"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
Certain components used in the packaging of this product contain natural rubber latex. Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) is initiated. No benefit may be expected from this product in treating other deficiencies.
The formation of neutralizing antibodies, inhibitors to factor VIII, is a known complication in the management of individuals with hemophilia A. The reported prevalence of these antibodies in patients receiving plasma derived AHF is 10-20%3-7,10-12. These inhibitors are invariably IgG immunoglobulins, the factor VIII procoagulant inhibitory activity of which is expressed as Bethesda Units (B.U.) per mL of plasma or serum3-7. Over the investigational period, none of the 69 previously treated individuals, without an inhibitor at entry into the study, developed an inhibitor. In the previously untreated patient group there were 73 eligible patients with factor VIII levels less than or equal to 2% who received at least one rAHF treatment (median days 100, range 3-821) and who were tested for inhibitor after treatment with RECOMBINATE (antihemophilic factor (recombinant)) rAHF. Of this group, 23 individuals developed detectable inhibitor (median days 10, range 3-69) and of these, 8 patients showed a titer greater than 10 B.U. Patients treated with rAHF should be carefully monitored for the development of antibodies to rAHF by appropriate clinical observations and laboratory tests.
Formation of Antibodies to Mouse, Hamster or Bovine Protein
As RECOMBINATE (antihemophilic factor (recombinant)) rAHF contains trace amounts of mouse protein (maximum of 0.1 ng/IU rAHF), hamster protein (maximum of 1.5 ng CHO protein/IU rAHF), and bovine protein (maximum of 1 ng BSA/IU rAHF), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Although dosage can be estimated by the calculations which follow, it is strongly recommended that whenever possible, appropriate laboratory tests be performed on the patient's plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained.
If the patient's plasma AHF fails to reach expected levels or if bleeding is not controlled after adequate dosage, the presence of inhibitor should be suspected. By performing appropriate laboratory procedures, the presence of an inhibitor can be demonstrated and quantified in terms of AHF International Units neutralized by each mL of plasma or by the total estimated plasma volume. If the inhibitor is present at levels less than 10 Bethesda Units per mL, administration of additional AHF may neutralize the inhibitor. Thereafter, the administration of additional AHF International Units should elicit the predicted response. The control of AHF levels by laboratory assay is necessary in this situation.
Inhibitor titers above 10 Bethesda Units per mL may make hemostasis control with AHF either impossible or impractical because of the very large dose required. In addition, the inhibitor titer may rise following AHF infusion because of an anamnestic response to the AHF antigen.
Carcinogenesis, Mutagenesis, Impairment of Fertility
RECOMBINATE (antihemophilic factor (recombinant)) rAHF was tested for mutagenicity at doses considerably exceeding plasma concentrations of rAHF in vitro and at doses up to ten times the expected maximum clinical dose in vivo, and did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei in bone marrow polychromatic erythrocytes. Long term studies in animals have not been performed to evaluate carcinogenic potential.
RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) is appropriate for use in children of all ages, including the newborn. Safety and efficacy studies have been performed in both previously treated (n=23) and previously untreated (n=75) children. (See CLINICAL PHARMACOLOGY and PRECAUTIONS).
Pregnancy Category C. Animal reproduction studies have not been conducted with Antihemophilic Factor (Recombinant). It is not known whether Antihemophilic Factor (Recombinant) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Antihemophilic Factor (Recombinant) should be given to a pregnant woman only if clearly needed.
3. Schwarzinger I, Pabinger I, Korninger C, Haschke F, Kundi M, Niessner H, Lechner K: Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematology 24:241-245, 1987
4. Penner JA, Kelly PE: Management of patients with factor VIII or IX inhibitors. Sem Thromb Hemostasis 1:386-399, 1975
5. Ehrenforth S, Kreuz W, Scharrer I, et al: Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 339:594-598, 1992
6. McMillan CW, Shapiro SS, Whitehurst D, et al: The natural history of factor VIII inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 71:344-348, 1988
7. Addiego JE Jr., Gomperts E, Liu S, et al: Treatment of hemophilia A with a highly purified Factor VIII concentrate prepared by Anti-FVIIIc immunoaffinity chromatography. Thrombosis and Haemostasis 67:19-27, 1992
8. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. New Eng J Med 275:471-475, 1966
9. Schimpf K, Rothman P, Zimmermann K: Factor VIII dosis in prophylaxis of hemophilia A; A further controlled study in Proc XIth Cong W.F.H. Kyoto, Japan, Academic Press, 1976, pp 363-366
10. Gill FM: The Natural History of Factor VIII Inhibitors in Patients with Hemophilia A. Hoyer LW (ed), Factor VIII Inhibitors, N.Y. AR Liss, 1984, pp 19-29
11. Rasi V, Ikkala E: Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 76:369-371, 1990
12. Lusher JM, Salzman PM: Viral Safety and Inhibitor Development Associated with Factor VIIIC Ultra-Purified From Plasma in Hemophiliacs Previo usly Unexposed to Factor VIIIC Concentrates. Seminars in Hematology 27:1-7, 1990
Last reviewed on RxList: 2/20/2009
This monograph has been modified to include the generic and brand name in many instances.
Additional Recombinate Information
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