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Refludan

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Refludan

INDICATIONS

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

DOSAGE AND ADMINISTRATION

Initial Dosage

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 REFLUDAN (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 REFLUDAN (lepirudin) , since REFLUDAN (lepirudin) should not be started in patients presenting with a baseline aPTT ratio of 2.5 or more, in order to avoid initial overdosing.

Monitoring and Adjusting Therapy

Standard Recommendations.

Monitoring.

• 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, REFLUDAN (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 REFLUDAN (lepirudin) infusion.

• Follow-up aPTT determinations are recommended at least once daily, as long as treatment with REFLUDAN (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.

Dose Modifications.

• 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.

Use in Renal Impairment.

As REFLUDAN (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 REFLUDAN (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.

Table 6: Reduction of infusion rate in patients with renal impairment

   

Adjusted infusion rate

Creatinine

Serum

[% of standard

 

clearance

creatinine

initial infusion

 

[mL/min]

[mg/dL]

rate]

[mg/kg/h]

45-60

1.6-2.0

50%

0.075

30-44

2.1 - 3.0

30%

0.045

15 - 29

3.1 - 6.0

15%

0.0225

below 15*

above 6.0*

avoid or STOP infusion!*

* 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 REFLUDAN (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).

Concomitant Use With Thrombolytic Therapy.

Clinical trials in HIT patients have provided only limited information on the combined use of REFLUDAN (lepirudin) and thrombolytic agents. The following dosage regimen of REFLUDAN (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 REFLUDAN (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 REFLUDAN (lepirudin) and thrombolytic therapy as compared to those who were started on REFLUDAN (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 REFLUDAN (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).

Use in Patients Scheduled for a Switch to Oral Anticoagulation.

If a patient is scheduled to receive coumarin derivatives (vitamin K antagonists) for oral anticoagulation after REFLUDAN (lepirudin) therapy, the dose of REFLUDAN (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.

Administration

Directions on Preparation and Dilution.

REFLUDAN (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 REFLUDAN (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.

Initial Intravenous Bolus.

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

Table 7: Standard bolus injection volumes according to body weight for a 5mg/mL concentration

Body Weight

Injection volume

[kg]

Dosage 0.4 mg/kg

Dosage 0.2 mg/kg*

50

4.0 mL

2.0 mL

60

4.8 mL

2.4 mL

70

5.6 mL

2.8 mL

80

6.4 mL

3.2 mL

90

7.2 mL

3.6 mL

100

8.0 mL

4.0 mL

>110

8.8 mL

4.4 mL

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

Intravenous Infusion

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

Table 8: Standard infusion rates according to body weight

 

Infusion rate at 0.15 mg/kg/h

Body Weight

500-mL infusion bag

250-mL infusion bag

[kg]

0.2 mg/mL

0.4 mg/mL

50

38 mL/h

19 mL/h

60

45 mL/h

23 mL/h

70

53 mL/h

26 mL/h

80

60 mL/h

30 mL/h

90

68 mL/h

34 mL/h

100

75 mL/h

38 mL/h

>110

83 mL/h

41 mL/h

HOW SUPPLIED

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 (36 to RECONSTITUTED, USE REFLUDAN (lepirudin) IMMEDIATELY.

REFERENCES

1. Fondu P. Heparin associated thrombocytopenia: an update. Acta Clinica Belgica. 1995;50(6):343-357.

2. Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Seminars Thromb Hemost.1995; 21:106-116.

3. Roethig HJ, Maree JS, Meyer BH. Clinical pharmacology of hirudin (HBW 023). In: Reidenberg, MM ed. The clinical pharmacology of biotechnology products.Elsevier Publishers; 1991:227-236.

4. Schiffmann H, Unterhalt M, Harms K, Figula HR, Voelpel H, GreinacherA. Successful treatment of heparin-induced thrombocytopenia (HIT) type II in childhood with recombinant hirudin. Monatsschr Kinderheilkd.1997; 145:606-612.

5. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemostas.1998; 79:1-7.

6. Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med.1997; 127:804-812.

Prescribing Information as of October 2002 revised 10/2002

Manufactured by: Aventis Behring Deutschland GmbH D-35002 Marburg Germany,Manufactured for: Laboratories Wayne, NJ 07470 Made in Germany www.refludan (lepirudin) .com 2222552 (SAG) 6058201 (BERLEX) 02-419-0069/October 2002

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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