Recombinate

Description for Recombinate

RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) 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 monoclonal 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)]. Structurally the protein has a similar combination of heterogenous heavy and light chains as found in AHF (Human).

RECOMBINATE (antihemophilic factor recombinant) rAHF is formulated as a sterile, nonpyrogenic, off- white to faint yellow, lyophilized powder preparation of concentrated recombinant AHF for intravenous injection. RECOMBINATE (antihemophilic factor recombinant) rAHF 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, the product 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's disease. The product contains no preservative.

Manufacturing of RECOMBINATE (antihemophilic factor recombinant) rAHF is shared by Baxter Healthcare Corporation and Wyeth BioPharma. The recombinant Antihemophilic Factor Concentrate (For Further Manufacturing Use), is produced by Baxter Healthcare Corporation and Wyeth BioPharma (For Further Manufacturing Use) and subsequently formulated and packaged at Baxter Healthcare Corporation.

Each bottle of RECOMBINATE (antihemophilic factor recombinant) rAHF is labeled with the AHF activity expressed in IU per bottle. Biological potency is determined by an in vitroassay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.

Uses for Recombinate

The use of RECOMBINATE (antihemophilic factor (recombinant)) rAHF is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes.¹ RECOMBINATE (antihemophilic factor (recombinant)) rAHF is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia).

RECOMBINATE (antihemophilic factor (recombinant)) rAHF can be of therapeutic value in patients with acquired AHF inhibitors not exceeding 10 Bethesda Units per mL². In clinical studies with RECOMBINATE (antihemophilic factor (recombinant)) rAHF, 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 (antihemophilic factor (recombinant)) rAHF should be controlled by frequent laboratory determinations of circulating AHF levels.

Dosage for Recombinate

Each bottle of RECOMBINATE (antihemophilic factor (recombinant)) rAHF 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 x 2 = 50 IU/dL (50% of normal).

(2) A peak level of 70% is required in a 40 kg child. In this situation the dose would be 70/2 x 40 = 1400 IU.

Recommended Dosage Schedule

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

Hemorrhage
Degree of hemorrhage	Required peak post-infusion AHF activity in the blood (as % of normal or IU/dL plasma)	Frequency of infusion
Early hemarthrosis or muscle bleed or oral bleed	20-40	Begin infusion every 12 to 24 hours for one-three days until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive hemarthrosis, muscle bleed, or hematoma	30-60	Repeat infusion every 12 to 24 hours for usually three days or more until pain and disability are resolved.
Life threatening bleeds such as head injury, throat bleed, severe abdominal pain	60-100	Repeat infusion every 8 to 24 hours until threat is resolved.
Surgery
Type of operation
Minor surgery, including tooth extraction	60-80	A single infusion plus oral antifibrinolytic therapy within one hour is sufficient in approximately 70% of cases.
Major surgery	80-100 (pre- and post-operative)	Repeat infusion every 8 to 24 hours depending on state of healing.

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 RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) (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 (antihemophilic factor (recombinant)) rAHF bottle, then rapidly insert free end of the needle through the RECOMBINATE (antihemophilic factor (recombinant)) rAHF 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 (antihemophilic factor (recombinant)) rAHF bottle. Swirl gently until all material is dissolved. Be sure that RECOMBINATE (antihemophilic factor (recombinant)) rAHF 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 (antihemophilic factor (recombinant)) rAHF 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 solut ion and container permit. A colorless to faint yellow appearance is acceptable for RECOMBINATE (antihemophilic factor (recombinant)) rAHF.

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 (antihemophilic factor (recombinant)) rAHF.
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 (antihemophilic factor (recombinant)) rAHF, the contents of multiple bottles may be drawn into the same syringe by drawing up each bottle through a separate unused filter needle. Filter needles are intended to filter the contents of a single bottle of RECOMBINATE (antihemophilic factor (recombinant)) rAHF only.

Rate of Administration

Preparations of RECOMBINATE, Antihemophilic Factor (Recombinant) (rAHF) 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 (antihemophilic factor (recombinant)) rAHF. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.

HOW SUPPLIED

RECOMBINATE (antihemophilic factor (recombinant)) rAHF is available in single-dose bottles which contain nominally 250, 500 and 1000 International Units per bottle. RECOMBINATE (antihemophilic factor (recombinant)) rAHF is packaged with 10 mL of Sterile Water for Injection, USP, a double-ended needle, a filter needle, one physician insert and one patient insert.

Storage

RECOMBINATE (antihemophilic factor (recombinant)) rAHF 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 box.

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

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

To enroll in the confidential, industry-wide Patient Notification System, call 1-888-UPDATE U (1-888-873-2838). Manufactured by: Baxter Healthcare Corporation Westlake Village, CA 91362, USA. Revised December 2004.

Side Effects for Recombinate

During the clinical studies conducted in the previously treated patient group, there were 13 infusion related minor adverse reactions reported out of 10,446 infusions (0.12%).

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 RECOMBINATE (antihemophilic factor (recombinant)) rAHF 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.

Drug Interactions for Recombinate

No information provided.

Warnings for Recombinate

None.

Precautions for Recombinate

General

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 serum^3-7. 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.

Laboratory Tests

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.

Pediatric Use

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

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.

REFERENCES

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

Overdose Information for Recombinate

No information provided.

Contraindications for Recombinate

Known hypersensitivity to mouse, hamster or bovine protein may be a contraindication to the use of Antihemophilic Factor (Recombinant) (see PRECAUTIONS).

Clinical Pharmacology for Recombinate

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 (antihemophilic factor (recombinant)) rAHF provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect in these patients. Pharmacokinetic studies on sixty-nine (69) patients revealed the circulating mean half- life for rAHF to be 14.6 ± 4.9 hours (n=67), which was not statistically significantly different from plasma-derived HEMOFIL M, Antihemophilic Factor (Human) (AHF) (pdAHF). The mean half- life of HEMOFIL M AHF was 14.7 ± 5.1 hours (n=61). The actual baseline recovery observed with rAHF was 123.9 ± 47.7 IU/dl (n=23) which is significantly higher than the actual HEMOFIL M AHF baseline recovery of 101.7 ± 31.6 IU/dl (n=61). However, the calculated ratio of actual to expected recovery with rAHF (121.2 ± 48.9%) is not different on average from HEMOFIL M AHF (123.4 ± 16.4%).

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 69 patients. These individuals received cumulative amounts of Factor VIII ranging from 20,914 to 1,383,063 IU over the 48- month study. Patie nts were given a total of 17,700 infusions totaling 28,090,769 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 as part of an ongoing study. The study group was comprised of seventy-nine (79) patients, of whom seventy-six (76) had received at least one infusion of rAHF. To date, this cohort has been given 12,209 infusions totaling over 11,277,043 IU rAHF. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.

Patient Information for Recombinate

The patient and physician should discuss the risks and benefits of this product.

Although allergic type hypersensitivity reactions were not observed in any patient receiving RECOMBINATE (antihemophilic factor (recombinant)) rAHF 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.