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REFLUDAN [lepirudin (rDNA) for injection] is a highly specific direct inhibitor of thrombin. It 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 110 kg) slowly intravenously (eg, over 15 to 20 seconds) as a bolus dose 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 patients 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; 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 (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 60 mL/min or serum creatinine above 1.5 mg/dL).
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.
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.
Reduction of infusion rate in patients with renal impairment
Creatinine clearance [mL/min]
45-60 30-44 15-29 <15
Serum creatinine [mg/dL]
1.6-2/0 2.1-3.0 3.1-6.0 >6.0
Adjusted infusion rate [% of standard
initial infusion rate]
50% 30% 15% avoid
[mg/kg/h]
0.075 0.045 0.0225 avoid
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