Refludan

Generic Name: Lepirudin
Class: Direct Thrombin Inhibitors
VA Class: BL110
Chemical Name: [Leu1, Thr2]-63-desulfohirudin

Introduction

Anticoagulant; biosynthetic 65-amino acid peptide analog of naturally occurring hirudin.^{1 2 3 13}

Uses for Refludan

Thrombosis associated with Heparin-induced Thrombocytopenia

Prevention of further thrombosis in patients with heparin-induced thrombocytopenia (HIT) accompanied by thromboembolic complications.^{1 5 6 13}

American College of Chest Physicians (ACCP) recommends the use of a nonheparin anticoagulant (i.e., lepirudin, argatroban, fondaparinux, bivalirudin) as an alternative to unfractionated heparin or low molecular weight heparin in patients with known or suspected HIT with or without thromboembolic complications†.¹⁴

Adjunctive Therapy for Coronary Intervention

Recommended instead of heparin by ACCP in patients with acute HIT or a history of HIT† who are undergoing PCI or cardiac catheterization†.¹⁴

Acute Coronary Syndromes

Adjunct to thrombolytic therapy in patients with a history of HIT who have acute MI†.^{10 19} Has been used in patients with acute coronary syndromes (i.e., unstable angina and/or non-ST-segment elevation MI)†; however, ACCP recommends unfractionated heparin, low molecular weight heparin, fondaparinux, or bivalrudin as initial anticoagulation in selected patients with acute coronary syndromes.^{18 a}

Refludan Dosage and Administration

General

Laboratory Monitoring

• 
  

  Determine aPTT prior to therapy; do not initiate until the patient’s baseline aPTT ratio is <2.5.¹

  
  


• 
  

  Monitor therapy using the aPTT.¹ Manufacturer recommends adjusting dosage generally to achieve a target aPTT ratio (ratio of patient aPTT to an aPTT reference value) of 1.5–2.5;¹ ACCP recommends a lower target aPTT ratio (1.5–2).¹⁴ Higher aPTT ratios may be associated with an increased risk for bleeding without an incremental increase in clinical efficacy.^{1 7 13 14}

  
  


• 
  

  Determine aPTT 4 hours after initiation of the infusion and/or following a change in infusion rate.¹ Determine aPTT ratio at least once daily during therapy.¹ Determine aPTT more frequently in patients with renal impairment, serious liver injuries, or other risk factors for bleeding.^{1 20 21} ACCP recommends aPTT monitoring every 4 hours until a steady-state anticoagulant effect is achieved.¹⁴ (See Hemorrhagic Effects and also Hepatic Injury and also Renal Impairment, under Cautions.)

  
  


• 
  

  When an aPTT ratio is out of the range of target values (i.e., target range 1.5–2.5), confirm the discrepant value unless immediate clinical response is necessary.^{1 21} If an aPTT ratio above the target range is confirmed, discontinue the infusion for 2 hours.^{1 21} When therapy is resumed, decrease the infusion rate by 50%.¹ Do not administer an additional loading dose.^{1 21} Determine the aPTT ratio 4 hours after resumption of the infusion.^{1 21}

  
  


• 
  

  If an aPTT ratio below the target range is confirmed, increase the infusion rate in increments of 20%; determine aPTT ratio 4 hours after each incremental increase, until the desired target aPTT ratio is achieved.^{1 21}

  
  


• 
  

  Do not exceed an infusion rate of 0.21 mg/kg per hour without evaluating patient for coagulation abnormalities that might be preventing an appropriate aPTT response to the drug.^{1 21}

  
  


• 
  

  Since thrombin time is frequently >200 seconds even with low plasma lepirudin concentrations, this assay is not suitable for routine monitoring of anticoagulation.¹

  
  

Converting to Oral Anticoagulant Therapy

• 
  

  Initiate warfarin therapy only after a substantial recovery from acute HIT has occurred (i.e., as indicated by platelet counts that have increased to ≥150,000/mm³ and are stable) with lepirudin therapy.^{1 14 15 16}

  
  


