Prescription Drugs

CLINICAL PHARMACOLOGY Pharmacokinetic Properties The pharmacokinetic properties of lepirudin following intra-venous administration are well described by a two-compartment model. Distribution is essentially confined to extracellular fluids and is characterized by an initial half-life of approximately 10 minutes. Elimination follows a first-order process and is characterized by a terminal half-life of about 1.3 hours in young healthy volunteers. As the intravenous dose is increased over the range of 0.1 to 0.4 mg/kg, the maximum plasma concen-tration and the area-under-the-curve increase proportionally. Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis of the parent drug. However, con-clusive data are not available. About 48% of the administration dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug. The systemic clearance of lepirudin is proportional to the glomerular filtration rate or creatinine clearance. Dose adjustment based on creatinine clearance is recommended (see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Renal Impairment). In patients with marked renal insufficiency (creatinine clearance below 15 mL/min), and on hemodialysis, elimination half-lives are prolonged up to 2 days. Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis of the parent drug. However, con-clusive data are not available. About 48% of the administration dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug. The systemic clearance of lepirudin in women is about 25% lower than in men. In elderly patients, the systemic clearance of lepirudin is 20% lower than in younger patients. This may be explained by the lower creatinine clearance in elderly patients compared to younger patients. Table 1 summarizes systemic clearance (Cl) and volume of dis-tribution at steady state (Vss) of lepirudin for various study populations. Table 1: Systemic clearance (Cl) and volume of distribution at steady state (Vss) of lepirudin Cl (mL/min) Mean (%CV*) Vss (L) Mean (% CV*) Healthy young subjects (n=18, age 18-60 years) 164 (19.3%) 12.2 (16.4%) Healthy elderly subjects (n=10, age 65-80 years) 139 (22.5%) 18.7 (20.6%) Renally impaired patients *n=16, creatinine clearance below 80mL/min) 61 (89.4%) 18.0 (41.1%) HIT patients (n=73) 114 (46.8%) 32.1 (98.9%) HAT: Heparin-associated thrombocytopenia * CV: Coefficient of variation Pharmacodynamic Properties The pharmacodynamic effect of REFLUDAN (lepirudin) on the proteolytic activity of thrombin was routinely assessed as an increase in aPTT. This was observed with increasing plasma concentrations of lepirudin, with no saturable effect up to the highest tested dose (0.5 mg/kg body weight intravenous bolus). Thrombin time (TT) frequently exceeded 200 seconds even at low plasma concentrations of lepirudin, which renders this test unsuitable for routine monitoring of REFLUDAN (lepirudin) therapy. The pharmacodynamic response defined by the aPTT ratio (aPTT at a time after REFLUDAN (lepirudin) administration over an aPTT reference value, usually median of the laboratory normal range for aPTT) depends on plasma drug levels which in turn depend on the individual patient's renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetic Properties). For patients undergoing additional thrombolysis, elevated aPTT ratios were already observed at low lepirudin plasma concentrations, and further response to increasing plasma concentrations was relatively flat. In other populations, the response was steeper. At plasma concentrations of 1500 ng/mL, aPTT ratios were nearly 3.0 for healthy volunteers, 2.3 for patients with heparin-associated thrombocy-topenia, and 2.1 for patients with deep venous thrombosis. Clinical Trial Data Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction to heparin. It can be found in about 1% to 2% of patients treated with heparin for more than 4 days. The clinical picture of HIT is characterized by thrombocytopenia alone or in combination with thromboembolic complications (TECs). These complications comprise the entire spectrum of venous and arterial thromboembolism including deep venous thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and occlusion of limb arteries, which may ultimately result in necroses requiring amputation. Furthermore, there is evidence to suggest that warfarin-induced venous limb gangrene may be associated with HIT. Without further treatment, the mortality in HIT patients with new TECs is about 20% to 30% (Fondu 1995; Greinacher 1995; Warkentin, Chong, et al., Warkentin, Elavathil, et al. 1997). The conclusion that REFLUDAN (lepirudin) is an effective treatment for HIT is based upon the data of two prospective, historically controlled clinical trials ("HAT-1" study and "HAT-2" study). The trials were comparable with regard to study design, primary and secondary objectives, and dosing regimens, as well as general study outline and organization. They both used the same historical control group for comparison. This historical control was mainly compiled from a recent retrospective registry of HIT patients. Overall, 198 (HAT-1: 82, HAT-2: 116) patients were treated with REFLUDAN (lepirudin) and 182 historical control patients were treated with other therapies. All except 5 (HAT-1: 1, HAT-2: 4) prospective patients and all historical control patients were diagnosed with HIT using the heparin-induced platelet activation assay (HIPAA) or equivalent assays for testing. In total, 113 (HAT-1: 