Refludin

Refludin (lepirudin) is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications.

Anticoagulation in adult patients with HIT and associated thromboembolic disease:

• 0.4 mg/kg body weight (up to 110kg) slowly intravenously (eg, over 15 to 20seconds) as a bolus dose,

† followed by 0.15 mg/kg body weight (up to 110kg)/hour as a continuous intravenous infusion for 2 to 10 days or longer if clinically needed.

Normally the initial dosage depends on the patient's body weight a body weight exceeding 110 kg, the initial dosage should not be increased beyond the 110 kg body weight dose (maximal initial bolus dose of 44 mg, maximal initial infusion dose of 16.5 mg/h; see also DOSAGE AND ADMINISTRATION: Administration; Initial Intravenous Bolus, Table 7 and DOSAGE AND ADMINISTRATION: Administration; Intravenous Infusion, Table 8).

In general, therapy with Refludin (lepirudin) is monitored using the aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually median of the laboratory normal range for aPTT, see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations). A patient baseline aPTT should be determined prior to initiation of therapy with Refludin (lepirudin) , since Refludin (lepirudin) should not be started in patients presenting with a baseline aPTT ratio of 2.5 or more, in order to avoid initial overdosing.

• In general, the dosage (infusion rate) should be adjusted according to the aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually median of the laboratory normal range for aPTT).

• The target range for the aPTT ratio during treatment (therapeutic window) should be 1.5 to 2.5. Data from clinical trials in HIT patients suggest that with aPTT ratios higher than this target range, the risk of bleeding increases, while there is no incremental increase in clinical efficacy.

• As stated in DOSAGE AND ADMINISTRATION: Initial Dosage, Refludin (lepirudin) should not be started in patients presenting with a baseline aPTT ratio of 2.5 or more, in order to avoid initial overdosing.

• The first aPTT determination for monitoring treatment should be done 4hours after start of the Refludin (lepirudin) infusion.

• Follow-up aPTT determinations are recommended at least once daily, as long as treatment with Refludin (lepirudin) is ongoing.

• More frequent aPTT monitoring is highly recommended in patients with renal impairment or serious liver injury (see DOSAGE AND ADMINISTRATION: Monitoring and AdjustingTherapy; Use in Renal Impairment) or with an increased risk of bleeding.

• Any aPTT ratio out of the target range is to be confirmed at once before drawing conclusions with respect to dose modifications, unless there is a clinical need to react immediately.

• If the confirmed aPTT ratio is above the target range, the infusion should be stopped for two hours. At restart, the infusion rate should be decreased by 50% (no additional intravenous bolus should be administered). The aPTT ratio should be determined again 4 hours later.

• If the confirmed aPTT ratio is below the target range, the infusion rate should be increased in steps of 20%. The aPTT ratio should be determined again 4hours later.

• In general, an infusion rate of 0.21 mg/kg/h should not be exceeded without checking for coagulation abnormalities which might be preventive of an appropriate aPTT response.

As Refludin (lepirudin) is almost exclusively excreted in the kidneys (see also CLINICAL PHARMACOLOGY: Pharmacokinetic Properties), individual renal function should be considered prior to administration. In case of renal impairment, relative overdose might occur even with the standard dosage regimen. Therefore, the bolus dose and the infusion rate must be reduced in case of known or suspected renal insufficiency (creatinine clearance below 60mL/min or serum creatinine above 1.5mg/dL).

There is only limited information on the therapeutic use of Refludin (lepirudin) in HIT patients with significant renal impairment. The following dosage recommendations are mainly based on single-dose studies in a small number of patients with renal impairment. Therefore, these recommendations are only tentative and aPTT monitoring should be used along with monitoring of renal status.

Dose adjustments should be based on creatinine clearance values, whenever available, as obtained from a reliable method (24 h urine sampling). If creatinine clearance is not available, the dose adjustments should be based on the serum creatinine.

In all patients with renal insufficiency, the bolus dose is to be reduced to 0.2 mg/kg body weight.

The standard initial infusion rate given in DOSAGE AND ADMINISTRATION: Initial Dosage and DOSAGE AND ADMINISTRATION: Administration; Intravenous Infusion, Table 8 must be reduced according to the recommendations given in Table 6. Additional aPTT monitoring is highly recommended.

* In hemodialysis patients or in case of acute renal failure (creatinine clearance below 15 mL/min or serum creatinine above 6.0 mg/dL), infusion of Refludin (lepirudin) is to be avoided or stopped. Additional intravenous bolus doses of 0.1 mg/kg body weight should be considered every other day only if the aPTT ratio falls below the lower therapeutic limit of 1.5 (see also DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations).

