No

Anticoagulant

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

B

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

Hypersensitivity to hirudins

Heparin can cause hyperkalemia by affecting aldosterone. A similar reaction may occur with lepirudin. Monitor for hyperkalemia. Discontinue therapy if platelets are <100,000/mm³. Cautiously administer after a thrombolytic episode; risk of intracranial bleeding. Hemorrhage is the most common complication. Monitor for signs and symptoms of 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; advanced renal impairment; recent major surgery; recent major bleeding (intracranial, GI, intraocular, or pulmonary). Reduce dose in severe renal impairment (Cl_cr <15 mL/minute and on hemodialysis). Strict monitoring of aPTT is required; formation of antihirudin antibodies can increase the anticoagulant effect of lepirudin. Use cautiously in cirrhosis. Allergic reactions may occur frequently in patients treated concomitantly with streptokinase. Be cautious in re-exposing patients (limited clinical experience).

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.

>10%: Hematologic: Anemia (12.4%), bleeding from puncture sites (10.6%), hematoma 10.8%

1% to 10%:

Central nervous system: Fever (7%)

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

Gastrointestinal: GI bleeding/rectal bleeding (5.3%)

Hepatic: Increased transaminases (6%)

Genitourinary: Vaginal bleeding (1.8%)

Renal: Hematuria (4.4%)

Respiratory: Epistaxis (4.4%)

Dermatologic: Eczema (3%), maculopapular rash (4%)

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

Symptoms of overdosage: In case of overdose (eg, suggested by excessively high APTT values), the risk of bleeding is increased

Treatment: No specific antidote for lepirudin is available; if life-threatening bleeding occurs and excessive plasma levels of lepirudin are suspected, the following steps should be followed:

Immediately STOP LEPIRUDIN administration

Determine APTT and other coagulation levels as appropriate

Determine hemoglobin and prepare for blood transfusion

Follow current guidelines for treating patients with shock

Individual clinical case reports and in vitro data suggest that either hemofiltration or hemodialysis (using high-flux dialysis membranes with a cutoff point of 50,000 daltons, eg, AN/69) may be useful in this situation

Cephalosporins which contain the MTT side chain may increase the risk of hemorrhage.

Drugs which affect platelet function (eg, aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel) may potentiate the risk of hemorrhage.

Penicillins (parenteral) may prolong bleeding time via inhibition of platelet aggregation, potentially increasing the risk of hemorrhage.

Thrombolytic agents increase the risk of hemorrhage.

Warfarin: Risk of bleeding may be increased during concurrent therapy. During the initiation of warfarin therapy, heparin is commonly continued to assure anticoagulation and to protect against possible transient hypercoagulability. It is probable that a similar approach would be used in situations where lepirudin is required.

Intact vials should be stored at 2°C to 25°C (36°F to 77°F)

Intravenous bolus: Use a solution with a concentration of 5 mg/mL

Preparation of a lepirudin 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

Preparation of a lepirudin solution with a concentration of 0.2 mg/mL or 0.4 mg/mL: 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

Reconstituted solutions of lepirudin are stable for 24 hours at room temperature

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

Distribution: Lepirudin follows a two-compartment model. Distribution is essential confined to extracellular fluids.

Metabolism: Metabolized by release of amino acids via catabolic hydrolysis of the parent drug. ~ 48% of the administered dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug.

Half-life:

Initial: ~10 minutes

Terminal: 1.3 hours in health volunteers; however, systemic clearance is proportional to glomerular filtration rate or creatinine clearance. Terminal half-life in patients with marked renal insufficiency (creatinine clearance <15 mL/minute) and on hemodialysis is prolonged up to 2 days.

Elimination: Renal

Adults: Maximum dose: Do not exceed 0.21 mg/kg/hour unless an evaluation of coagulation abnormalities limiting response has been completed. Dosing is weight-based, however patients weighing >110 kg should not receive doses greater than the recommended dose for a patient weighing 110 kg (44 mg bolus and initial maximal infusion rate of 16.5 mg/hour).

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 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, decrease infusion rate by 50%. A repeat APTT should be obtained 4 hours after any dosing change.

Use in patients scheduled for switch to oral anticoagulants: Reduce lepirudin dose gradually to reach aPTT ratio just above 1.5 before starting warfarin therapy; as soon as INR reaches 2.0, lepirudin therapy should be discontinued.

Dosage adjustment in renal impairment: Initial: Bolus dose: 0.2 mg/kg IVP (over 15-20 seconds) see table; additional bolus doses of 0.1 mg/kg may be administered every other day (only if APTT falls below lower therapeutic limit). Refer to the following infusion rate adjustments based on creatinine clearance (mL/minute) and serum creatinine (mg/dL):

Lepirudin infusion rates in patients with renal impairment:

Cl_cr 45-60; S_cr 1.6-2.0:

Adjust rate to 50% of standard infusion rate: 0.075 mg/kg/hour

Cl_cr 30-44; S_cr 2.1-3.0:

Adjust rate to 30% of standard infusion rate: 0.045 mg/kg/hour

Cl_cr 15-29; S_cr 3.1-6.0:

Adjust rate to 15% of standard infusion rate: 0.0225 mg/kg/hour

Cl_cr <15*; S_cr >6.0:

Avoid or STOP infusion

APTT levels

APTT 1.5 to 2.5 times the control value

None reported

Contraindicated in patients with a recent stroke

No information available to require special precautions

Mouth bleeding, tongue edema has been reported

This medication can only be administered I.V. You will have a tendency to bleed easily following this medication. Use caution to prevent injury (use electric razor, use soft toothbrush, use caution with sharps). If bleeding occurs, apply pressure to bleeding spot until bleeding stops completely. Report unusual bruising or bleeding (eg, blood in urine, stool, or vomitus, bleeding gums, vaginal bleeding, nosebleeds); dizziness or changes in vision; back pain; skin rash; swelling of face, mouth, or throat; or difficulty breathing. Breast-feeding precautions: Consult prescriber if breast-feeding.

Injection: 50 mg vials