Antihemophilic Factor (Recombinant) Recombinate™ is a glycoprotein synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line. In culture the CHO cell line secretes recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF is purified from the culture medium utilizing a series of chromatography columns. A key step in the purification process is an immunoaffinity chromatography methodology in which a purification matrix, prepared by immobilization of a monclonal antibody directed to factor VIII, is utilized to selectively isolate the rAHF in the medium. The synthesized rAHF produced by the CHO cells has the same biological effects as Antihemophilic Factor (Human) [AHF (Human)] and structurally has a similar combination of heterogenous heavy and light chains as found in AHF (Human).
Recombinate™ is formulated as a sterile, nonpyrogenic, off-white to faint yellow, lyophilized powder preparation of concentrated recombinant AHF for intravenous injection and is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. When reconstituted with the appropriate volume of diluent, it contains the following stabilizers in maximum amounts: 12.5 mg/mL Albumin (Human), 0.20 mg/mL calcium, 1.5 mg/mL polyethylene glycol (3350), 180 mEq/L sodium, 55 mM histidine, 1.5 µg/AHF International Unit (IU) polysorbate-80. Von Willebrand Factor (vWF) is coexpressed with the Antihemophilic Factor (Recombinant) and helps to stabilize it. The final product contains not more than 2 ng vWF/IU rAHF which will not have any clinically relevant effect in patients with von Willebrand' disease. The product contains no preservative.
Manufacturing of Recombinate™ is shared by Baxter Healthcare Corporation, Hyland Division and Genetics Institute, Inc. The Antihemophilic Factor Concentrate (Recombinant), is produced by Baxter Healthcare Corporation, Hyland Division and Genetics Institute (For Further Manufacturing Use) and subsequently formulated and packaged at Baxter Healthcare Corporation, Hyland Division.
Each bottle of Recombinate™ is labeled with the AHF activity expressed in IU per bottle. Biological potency is determined by an in vitro assay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.
AHF is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). Hemophilia A is a genetic bleeding disorder characterized by hemorrhages which may occur spontaneously or after minor trauma. The administration of Recombinate™ provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect in these patients. Pharmacokinetic studies on sixty-six (66) patients revealed the circulating mean half-life for rAHF to be 14.4 ± 4.9 hours, which was not statistically significantly different from plasma-derived Antihemophilic Factor (Human), Hemofil® M, (pdAHF), which had a mean half-life of 14.0 ± 3.9 hours (n=59). Mean highest in vivo recovery in plasma was also similar at 2.18 ± 0.72 (n=19) IU/dL per IU/kg body weight compared to the mean highest recovery point above the pre-infusion baseline for Hemofil® M of 1.97 ± 0.66 (n=57) IU/dL per IU/kg.
The clinical study of rAHF in previously treated patients (individuals with hemophilia A who had been treated with plasma derived AHF) was based on observations made on a study group of 67 patients. These individuals received 18,451 to 1,110,111 IU over the 58.2 month study period, 13,394 infusions for a total of 21,437,195 IU rAHF.
These patients were successfully treated for bleeding episodes on a demand basis and also for the prevention of bleeds (prophylaxis). Spontaneous bleeding episodes successfully managed include hemarthroses, soft tissue and muscle bleeds. Management of hemostasis was also evaluated in surgeries. A total of 24 procedures on 13 patients were performed during this study. These included minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies, thoracotomy and liver transplant) procedures. Hemostasis was maintained perioperatively and postoperatively with individualized AHF replacement.
A study of rAHF in previously untreated patients was also performed. The study group comprised seventy-nine (79) patients, of whom seventy-five (75) had received at least one infusion of rAHF. In total, this cohort has been given 1,054 infusions totaling 437,126 IU rAHF. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.
The use of Antihemophilic Factor (Recombinant), Recombinate™ is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes. 1 Recombinate™ is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia).
Recombinate™ 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™, 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™ should be controlled by frequent laboratory determinations of circulating AHF levels.
Recombinate™ is not indicated in von Willebrand' disease.
Known hypersensitivity to mouse, hamster or bovine protein may be a contraindication to the use of Antihemophilic Factor (Recombinant) (see Precautions ).
None.
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 Antihemophilic Factor (Recombinant), Recombinate™ 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% 3,4,5,6,7,10,11,12 . 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 serum 3,4,5,6,7 . Over the investigational period, none of the 65 previously treated individuals, without an inhibitor at entry into the study, developed an inhibitor. In the previously untreated patient group there were 66 patients with factor VIII levels less than or equal to 2% who were tested for inhibitor after treatment with Recombinate™ rAHF. Of this group 12 individuals developed detectable inhibitor and of these, 3 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.
As Antihemophilic Factor (Recombinant), Recombinate™ 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 allergic type hypersensitivity reactions were not observed in any patient receiving Recombinate™ on study, such reactions are theoretically possible. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur.
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' plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained.
If the patient' 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.
Recombinate™ 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™ 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.
During the clinical studies conducted in the previously treated patient group, there were 13 infusion related minor adverse reactions reported out of 13,394 infusions (0.097%). One patient experienced flushing and nausea during his first infusion which abated on decreasing the infusion rate. A second patient experienced mild fatigue during and following one infusion and a third patient had a series of eleven nose bleeds with a periodicity associated with the infusions.
The protein in greatest concentration in Antihemophilic Factor (Recombinant) Recombinate™ is Albumin (Human). Reactions associated with intravenous administration of albumin are extremely rare, although nausea, fever, chills or urticaria have been reported. Other allergic reactions could theoretically be encountered in the use of this Antihemophilic Factor preparation. See Information for Patients .
Each bottle of Recombinate™ 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' baseline AHF level is at <1%):
Physician supervision of the dosage is required. The following dosage schedule may be used as a guide.
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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' 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
NOTE: Do not refrigerate after reconstitution. See Administration .
Administer at room temperature.
Recombinate™ should be administered not more than 3 hours after reconstitution.
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™.
Plastic syringes are recommended for use with this product since proteins such as AHF tend to stick to the surface of all-glass syringes.
Preparations of Recombinate™ 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™. 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™ is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. Recombinate™ is packaged with 10 mL of Sterile Water for Injection, USP, a double-ended needle, a filter needle, and a package insert.
Recombinate™ 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.
©Copyright 1992, 1997 Baxter Healthcare Corporation. All rights reserved.
Baxter Healthcare Corporation
Hyland Division
Glendale, CA 91203 USA
U.S. License No. 140
6891 Revised August 1998