Refludan

Contraindications

Hypersensitivity to hirudins

Severe renal insufficiency (CrCl <15 mL/min)

Cautions

Formation of antihirudin antibodies (40%) may increase anticoagulant effect; monitor aPTT carefully

Cirrhosis may enhance anticoagulant effect

Patients with increased risk of bleeding

Cautiously administer after a thrombolytic episode (risk of intracranial bleeding)

Allergic reactions frequently reported in patients treated concomitantly with streptokinase

Lepirudin is injected into a vein through an IV. A healthcare provider will give you this injection.

You will need frequent medical tests to help your doctor determine how long to treat you with lepirudin.

Because lepirudin keeps your blood from coagulating (clotting) to prevent unwanted blood clots, it can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose may cause severe bleeding.

Because you will receive lepirudin in a clinical setting, you are not likely to miss a dose.

Adverse Events Reported in Clinical Trials in HIT Patients

The following safety information is based on all 198 patients treated with REFLUDAN (lepirudin) in the HAT-1 and HAT-2 studies. The safety profile of 113 REFLUDAN (lepirudin) patients from these studies who presented with TECs at baseline is compared to 91 such patients in the historical control.

Hemorrhagic Events. Bleeding was the most frequent adverse event observed in patients treated with REFLUDAN (lepirudin) . Table 4 gives an overview of all hemorrhagic events which occurred in at least two patients.

Table 4: Hemorrhagic Events*

Other hemorrhagic events (hemoperitoneum, hemoptysis, liver bleeding, lung bleeding, mouth bleeding, retroperi-toneal bleeding) each occurred in one individual among all 198 patients treated with REFLUDAN (lepirudin) .

Nonhemorrhagic events. Table 5 gives an overview of the most frequently observed nonhemorrhagic events.

Table 5: Nonhemorrhagic adverse events*

Adverse Events Reported in Clinical Trials in Other Populations

The following safety information is based on a total of 2302 individuals who were treated with REFLUDAN (lepirudin) in clinical pharmacology studies (n = 323) or for clinical indications other than HIT (n = 1979).

Intracranial bleeding was the most serious adverse reaction found in populations other than HIT patients. It occurred in patients with acute myocardial infarction who were started on both REFLUDAN (lepirudin) and thrombolytic therapy with rt-PA or streptokinase. The overall frequency of this potentially life-threat-ening complication among patients receiving both REFLUDAN (lepirudin) and thrombolytic therapy was 0.6% (7 out of 1134 patients). Although no intracranial bleeding was observed in 1168 subjects or patients who did not receive concomitant thrombolysis, there have been post marketing reports of intracranial bleeding with REFLUDAN (lepirudin) in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS- Adverse Events from Post Marketing Reports and WARNINGS.)

(See PRECAUTIONS.)

Allergic reactions or suspected allergic reactions in populations other than HIT patients include (in descending order of frequency*):

About 53% (n = 46) of all allergic reactions or suspected aller-gic reactions occurred in patients who concomitantly received thrombolytic therapy (eg, streptokinase) for acute myocardial infarction and/or contrast media for coronary angiography.

Adverse Events from Post Marketing Reports

Serious anaphylactic reactions that have resulted in shock or death have been reported. (See PRECAUTIONS.)

Intracranial bleeding has been reported in patients treated with REFLUDAN (lepirudin) with or without concomitant thrombolytic therapy. (See WARNINGS.) Although no intracranial bleeding was observed in Clinical Trials in those patients who did not receive concomitant thrombolytic therapy (see Adverse Events Reported in Clinical Trials in HIT Patients and Adverse Events Reported in Clinical Trials in Other Populations below), there have been post marketing reports of intracranial bleeding in patients who received REFLUDAN (lepirudin) without concomitant throm-bolytic therapy.

• Heart Attack

© Refludan Patient Information is supplied by Cerner Multum, Inc. and Refludan Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Thrombosis associated with Heparin-induced Thrombocytopenia (HIT)

Prevention of further thrombosis in patients with HIT accompanied by thromboembolic complications.1 5 6 13

The American College of Chest Physicians (ACCP) recommends use of a nonheparin anticoagulant (e.g., lepirudin, argatroban) as an alternative to further use of heparin (referring throughout this monograph to unfractionated heparin), or low molecular weight heparins, or the initiation/continuation of warfarin for initial management of patients with HIT with or without thrombosis.1006

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 Clcr.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., Clcr <15 mL/minute) who require hemodialysis.1

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

Storage

Parenteral

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

Refludan is contraindicated in patients with known hypersensitivity to hirudins or to any of the components in Refludan [lepirudin (rDNA) for injection].

In case of overdose (eg, suggested by excessively high aPTT values) the risk of bleeding is increased.

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

• Immediately STOP Refludan administration
• Determine aPTT and other coagulation levels as appropriate
• Determine hemoglobin and prepare for blood transfusion
• Follow the 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.

In studies in pigs, the application of von Willebrand Factor (vWF, 66 IU/kg body weight) markedly reduced the bleeding time. The clinical significance of this data is unknown.

Refludan [lepirudin (rDNA) for injection] is supplied in boxes of 10 vials, each vial containing 50 mg lepirudin (NDC 50419-150-57).

Store unopened vials at 2 to 25°c (35.6 to 77°f). Use Refludan before the expiration date given on the carton and container. Once reconstituted, use Refludan immediately.