REFLUDAN [lepirudin( rDNA) for injection] is a highly specific direct
inhibitor of thrombin. Lepirudin (chemical designation: [Leul, Thr 2]-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 neutralizes 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, e.g., activated partial thromboplastin
time (aPTT) values increase in a dose-dependent fashion (Roethig 1991).
REFLUDAN is supplied as a sterile, white, freeze-dried powder for injection
or infusion and is freely soluble in Water for Injection USP or 0.9% Sodium
Chloride Injection USP.
Each vial of REFLUDAN contains 50 mg lepirudin. Other ingredients are
40 mg mannitol and sodium hydroxide for adjustment of pH to approximately