• 
  

  Reduce dosage gradually until the aPTT ratio is just above 1.5, then initiate therapy with warfarin.¹ Initiate oral anticoagulation therapy using modest dosages of warfarin (2.5–5 mg daily, maximum of 5 mg daily); a loading dose should not be used.^{1 14 15 16 17}

  
  


• 
  

  Overlap lepirudin and warfarin therapy for a minimum of 4–5 days until the desired INR has been achieved.^{1 14}

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer as an initial IV injection followed by continuous IV infusion.¹

Reconstitution

Reconstitute vial containing 50 mg of lepirudin with 1 mL of either sterile water for injection or 0.9% sodium chloride injection.¹

Shake the vial gently.¹ Must be diluted further before IV administration.^{1 21}

Dilution

For initial IV injection, transfer the reconstituted contents of the vial into a sterile, single-use syringe with a capacity of ≥10 mL.¹ Dilute to a total volume of 10 mL with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to provide a solution with a final concentration of 5 mg/mL.¹

For continuous IV infusion, transfer the reconstituted contents of 2 vials each labeled as containing 50 mg of lepirudin into a 500- or 250-mL IV infusion bag containing 0.9% sodium chloride or 5% dextrose injection to yield solutions with a final concentration of 0.2 or 0.4 mg/mL, respectively.¹ Do not mix other drugs with lepirudin.¹

Discard any unused reconstituted solution.¹

Rate of Administration

Initial IV injection: administer over 15–20 seconds.¹

Maintenance IV infusions: Rate of administration based on body weight.¹ (See Table 1.)

Dosage

Adults

Thrombosis Associated with HIT

IV

Patients weighing ≤110 kg: Initially, manufacturer recommends 0.4 mg/kg administered by slow IV injection (over 15–20 seconds), followed by continuous IV infusion of 0.15 mg/kg per hour for 2–10 days or longer as clinically indicated.^{1 13 21}

Patients weighing >110 kg: Initially, manufacturer recommends 44 mg administered by slow IV injection (over 15–20 seconds), followed by continuous IV infusion of 16.5 mg/hour.^{1 21}

Maintenance IV infusion: Manufacturer-recommended infusion rates to administer a dosage of 0.15 mg/kg per hour in patients without renal impairment are shown in Table 1.¹

Table 1. Standard Maintenance Infusion Rates of Lepirudin1

Body Weight (kg)	Infusion Rate To Deliver a Dosage of 0.15 mg/kg per hour
	500-mL IV Container (0.2 mg/mL)	250-mL IV Container (0.4 mg/mL)
50	38 mL/hour	19 mL/hour
60	45 mL/hour	23 mL/hour
70	53 mL/hour	26 mL/hour
80	60 mL/hour	30 mL/hour
90	68 mL/hour	34 mL/hour
100	75 mL/hour	38 mL/hour
≥110	83 mL/hour	41 mL/hour

ACCP states that the loading dose of lepirudin should be omitted or reduced (compared with manufacturer recommendations) and a lower maintenance infusion rate should be used in most situations to minimize the risk of bleeding.¹⁴ (See Hemorrhagic Effects under Cautions.)

ACCP recommends a reduced lepirudin loading dose of 0.2 mg/kg¹⁴ administered by slow IV injection (over 15–20 seconds)¹ in patients with possible life- or limb-threatening thrombosis, and omission of the loading dose in other patients.¹⁴

Dosage in Patients Receiving Concomitant Thrombolytic Therapy

IV

Initially, 0.2 mg/kg administered by slow IV injection, followed by continuous IV infusion of 0.1 mg/kg per hour.^{1 6} (See Specific Drugs under Interactions.)

Prescribing Limits

Adults

Thrombosis Associated with HIT

IV

Initial IV injection: Maximum 44 mg for patients weighing ≥110 kg.¹

Initial maintenance infusion rate: Maximum 16.5 mg/hour for patients weighing ≥110 kg.¹

Special Populations

Hepatic Impairment

No special recommendations at this time.¹

Renal Impairment

Reduced initial IV loading dose and maintenance dosage recommended in patients with Cl_cr <60 mL/minute or S_cr >1.5 mg/dL.^{1 20} Initially, 0.2 mg/kg administered by slow IV injection.^{1 21}

ACCP states that omission of loading dose may reduce the risk of drug accumulation in patients with unrecognized mild renal failure.¹⁴

