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Refludan

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Refludan

Refludan

WARNINGS

Hemorrhagic Events

As with other anticoagulants, hemorrhage can occur at any site in patients receiving REFLUDAN (lepirudin) . An unexpected fall in hemoglobin, fall in blood pressure or any unexplained symptom should lead to consideration of a hemorrhagic event. While patients are being anticoagulated with REFLUDAN (lepirudin) , the antico-agulation status should be monitored closely using an appropriate measure such as the aPTT (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION: Monitoring section.)

Intracranial bleeding following concomitant thrombolytic therapy with rt-PA or streptokinase may be life-threatening. There have been reports of intracranial bleeding with REFLU-DAN in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS.)

For patients with increased risk of bleeding, a careful assessment weighing the risk of REFLUDAN (lepirudin) administration vs its anticipated benefit has to be made by the treating physician:

In particular, this includes the following conditions:

  • Recent puncture of large vessels or organ biopsy
  • Anomaly of vessels or organs
  • Recent cerebrovascular accident, stroke, intracerebral surgery, or other neuraxail procedures
  • Severe uncontrolled hypertension
  • Bacterial endocarditis
  • Advanced renal impairment (see also WARNINGS: Renal Impairment)
  • Hemorrhagic diathesis
  • Recent major surgery
  • Recent major bleeding (eg, intracranial, gastrointestinal, intraocular, or pulmonary bleeding)
  • Recent active peptic ulcer

Renal Impairment

With renal impairment, relative overdose might occur even with standard dosage regimen. Therefore, the bolus dose and the rate of infusion must be reduced in patients with known or sus-pected renal insufficiency CAUTION: Preparation of a Refludan (lepirudin) bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL. (see CLINICAL PHARMACOLOGY: Pharmacokinetic Properties and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Renal Impairment).

PRECAUTIONS

General

Antibodies

Formation of antihirudin antibodies was observed in about 40% of HIT patients treated with REFLUDAN (lepirudin) . This may increase the anticoagulant effect of REFLUDAN (lepirudin) possibly due to delayed renal elimination of active lepirudin-antihirudin complexes (see also: Animal Pharmacology and Toxicology). Therefore, strict monitoring of aPTT is necessary also during prolonged therapy (see also PRECAUTIONS: Laboratory tests and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations). No evidence of neutralization of REFLUDAN (lepirudin) or of allergic reactions associated with positive antibody test results was found.

Liver Injury

Serious liver injury (eg, liver cirrhosis) may enhance the anticoagulant effect of REFLUDAN (lepirudin) due to coagula-tion defects secondary to reduced generation of vitamin K-dependent coagulation factors.

Reexposure

During the HAT-1 and HAT-2 studies, a total of 13 patients were reexposed to REFLUDAN (lepirudin) . One of these patients experienced a mild allergic skin reaction during the second treatment cycle. In post marketing experience, anaphy-laxis after reexposure has been reported. (see PRECAUTIONS -Allergic Reactions below and ADVERSE REACTIONS-Adverse Events from Post Marketing Reports.)

Allergic Reactions

There have been reports of allergic and hyper-sensitivity reactions including anaphylactic reactions. Serious ana-phylactic reactions that have resulted in shock or death have been reported. These reactions have been reported during initial admin-istration or upon second or subsequent reexposure(s).

Laboratory tests

In general, the dosage (infusion rate) should be adjusted accord-ing to the aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually median of the laboratory normal range for aPTT); for full information, see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations. Other thrombin-dependent coagulation assays are changed by REFLUDAN (see also DESCRIPTION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the potential for carcinogenesis have not been performed with lepirudin. Lepirudin was not genotoxic in the Ames test, the Chinese hamster cell (V79/HGPRT) forward mutation test, the A549 human cell line unscheduled DNA synthesis (UDS) test, the Chinese hamster V79 cell chromosome aberration test, or the mouse micronucleus test. An effect on fertility and reproductive performance of male and female rats was not seen with lepirudin at intravenous doses up to 30 mg/kg/day (180 mg/m²/day, 1.2 times the recommended maximum human total daily dose based on body surface area of 1.45m²for a 50 kg subject).

Pregnancy

Teratogenic Effects

Category B. Teratology studies with lep-irudin performed in pregnant rats at intravenous doses up to 30 mg/kg/day (180 mg/m²/day, 1.2 times the recommended maximum human total daily dose based on body surface area) and in pregnant rabbits at intravenous doses up to 30 mg/kg/day (360 mg/m²/day, 2.4 times the recommended maximum human total daily dose based on body surface area) have revealed no evi-dence of harm to the fetus due to lepirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lepirudin (1 mg/kg) by intravenous administration crosses the placental barrier in pregnant rats. It is not known whether the drug crosses the placental barrier in humans.

Following intravenous administration of lepirudin at 30 mg/kg/day (180 mg/m²/day, 1.2 times the recommended maximum human total daily dose based on body surface area) during organogen-esis and perinatal-postnatal periods, pregnant rats showed an increased maternal mortality due to undetermined causes.

Nursing Mothers

It is not known whether REFLUDAN (lepirudin) is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from REFLUDAN (lepirudin) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In the HAT-2 study, two children, an 11-year-old girl and a 12-year-old boy, were treated with REFLUDAN (lepirudin) . Both children presented with TECs at baseline. REFLUDAN (lepirudin) doses given ranged from 0.15 mg/kg/h to 0.22 mg/kg/h for the girl, and from 0.1 mg/kg/h (in conjunction with urokinase) to 0.7 mg/kg/h for the boy. Treatment with REFLUDAN (lepirudin) was completed after 8 and 58 days, respectively, without serious adverse events (Schiffmann 1997).

Last reviewed on RxList: 7/31/2007
This monograph has been modified to include the generic and brand name in many instances.

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