hule G, Hoffman U, Hoffman I, et al, "A New Therapeutic Option by Subcutaneous Hirudin in Patients With Heparin-Induced Thrombocytopenia Type II: A Pilot Study," Thrombosis Res, 2000, 99:325-34.

Liu H. Fleming NW, and Moore PG, “Anticoagulation for Patients With Heparin-Induced Thrombocytopenia Using Recombinant Hirudin During Cardiopulmonary Bypass,” J Clin Anesth, 2002, 14(6):452-5.

Lubenow N, Eichler P, Lietz T, et al, “Lepirudin in Patients With Heparin-Induced Thrombocytopenia-Results of the Third Prospective Study (HAT-3) and a Combined Analysis of HAT-1. HAT-2, and HAT-3,” J Thromb Haemost, 2005, 3(11):2428-36.

Pinto DS, Sperling RT, Tu TM, et al, “Combination Platelet Glycoprotein IIb/IIIa Receptor and Lepirudin Administration During Percutaneous Coronary Intervention in Patients With Heparin-Induced Thrombocytopenia,” Catheter Cardiovasc Interv, 2003, 58(1):65-8.

Schiele F, Lindgaerde F, Eriksson H, et al, "Subcutaneous Recombinant Hirudin (HBW 023) Versus Intravenous Sodium Heparin in Treatment of Established Acute Deep Vein Thrombosis of the Legs: A Multicentre Prospective Dose-Ranging Randomized Trial. International Multicentre Hirudin Study Group," Thromb Haemost, 1997, 77(5):834-8.

Selleng K, Warkentin TE, Greinacher A, “Heparin-Induced Thrombocytopenia in Intensive Care Patients,” Crit Care Med, 2007, 35(4):1165-76.

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.

International Brand Names

• Refludan (AT, AU, BE, BG, CH, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HN, HU, IE, IT, KP, MT, NL, NO, PL, PT, RU, SE, SK, TR)

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Last full review/revision October 2011