Base the IV maintenance dosage on Cl_cr determined using a reliable method (e.g., sampling of urine over 24 hours).¹ If Cl_cr determinations are not available, adjust the dosage according to the patient’s S_cr.¹ More frequent aPTT determinations recommended.¹

Manufacturer states that the maintenance dosage recommendations are based principally on single-dose studies of lepirudin in a limited number of patients with renal impairment and therefore should be considered tentative.¹

In hemodialysis patients or in cases of acute renal failure (Cl_cr <15 mL/minute or S_cr >6 mg/dL), infusion should be avoided or stopped.^{1 21} Consider additional doses of 0.1 mg/kg by IV injection every other day only if the aPTT ratio drops below the lower therapeutic limit of 1.5.¹

Table 2. Maintenance Dosage of Lepirudin in Patients with Renal Impairment121

		Adjusted Infusion Rate
Clcr (mL/minute)	Scr (mg/dL)	% of standard initial infusion rate (0.15 mg/kg per hour)	Rate in mg/kg per hour
45–60	1.6–2	50%	0.075
30–44	2.1–3	30%	0.045
15–29	3.1–6	15%	0.0225
< 15	>6	avoid or STOP infusion

ACCP recommends a maximum initial maintenance infusion rate of 0.1 mg/kg per hour in patients with S_cr <1 mg/dL, 0.05 mg/kg per hour in patients with S_cr approximately 1–1.6 mg/dL; maximum 0.01 mg/kg per hour in patients with S_cr approximately 1.6–4.5 mg/dL; or 0.005 mg/kg per hour in patients with S_cr >4.5 mg/dL.¹⁴

Geriatric Patients

No special recommendations at this time.¹

Cautions for Refludan

Contraindications

• 
  

  Known hypersensitivity to hirudins or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Hemorrhagic Effects

As with other anticoagulants, bleeding may occur at any site during therapy.¹ Consider the potential for a hemorrhagic event if an unexplained fall in hemoglobin or BP or unexplained symptoms occur.¹ Monitor anticoagulation status closely using the aPTT.¹

Weigh risk versus benefit in patients with an increased risk of hemorrhage or bleeding complications (e.g., bleeding from puncture sites and wounds, anemia or isolated drop in hemoglobin, other hematoma or unclassified bleeding, hematuria, GI or rectal bleeding, epistaxis, or hemothorax),¹ especially in patients with recent puncture of large vessels or organ biopsy; anomaly of vessels or organs; recent cerebrovascular accident, stroke, intracerebral surgery, or other neuraxial procedures; severe uncontrolled hypertension; bacterial endocarditis; advanced renal impairment; hemorrhagic diathesis; recent major surgery; recent active peptic ulcer; and recent major bleeding (e.g., intracranial, GI, intraocular, pulmonary bleeding).¹

Concomitant use with thrombolytic agents (e.g., alteplase, streptokinase [no longer commercially available in the US], urokinase) may result in life-threatening intracranial bleeding.¹ Intracranial hemorrhage also observed in absence of concomitant thrombolytic therapy.¹ (See Specific Drugs under Interactions.)

No specific antidote for lepirudin overdosage.¹ Risk of bleeding is increased if coagulation tests (e.g., aPTT) are unduly prolonged.¹ If life-threatening bleeding occurs and excessive plasma concentrations of the drug are suspected, discontinue the drug immediately.¹ Perform aPTT and other coagulation tests as appropriate.¹ Determine hemoglobin concentration and prepare for blood transfusion.¹ Institute appropriate therapy for shock.¹

Sensitivity Reactions

Allergic Reactions

Allergic and hypersensitivity reactions, including occasionally fatal anaphylaxis, reported during initial or subsequent exposure(s).¹

Possible increased risk of anaphylaxis following reexposure to lepirudin.²⁰ ACCP recommends against repeated use of the drug.²⁰ Use an alternative nonheparin anticoagulant in patients with HIT previously treated with lepirudin.²⁰ Omission of the loading dose may reduce the risk or severity of anaphylaxis.¹⁴

Antibody Formation

Development of antihirudin antibodies reported;^{1 8} may be associated with an increased anticoagulant effect.^{1 8} Antihirudin antibodies have not been associated with neutralization of lepirudin or allergic reactions.^{1 8} Closely monitor the aPTT during prolonged therapy.¹

General Precautions

Hepatic Injury

Possible enhanced anticoagulant effect in patients with serious liver injuries (e.g., cirrhosis);¹ more frequent aPTT determinations recommended.¹ (See Laboratory Monitoring under Dosage and Administration.)