Clinical trials in HIT patients have provided only limited information on the combined use of Refludin (lepirudin) and thrombolytic agents. The following dosage regimen of Refludin (lepirudin) was used in a total of 9 HIT patients in the HAT-1 and HAT-2 studies who presented with TECs at baseline and were started on both Refludin (lepirudin) and thrombolytic therapy (rt-PA, urokinase or streptokinase):

• Initial intravenous bolus: 0.2 mg/kg body weight

• Continuous intravenous infusion: 0.1 mg/kg body weight/h

The number of patients receiving combined therapy was too small to identify differences in clinical outcome of patients who were started on both Refludin (lepirudin) and thrombolytic therapy as compared to those who were started on Refludin (lepirudin) alone. The combined incidences of death, limb amputation, or new TEC were 22.2% and 20.7%, respectively. While there was a 47% relative increase in the overall bleeding rate in patients who were started on both Refludin (lepirudin) and thrombolytic therapy (55.6% vs 37.9%), there were no differences in the rates of serious bleeding events (fatal or life-threatening bleeds, bleeds that were permanently or significantly disabling, overt bleeds requiring transfusion of 2 or more units of packed red blood cells, bleeds necessitating surgical intervention, intracranial bleeds) between the groups (11.1% vs 11.2%). Although no intracranial bleeding has been observed in any of these patients, there have been reports of intracranial bleeding in the presence or absence of concomitant thrombolytic therapy. (See WARNINGS and ADVERSE REACTIONS.)

Special attention should be paid to the fact that thrombolytic agents per se may increase the aPTT ratio. Therefore, aPTT ratios with a given plasma level of lepirudin are usually higher in patients who receive concomitant thrombolysis than in those who do not (see also CLINICAL PHARMACOLOGY: Pharmacodynamic Properties).

If a patient is scheduled to receive coumarin derivatives (vitamin K antagonists) for oral anticoagulation after Refludin (lepirudin) therapy, the dose of Refludin (lepirudin) should first be gradually reduced in order to reach an aPTT ratio just above 1.5 before initiating oral anticoagulation. Coumarin derivatives should be initiated only when platelet counts are normalizing. The intended maintenance dose should be started with no loading dose. To avoid prothrombotic effects when initiating coumarin, continue parenteral anticoagulation for 4 to 5 days (see oral anticoagulant package insert for information.) The parenteral agent can be discontinued when the INR stabilizes within the desired target range.

Refludin (lepirudin) should not be mixed with other drugs except for Sterile Water for Injection USP, 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection.

Use Refludin (lepirudin) before the expiration date given on the carton and container. Reconstitution and further dilution are to be carried out under sterile conditions:

• For reconstitution, Sterile Water for Injection USP or 0.9% Sodium Chloride Injection USP are to be used.

• For further dilution, 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection are suitable.

• For rapid, complete reconstitution, inject 1 mL of diluent into the vial and shake it gently. After reconstitution a clear, colorless solution is usually obtained in a few seconds, but definitely in less than 3 minutes.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use solutions that are cloudy or contain particles.

• The reconstituted solution is to be used immediately. It remains stable for up to 24hours at room temperature (eg, during infusion).

• The preparation should be warmed to room temperature before administration.

• Discard any unused solution appropriately.

For intravenous bolus injection, use a solution with a concentration of 5 mg/mL. Preparation of a Refludin (lepirudin) solution with a concentration of 5 mg/mL:

• Reconstitute one vial (50 mg of lepirudin) with 1mL of Sterile Water for Injection USP or 0.9% Sodium Chloride Injection USP.

• 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 USP, 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection.

• The final solution is to be administered according to body weight (see Table7below and DOSAGE AND ADMINISTRATION: Initial Dosage). Intravenous injection of the bolus is to be carried out slowly (eg, over 15 to 20seconds).

*Dosage recommended for all patients with renal insufficiency (see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Renal Impairment)

For continuous intravenous infusion, solutions with concentration of 0.2mg/mL or 0.4 mg/mL may be used. Preparation of a Refludin (lepirudin) solution with a concentration of 0.2 or 0.4mg/mL:

• Reconstitute two vials (each containing 50 mg of lepirudin) with 1 mL each using either Sterile Water for Injection USP or 0.9% Sodium Chloride Injection USP.

• The final concentrations of 0.2 mg/mL or 0.4 mg/mL are obtained by transferring the contents of both vials into an infusion bag containing 500mL or 250mL of 0.9% Sodium Chloride Injection USP or 5%Dextrose Injection.

The infusion rate [mL/h] is to be set according to body weight (see Table 8 below and DOSAGE AND ADMINISTRATION: Initial Dosage).

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

WARNINGS

Hemorrhagic Events

As with other anticoagulants, hemorrhage can occur at any site in patients receiving Refludin (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 Refludin (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 Refludin (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 Refludin (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 Refludin (lepirudin). This may increase the anticoagulant effect of Refludin (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 Refludin (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 Refludin (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 Refludin (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 Refludin (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 Refludin (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 Refludin (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 Refludin (lepirudin). Both children presented with TECs at baseline. Refludin (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 Refludin (lepirudin) was completed after 8 and 58 days, respectively, without serious adverse events (Schiffmann 1997).

Adverse Events Reported in Clinical Trials in HIT Patients

The following safety information is based on all 198 patients treated with Refludin (lepirudin) in the HAT-1 and HAT-2 studies. The safety profile of 113 Refludin (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 Refludin (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 Refludin (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 Refludin (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 Refludin (lepirudin) and thrombolytic therapy with rt-PA or streptokinase. The overall frequency of this potentially life-threat-ening complication among patients receiving both Refludin (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 Refludin (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*):

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 Refludin (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 Refludin (lepirudin) without concomitant throm-bolytic therapy.

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

No specific antidote for Refludin (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 Refludin (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.