54, HAT-2: 59) prospective patients ("REFLUDAN (lepirudin) ") and 91 historical control patients ("historical control") presented with TECs at baseline (day of positive test result) and qualified for direct comparison of clinical endpoints. The gender distribution was found to be similar in REFLUDAN (lepirudin) patients and historical control patients. Overall, REFLUDAN (lepirudin) patients tended to be younger than historical control patients. Table 2 summarizes the demographic baseline characteristics of patients presenting with TECs at baseline. Table 2: Demographic baseline characteristics of patients presenting with TECs REFLUDAN Historical Control HAT-1 (n=54) HAT-2 (n=59) (n=91) Males 27.8% 44.1% 35.2% Females 72.2% 55.9% 64.8% Age < 65 years 63.0% 67.8% 44.0% Age > 65years 57.0% 32.2% 56.0% Mean age ± SD (years) 57 ± 17 58 ± 12 64 ± 14 The key criteria of efficacy from a laboratory standpoint (n = 115 evaluable patients) were platelet recovery (increase in platelet count by at least 30% of nadir to values > 100,000) and effective anticoagulation (aPTT ratio > 1.5 with a maximum total 40% increase in the initial infusion rate). The proportions of REFLUDAN (lepirudin) patients presenting with TECs at baseline who showed platelet recovery, effective anticoagulation, or both (laboratory responders) are shown in Table 3. Comparable rates for the historical control group cannot be given, because (1) platelet counts were not monitored as closely as in the REFLUDAN (lepirudin) group, and (2) most historical control patients did not receive therapies affecting aPTT. Table 3: Proportions of laboratory responders among REFLUDAN (lepirudin) patients presenting with TECs HAT-1 HAT-2 Number of evaluable patients 55 60 Platelet recovery 90.9% 95.0% Effective anticoagulation 81.8% 75.0% Both 72.7% 71.7% Comparisons of clinical efficacy were made between REFLUDAN (lepirudin) patients and historical control patients with regard to the combined and individual incidences of death, limb amputation, or new TEC. The original main analyses included all events that occurred after laboratory confirmation of HIT. This approach revealed to be substantially confounded by the relative contribution of the pretreatment period (time between laboratory confirmation of HIT and start of treatment). Although short in duration (mean length 1.5 days in HAT-1 and 2.0 days in HAT-2), the pretreatment period accounted for 45% and 26% of events observed in the main analyses of HAT-1 REFLUDAN (lepirudin) patients and HAT-2 REFLUDAN (lepirudin) patients, respectively. Therefore, initiation of treatment was set as the starting point for the analyses. For the historical control group, the first treatment selected within 2 days of laboratory confirmation of HIT was used for reference. Seven days after start of treatment, the cumulative risk of death, limb amputation, or new TEC was 3.7% in the HAT-1 REFLUDAN (lepirudin) patients and 16.9% in the HAT-2 REFLUDAN (lepirudin) patients, as compared to 24.9% in the historical control group. At 35 days, when approximately 10% of patients were still at risk, the cumulative risk was 13.0% in the HAT-1 REFLUDAN (lepirudin) patients and 28.9% in the HAT-2 REFLUDAN (lepirudin) patients, as compared to 47.8% in the his-torical control group. In an additional meta-analysis, the pooled REFLUDAN (lepirudin) patients of the HAT-1 and HAT-2 studies who presented with TECs at baseline were compared to the respective historical control patients. Seven and 35 days after start of treatment, the cumulative risks of death were 4.4% and 8.9% in the REFLUDAN (lepirudin) group, as compared to 1.4% and 17.6% in the historical control group. The cumulative risks of limb amputation were 2.7% and 6.5% in the REFLUDAN (lepirudin) group, as compared to 2.6% and 10.4% in the historical control group. Most importantly, the cumulative risks of new TEC were 6.3 % and 10.1% in the REFLUDAN (lepirudin) group, as compared to 22.2% and 27.2% in the historical con-trol group. As shown in Fig 1, differences in the cumulative risk of death, limb amputation, or new TEC between the groups were statistically significant in favor of REFLUDAN (lepirudin) in the analysis of time to event (P=0.004 according to log-rank test). Fig 1: Cumulative risk of death, limb amputation, or new thromboembolic complication after start of treatment The immediate impact of treatment on the combined risk of death, limb amputation, or new TEC is demonstrated by comparing pre-treatment period and treatment period in regard to average combined event rates per patient day. In the pretreatment period, these rates were found to be 0.075 in the HAT-1 REFLUDAN (lepirudin) patients, 0.052 in the HAT-2 REFLUDAN (lepirudin) patients, and 0.040 in the historical control group. In the treatment period, the rates showed a marked reduction in the REFLUDAN (lepirudin) patients, where they dropped to 0.005 (HAT-1) and to 0.018 (HAT-2), while there was only a moderate decrease to 0.030 in the historical control group. In conclusion, REFLUDAN (lepirudin) substantially reduced the risk of serious sequelae of HIT in comparison to a historicalcontrol group. Animal Pharmacology and Toxicology General Toxicity Lepirudin caused bleeding in animal toxicity studies. Antibodies against hirudin which appeared in several monkeys treated with lepirudin resulted in a prolonga-tion of the terminal half-life and an increase of AUC plasma val-ues of lepirudin.