Specific Populations

Pregnancy

Category B.¹

Lactation

Not known whether lepirudin is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Limited clinical experience; no established differences in efficacy relative to younger adults.¹

Renal Impairment

Monitor aPTT more frequently.¹ Reduced dosage recommended based on degree of renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

ACCP states that omission of loading dose may reduce risk of drug accumulation in patients with mild renal failure.¹⁴

ACCP does not recommend use of lepirudin in patients with severe renal impairment (Cl_cr <30 mL/minute).²⁰

Common Adverse Effects

Hemorrhage or bleeding, fever, abnormal liver function, pneumonia, sepsis, allergic skin reactions, heart failure.¹

Interactions for Refludan

Drugs Affecting Platelet Function

Possible increased risk of bleeding complications.¹

Specific Drugs

Drug	Interaction	Comments
Anticoagulants, oral	Possible increased risk of bleeding complications1
Thrombolytic agents	Possible increased risk of bleeding complications (e.g., life-threatening intracranial bleeding) and enhanced effect on aPTT1	Reduce initial lepirudin dosage to 0.2 mg/kg, followed by continuous IV infusion of 0.1 mg/kg per hour1 6

Refludan Pharmacokinetics

Distribution

Extent

Confined to extracellular fluids with a distribution half-life of approximately 10 minutes.¹ Volume of distribution at steady state in healthy young adults is 12.2 L.¹ Volume of distribution at steady state in patients with HIT is 32.1 L.¹

Crosses the placenta in animals.¹ Not known whether lepirudin crosses the placenta in humans or is distributed into human milk.¹

Special Populations

Volume of distribution at steady state in healthy geriatric individuals is 18.7 L.¹

Volume of distribution at steady state in patients with renal impairment is 18 L.¹

Elimination

Metabolism

Thought to be metabolized by release of amino acids via catabolic hydrolysis.¹

Elimination Route

Eliminated principally by the kidneys.^{1 13} Excreted in urine (48%) as unchanged drug (35%) and metabolites.¹ Systemic clearance proportional to the GFR or Cl_cr.¹ Systemic clearance is 164 mL/minute in healthy young individuals.¹

Half-life

Terminal half-life is approximately 1.3 hours.¹ Systemic clearance is lower (about 25%) in women than in men.¹

Special Populations

Prolonged elimination half-life (up to 2 days) in patients with marked renal insufficiency (i.e., Cl_cr <15 mL/minute) who require hemodialysis.¹

Systemic clearance is 20% lower in geriatric patients than in younger patients.¹

Stability

Storage

Parenteral

Powder for Injection

Unopened vials at 2–25°C.¹ Reconstituted solutions with concentrations of 0.2–5 mg/mL are stable at room temperature for up to 24 hours.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility^HID

Y-Site Compatibility

Compatible
Amiodarone HCl

ActionsActions

• 
  

  Specific, direct thrombin inhibitor; binds irreversibly¹³ to circulating and clot-bound thrombin.^{1 2 3 4 6 13}

  
  


• 
  

  Prevents various steps in the coagulation process (e.g., activation of factors V, VIII, and XIII and of protein C; conversion of fibrinogen to fibrin; platelet activation and aggregation).²

  
  


• 
  

  Affects all coagulation assays dependent on thrombin; increases aPTT in a dose-dependent manner.¹

  
  

Advice to Patients

• 
  

  Risk of serious bleeding or hemorrhage.¹

  
  


• 
  

  Importance of reporting any signs of bleeding (e.g., bruising, petechiae, hematuria) to clinician immediately.¹

  
  


• 
  

  Importance of patients informing clinician of history of bleeding disorders or impaired renal function.¹

  
  


• 
  

  Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Lepirudin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	50 mg	Refludan	Berlex

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Berlex Laboratories. Refludan (lepirudin) injection prescribing information. Montville, NJ; 2004 Oct.

