The use of Antihemophilic Factor (Recombinant), Recombinate^TM is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes. ¹ Recombinate^TM is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia).

Recombinate^TM can be of significant therapeutic value in patients with acquired AHF inhibitors not exceeding 10 Bethesda Units per mL ² . In clinical studies with Recombinate^TM, patients with inhibitors who were entered into the previously treated patient trial and those previously untreated children who have developed inhibitor activity on study, showed clinical hemostatic response when the titer of inhibitor was less than 10 Bethesda Units per mL. However, in such uses, the dosage of Recombinate^TM should be controlled by frequent laboratory determinations of circulating AHF levels.

Recombinate is not indicated in von Willebrand's disease.

Each bottle of Recombinate^TM is labeled with the AHF activity expressed in IU per bottle. This potency assignment is referenced to the World Health Organization International Standard for Factor VIII:C Concentrate and is evaluated by appropriate methodology to ensure accuracy of the results.

The expected in vivo peak increase in AHF level expressed as IU/dL of plasma or % (percent) of normal can be estimated by multiplying the dose administered per kg body weight (IU/kg) by two. This calculation is based on the clinical findings of Abildgaard et al ⁸ and is supported by the data generated by 419 clinical pharmacokinetic studies with rAHF in 67 patients over time. This pharmacokinetic data demonstrated a peak recovery point above the pre-infusion baseline of approximately 2.0 IU/dL per IU/kg body weight.

Example (Assuming patient's baseline AHF level is at <1%):

1. A dose of 1750 IU AHF administered to a 70 kg patient, i.e. 25 IU/kg (1750/70), should be expected to cause a peak post-infusion AHF increase of 25 2 = 50 IU/dL (50% or normal).
2. A peak level of 70% is required in a 40 kg child. In this situation the dose would be 70/2 40 = 1400 IU.

Recommended Dosage Schedule

Physician supervision of the dosage is required. The following dosage schedule may be used as a guide.

The careful control of the substitution therapy is especially important in cases of major surgery or life threatening hemorrhages.

Although dosage can be estimated by the calculations above, it is strongly recommended that whenever possible, appropriate laboratory tests including serial AHF assays be performed on the patient's plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained.

Other dosage regimens have been proposed such as that of Schimpf, et al , which describes continuous maintenance therapy. ⁹

Reconstitution: Use Aseptic Technique

1. Bring Antihemophilic Factor (Recombinant), Recombinate^TM (dry concentrate) and Sterile Water for Injection, USP, (diluent) to room temperature.
2. Remove caps from concentrate and diluent bottles.
3. Cleanse stoppers with germicidal solution and allow to dry prior to use.
4. Remove protective covering from one end of double-ended needle and insert exposed needle through the center of the stopper.
5. Remove protective covering from other end of double-ended needle. Invert diluent bottle over the upright Recombinate^TM bottle, then rapidly insert free end of the needle through the Recombinate^TM bottle stopper at its center. The vacuum in the bottle will draw in the diluent.
6. Disconnect the two bottles by removing needle from diluent bottle stopper, then remove needle from Recombinate^TM bottle. Swirl gently until all material is dissolved. Be sure that Recombinate^TM is completely dissolved, otherwise active material will be removed by the filter needle.

NOTE: Do not refrigerate after reconstitution. See Administration .

Administration:  

Use Aseptic Technique

Administer at room temperature.

Recombinate^TM should be administered not more than 3 hours after reconstitution.

Intravenous Syringe Injection

Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. A colorless to faint yellow appearance is acceptable for Antihemophilic Factor (Recombinant), Recombinate^TM.

Plastic syringes are recommended for use with this product since proteins such as AHF tend to stick to the surface of all-glass syringes.

1. Attach filter needle to a disposable syringe and draw back plunger to admit air into the syringe.
2. Insert needle into reconstituted Recombinate^TM.
3. Inject air into bottle and then withdraw the reconstituted material into the syringe.
4. Remove and discard the filter needle from the syringe; attach a suitable needle and inject intravenously as instructed under Rate of Administration .
5. If a patient is to receive more than one bottle of Recombinate^TM, the contents of multiple bottles may be drawn into the same syringe by drawing up each bottle through separate unused filter needle. Please note filter needles are intended to filter the contents of a single bottle of Recombinate^TM only.

Rate of Administration

Preparations of Recombinate^TM can be administered at a rate of up to 10 mL per minute with no significant reactions.

The pulse rate should be determined before and during administration of Recombinate^TM. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allow the symptoms to disappear promptly.

Antihemophilic Factor (Recombinant), Recombinate^TM is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. Recombinate^TM is packaged with 10 mL of Sterile Water for Injection, USP, a double-ended needle, a filter needle, and a package insert.

Storage

Recombinate^TM can be stored under refrigeration [2-8°C (36-46°F)] or at room temperature, not to exceed 30°C (86°F). Avoid freezing to prevent damage to the diluent bottle. Do not use beyond the expiration date printed on the bottle.

REFERENCES

1. White GC, McMillan CW, Kingdon HS, et al: Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. New Eng J Med 320: 166-170, 1989
2. Kessler CM: An Introduction to Factor VIII Inhibitors: The Detection and Quantitation. Am J Med 91 (Suppl 5A): 1S-5S, 1991
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 hemophiliacs. 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 Xlth 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 Haemotol 76: 369-371, 1990
12. Lusher JM, Salzman PM: Viral Safety and Inhibitor Development Associated with Factor VIIIC Ultra-Purified From Plasma in Hemophiliacs Previously Unexposed to Factor VIIIC Concentrates. Seminars in Hematology 27: 1-7, 1990

©Copyright 1992, 1997 Baxter Healthcare Corporation. All rights reserved.

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Hyland Division
Glendale, CA 91203 USA

©Copyright 2000, 2003. Baxter Healthcare Corporation. All rights reserved.
Manufactured by:
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