(leh puh ROO din)
Indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications
Hypersensitivity to hirudins or any component of the formulation
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 (off-label dose; Selleng, 2007; Linkins, 2012): 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: IV: 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.
Transition 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.
Refer to adult dosing.
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 (Linkins, 2012). 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.
Lepirudin Infusion Rates in Patients With Renal ImpairmentCreatinine Clearance
(mL/min)
Serum Creatinine
(mg/dL)
Adjusted Infusion Rate
% of Standard Initial Infusion Rate
mg/kg/h
45-60
1.6-2.0
50%
0.075
30-44
2.1-3.0
30%
0.045
15-29
3.1-6.0
15%
0.0225
<15
>6.0
Avoid or STOP infusion
Table has been converted to the following text.
Lepirudin Infusion Rates in Patients With Renal Impairment
CrCl 45-60 mL/minute; Scr 1.6-2.0 mg/dL:
Adjust rate to 50% of standard infusion rate: 0.075 mg/kg/hour.
CrCl 30-44 mL/minute; Scr 2.1-3.0 mg/dL:
Adjust rate to 30% of standard infusion rate: 0.045 mg/kg/hour.
CrCl 15-29 mL/minute; Scr 3.1-6.0 mg/dL:
Adjust rate to 15% of standard infusion rate: 0.0225 mg/kg/hour.
CrCl <15 mL/minute; Scr >6.0 mg/dL:
Avoid or STOP infusion
Alternate Dosing Regimen for Renal Impairment (based on Chest 2012 guidelines1,2)Serum Creatinine
(mg/dL)
Adjusted Infusion Rate
% of Standard Initial Infusion Rate3
mg/kg/h
1Recommendation based on low or very low-quality evidence.
2In patients with renal insufficiency, the American College of Chest Physicians suggests the use of argatroban instead of lepirudin (Linkins, 2012).
3Recommended standard initial infusion rate: 0.1 mg/kg/hour
4Recommendation based on manufacturers labeling.
Note: The initial bolus should either be omitted, or in the case of perceived life- or limb-threatening thrombosis, be given at a reduced dose of 0.2 mg/kg.
1.0-1.6
50%
0.05
1.7-4.5
10%
0.01
>4.5-6.0
5%
0.005
>6.0
Avoid or STOP infusion4
Table has been converted to the following text.
Alternate Dosing Regimen for Renal Impairment (based on Chest 2012 guidelines1, 2)
Scr 1.0-1.6 mg/dL:
Adjust rate to 50% of standard infusion rate3: 0.05 mg/kg/hour.
Scr 1.7-4.5 mg/dL:
Adjust rate to 10% of standard infusion rate3: 0.01 mg/kg/hour.
Scr >4.5-6.0 mg/dL:
Adjust rate to 5% of standard infusion rate3: 0.005 mg/kg/hour
Scr >6.0 mg/dL:
Avoid or STOP infusion4
1Recommendation based on low or very low-quality evidence.
2In patients with renal insufficiency, the American College of Chest Physicians suggests the use of argatroban instead of lepirudin (Linkins, 2012)
3Recommended standard initial infusion rate: 0.1 mg/kg/hour
4Recommendation based on manufacturer 's labeling.
Note: The initial bolus should either be omitted, or in the case of perceived life- or limb-threatening thrombosis, be given at a reduced dose of 0.2 mg/kg.
No dosage adjustment provided in manufacturer 's labeling.
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.
Administer only intravenously; administer IV bolus over 15-20 seconds
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.
Stable in D5W, NS.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Anticoagulants: May enhance the anticoagulant effect of other Anticoagulants. Monitor therapy
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
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
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. 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
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
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
Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. 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
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. 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. Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
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
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) (Linkins, 2012). 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
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.
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, injection site reactions, intracranial bleeding, liver bleeding, mouth bleeding, pruritus, pulmonary bleeding, retroperitoneal bleeding, thrombocytopenia, urticaria
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): Allergic reactions (unspecified), anaphylactoid reactions, anaphylaxis, angioedema, intracranial bleeding (0.6%), laryngeal edema, thrombocytopenia, tongue edema
In patients with marked renal insufficiency (CrCl less than 15 " ‰mL/min)and on hemodialysis, the elimination t ‚ ½ is prolonged up to 2 days.
Systemic Cl is 20% lower in elderly than in younger patients.
Systemic Cl is about 25% lower in women than men.
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.
B
Adverse events were not observed in animal reproduction studies. Data are insufficient to evaluate the safety of thrombin inhibitors during pregnancy. Use of parenteral thrombin inhibitors in pregnancy should be limited to those women who have severe allergic reactions to heparin, including heparin induced thrombocytopenia, and who cannot receive danaparoid (Guyatt, 2012).
Lepirudin is a highly specific direct inhibitor of thrombin; lepirudin is a recombinant hirudin derived from yeast cells
Two-compartment model; confined to extracellular fluids
Via release of amino acids via catabolic hydrolysis of parent drug
Urine (~48%, 35% as unchanged drug and unchanged drug fragments of parent drug); systemic clearance is proportional to glomerular filtration rate or creatinine clearance
Initial: ~10 minutes: Terminal: Healthy volunteers: 1.3 hours; Significant renal impairment (CrCl <15 mL/minute and on hemodialysis): ≤2 days
- 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?)
- Patient may experience injection site irritation. Have patient report immediately to prescriber severe dizziness, syncope, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, illogical thinking, significant headache, ecchymosis, hemorrhaging, hematemesis, hematuria, melena, or signs of hepatic impairment (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.