| EXP: 1 DAY (RT).
Recombinant hirudin derived from yeast cells. Used for treatment of disseminated intravascular coagulation, in particular heparin-induced thrombocytopenia type II.
Mechanism of action: reacts with thrombin in a 1:1 molar ratio to form a noncovalent complex; directly inhibits all actions of thrombin. There is no physiologic inhibitor of lepirudin.
Lepirudin provides more stable level of anticoagulation than heparin. Lepirudin does not require endogenous cofactors and acts independently of antithrombin-III.
Preparation: Bolus dose: use concentration of 5 mg/ml. Dilute 50mg vial with 1 ml NS or sterile water, then transfer to at least 10 ml syringe and qs to 10ml with sterile water, NS or D5W.
Continuous infusion: Dilute two 50mg vials, each with 1 ml sterile water or NS and add to 250 or 500ml bag of D5W or NS. (Concentration: 0.2 or 0.4 mg/ml)
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DOSAGE AND ADMINISTRATION
Initial Dosage
Anticoagulation in adult patients with HIT and associated thromboembolic disease:
* 0.4 mg/kg body weight (up to 110 kg) slowly intravenously (eg, over 15 to 20 seconds) as a bolus dose. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL.
* followed by 0.15 mg/kg body weight (up to 110 kg)/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. This is valid up to a body weight of 110 kg. In patients with 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 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, since REFLUDAN 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 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 4 hours after start of the REFLUDAN infusion.
* Follow-up aPTT determinations are recommended at least once daily, as long as treatment with REFLUDAN is ongoing.
* More frequent aPTT monitoring is highly recommended in patients with renal impairment or serious liver injury (see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; 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 4 hours 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 is almost exclusively excreted in the kidneys, 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 60 mL/min or serum creatinine above 1.5 mg/dL). CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL. There is only limited information on the therapeutic use of REFLUDAN 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. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL.
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
| Creatinine clearance [mL/min] |
Serum creatinine [mg/dL] |
Adjusted infusion rate |
|
| |
|
[% of standard initial infusion 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 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. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL. |
Concomitant Use With Thrombolytic Therapy
Clinical trials in HIT patients have provided only limited information on the combined use of REFLUDAN and thrombolytic agents. The following dosage regimen of REFLUDAN 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 and thrombolytic therapy (rt-PA, urokinase or streptokinase):
* Initial intravenous bolus: 0.2 mg/kg body weight. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL
* 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 and thrombolytic therapy as compared to those who were started on REFLUDAN 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 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 package insert for 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.
Use in Patients Scheduled for a Switch to Oral Anticoagulation
In the absence of other anticoagulants, REFLUDAN influences the INR/prothrombin time in a dose dependent, gradual and linear fashion when aPTT values are within the recommended therapeutic range.
In REFLUDAN-treated patients receiving overlapping therapy with oral anticoagulants, there may be a small reduction in INR upon cessation of REFLUDAN treatment. When transitioning from REFLUDAN to oral anticoagulation, PT/INR should be monitored closely until results stabilize in the therapeutic range.
If a patient is scheduled to receive coumarin derivatives (vitamin K antagonists) for oral anticoagulation after REFLUDAN therapy, the dose of REFLUDAN 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.
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Administration
Directions on Preparation and Dilution
REFLUDAN 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 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. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL.
* 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 24 hours at room temperature (eg, during infusion).
* The preparation should be warmed to room temperature before administration.
* Discard any unused solution appropriately.
Initial Intravenous Bolus
CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL.
For intravenous bolus injection, use a solution with a concentration of 5 mg/mL.
Preparation of a REFLUDAN solution with a concentration of 5 mg/mL:
* Reconstitute one vial (50 mg of lepirudin) with 1 mL of Sterile Water for Injection USP or 0.9% Sodium Chloride Injection USP. Reconstitution with 1 mL of diluent results in a concentration of 50 mg/mL. Once reconstituted, this product must be further diluted prior to administration.
* 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 Table 7 below and DOSAGE AND ADMINISTRATION: Initial Dosage).
* Intravenous injection of the bolus is to be carried out slowly (eg, over 15 to 20 seconds).
Table 7: Standard bolus injection volumes according to body weight for a 5 mg/mL concentration
| Body Weight [kg] |
Injection volume |
| |
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 0.2 mg/mL or 0.4 mg/mL may be used.
Preparation of a REFLUDAN solution with a concentration of 0.2 or 0.4 mg/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 500 mL or 250 mL 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
| Body Weight [kg] |
Infusion rate at 0.15 mg/kg/h |
| |
500-mL infusion bag
0.2 mg/mL |
250-mL infusion bag
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 (35.6 TO 77°F). USE REFLUDAN BEFORE THE EXPIRATION DATE GIVEN ON THE CARTON AND CONTAINER. ONCE RECONSTITUTED, USE REFLUDAN 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 non-immunologic type and the immunologic type are closely linked in their pathogenesis. Seminars Thromb Hemost. 1995; 2l: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, Greinacher A. 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. In Press.
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 December 2006
Manufactured by: CSL Behring GmbH D-35002 Marburg Germany
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470
Made in Germany www.refludan.com
64011246
6701500 US
Source: [package insert] |