REFLUDAN ® 50 mg/Vial [lepirudin (rDNA)] For Injection DESCRIPTION REFLUDAN [lepirudin (rDNA) for injection] is a highly specific direct inhibitor of thrombin. Lepirudin, (chemical designation: [Leu1, Thr2]-63-desulfohirudin) is a recombinant hirudin derived from yeast cells. The polypeptide composed of 65 amino acids has a molecular weight of 6979.5 daltons. Natural hirudin is produced in trace amounts as a family of highly homologous isopolypeptides by the leech Hirudo medicinalis. The biosynthetic molecule (lepirudin) is identical to natural hirudin except for substitution of leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63. The activity of lepirudin is measured in a chromogenic assay. One antithrombin unit (ATU) is the amount of lepirudin that neu-tralizes one unit of World Health Organization preparation 89/588 of thrombin. The specific activity of lepirudin is approximately 16,000 ATU/mg. Its mode of action is independent of antithrombin III. Platelet factor 4 does not inhibit lepirudin. One molecule of lepirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected, eg, activated partial thromboplastin time (aPTT) and prothrom-bin time (PT /INR) values increase in a dose-dependent fashion (Roethig 1991). REFLUDAN (lepirudin) is supplied as a sterile, white, freeze-dried powder for injection or infusion and is freely soluble in Sterile Water for Injection USP or 0.9% Sodium Chloride Injection USP. Each vial of REFLUDAN contains 50 mg lepirudin. Other ingre-dients are 40 mg mannitol and sodium hydroxide for adjust-ment of pH to approximately 7.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE In case of overdose (eg, suggested by excessively high aPTT values) the risk of bleeding is increased. No specific antidote for REFLUDAN (lepirudin) is available. If life-threatening bleeding occurs and excessive plasma levels of lep-irudin are suspected, the following steps should be followed: Immediately STOP REFLUDAN (lepirudin) 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. CONTRAINDICATIONS REFLUDAN (lepirudin) is contraindicated in patients with known hypersensitivity to hirudins or to any of the components in REFLUDAN [lepirudin (rDNA) for injection].

SIDE EFFECTS 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* HAT-1 HAT-2 (All patients) (n=198) Patients with TECs REFLUDAN (n=113) Historical control (n=91) Bleeding from puncture sites and wounds 14.1% 10.6% 4.4% Anemla or Isolated drop in hemoglobin 13.1% 12.4% 1.1% Other hematoma and unclassified bleeding 11.1% 10.6% 4.4% Hematuria 6.6% 4.4% 0 Gastrointestinal and rectal bleeding 5.1% 5.3% 6.6% Epistaxis 3.0% 4.4% 1.1% Hemothorax 3.0% 0 1.1% Vaginal bleeding 1.5% 1.8% 0 Intracranial bleeding 0 0 2.2% *Patients may have suffered more than one event 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* HAT-1 HAT-2(All patients) (n=198) Patients with TECs REFLUDAN (n=113) Historical control (n=91) Fever 6.1% 4.4% 8.8% Abnormal Ilver function 6.1% 5.3% 0 Pneumonla 4.0% 4.4% 5.5% Sepsis 4.0% 3.5% 5.5% Allergic skin reactions 3.0% 3.5% 1.1% Heart failure 3.0% 1.8% 2.2% Abnormal kidney function 2.5% 1.8% 4.4% Unspecified Infections 2.5% 1.8% 1.1% Multiorgan fallure 2.0% 3.5% 0 Pericardlal effusion 1.0% 0 1.1% Ventricular fibrillation 1.0% 0 0 * Patients may have suffered more than one event 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 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.) Allergic Reactions (See PRECAUTIONS.) Allergic reactions or suspected allergic reactions in populations other than HIT patients include (in descending order of frequency*): Airway reactions (cough, bronchospasm, stridor, dyspnea): Common Unspecified allergic reactions: uncommon Skin reactions (pruritus, urticaria, rash, flushes, chills): uncommon General reactions (anaphylactoid or anaphylactic reactions): uncommon Ederna (facial edema, tongue edema, larynx edema, angioedema): rare The CIOMS (Council for International Organization of Medical Sciences) III standard categories are used for classification of freguencies: very common 10% or more common (frequent) 1 to < 10% uncommon (infrequent) 0.1 to < 1% rare 0.01 to < 0.1% very rare 0.01% or less 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. DRUG INTERACTIONS Concomitant treatment with thrombolytics (eg, rt-PA or strep-tokinase) may increase the risk of bleeding complications considerably enhance the effect of REFLUDAN (lepirudin) on aPTT prolongation. (See also WARNINGS: Hemorrhagic Events, ADVERSE REACTIONS: Adverse Events Reported in Other Populations; Intracranial Bleeding and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Concomitant Use With Thrombolytic Therapy.) Concomitant treatment with coumarin derivatives (vitamin K antagonists) and drugs that affect platelet function may also increase the risk of bleeding (see also DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Patients Scheduled for a Switch to Oral Anticoagulation).

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).