2. Fareed J, Lewis BE, Callas DD et al. Antithrombin agents: the new class of anticoagulant and antithrombotic drugs. Clin Appl Thromb Hemost. 1999; 5(Suppl 1):S45-55. [PubMed 10726036]

3. Greinacher A, Lubenow N. Recombinant hirudin in clinical practice. Circulation. 2001; 103:1479-84. [IDIS 462767] [PubMed 11245656]

4. Rydel TJ, Ravichandran KG, Tulinsky A et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science. 1990; 249:277-80. [PubMed 2374926]

5. Greinacher A, Volpel H, Janssens U et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. Circulation. 1999; 99:73-80. [IDIS 421379] [PubMed 9884382]

6. Greinacher A, Janssens U, Berg G et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation. 1999; 100:587-93. [IDIS 435576] [PubMed 10441094]

7. Greinacher A, Eichler P, Lubenow N et al. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood. 2000; 96:846-51. [IDIS 451191] [PubMed 10910895]

8. Eichler P, Friesen H-J, Lubenow N et al. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood. 2000; 96:2373-8. [IDIS 453793] [PubMed 11001886]

9. Cairns JA, Theroux P, Lewis HD Jr et al. Antithrombotic agents in coronary artery disease. Chest. 2001; 119(Suppl Jan):228S-52S. [IDIS 459452] [PubMed 11157652]

10. Ohman EM, Harrington RA, Cannon CP et al. Intravenous thrombolysis in acute myocardial infarction. Chest. 2001; 119(Suppl Jan):253S-77S. [IDIS 459453] [PubMed 11157653]

11. Popma JJ, Ohman EM, Weitz J et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention. Chest. 2001; 119(Suppl Jan):321S-36S. [IDIS 459457] [PubMed 11157657]

12. Eikelboom JW, Anand SS, Mehta SR et al. Prognostic significance of thrombocytopenia during hirudin and heparin therapy in acute coronary syndrome without ST elevation. Circulation. 2001; 103:643-50. [IDIS 460128] [PubMed 11156874]

13. Januzzi JL, Jang IK. Heparin induced thrombocytopenia: diagnosis and contemporary antithrombin management. J Thromb Thrombolysis. 1999; 7:259-64. [PubMed 10375387]

14. Warkentin TE, Greinacher A, Koster A et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133:340S-80S. [PubMed 18574270]

15. Bartholmew JR. Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Chest. 2005; 127 (Suppl. 2):27-34S.

16. Messmore HL, Jeske WP, Wehmacher WH et al. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Drug Safety. 2003; 26:625-41. [PubMed 12814331]

17. GlaxoSmithKline. Argatroban injection prescribing information. Research Triangle Park, NC; 2005 Apr.

18. Harrington RA, Becker RC, Ezekowitz M et al. Antithrombotic therapy for coronary artery disease. Chest. 2004; 126(Suppl):513-48S.

19. Goodman SG, Menon V, Cannon CP et al. Acute ST-segment elevation myocardial infarction: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133(Suppl):708S-75S. [PubMed 18574277]

20. Hirsh J, Bauer KA, Donati MB et al. Parenteral anticoagulants: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008:133:141S-159S.

21. Bayer Healthcare, Wayne, MJ: Personal communication.

HID. Trissel LA. Handbook on injectable drugs. 13th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2005:903.

a. Harrington RA, Becker RC, Cannon CP et al. Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes.American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133:670S-707S. [PubMed 18574276]

More Refludan resources

• Refludan Side Effects (in more detail)
• Refludan Use in Pregnancy & Breastfeeding
• Refludan Drug Interactions
• Refludan Support Group
• 0 Reviews for Refludan - Add your own review/rating

• Refludan Prescribing Information (FDA)


• Refludan MedFacts Consumer Leaflet (Wolters Kluwer)


• Refludan Concise Consumer Information (Cerner Multum)


• Refludan Advanced Consumer (Micromedex) - Includes Dosage Information


• Lepirudin Professional Patient Advice (Wolters Kluwer)

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