Bioclate

Drug Description

BIOCLATE™
(antihemophilic factor [recombinant])

 

DESCRIPTION

Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) ^TM is a glyco-protein 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 rAHF produced has the same biological effects as Antihemophilic Factor (Human) [AHF(Human)] and structurally has a similar combination of heterogeneous heavy and light chains as found in AHF (Human).

Bioclate (antihemophilic factor) ^TM 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), 1.5 mg/mL polyethylene glycol (3350),180 mEq/L sodium, 55 mM histidine, 1.5 pg/AHF International Unit (IU) polysorbate-80 and 0.20 mg/mL calcium. 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 Willebrands disease. The product contains no preservative.

Manufacturing of Bioclate (antihemophilic factor) ^TM is shared by Baxter Healthcare Corporation, Hyland Division and Genetics Institute, Inc. Genetics Institute produces Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) which is then formulated and packaged at Baxter Healthcare Corporation, Hyland Division.

Each bottle of Bioclate (antihemophilic factor) ^TM 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.

 

Indications

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

Bioclate (antihemophilic factor) ^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 Bioclate (antihemophilic factor) ^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 s.c. uses, the dosage of Bioclate (antihemophilic factor) ^TM should be controlled by frequent laboratory determinations of circulating AHF levels.

Bioclate (antihemophilic factor) ^TM is not indicated in von Willebrands disease.

 

Dosage

DOSAGE AND ADMINISTRATION

Each bottle of Bioclate (antihemophilic factor) ^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. The high purity of Bioclate (antihemophilic factor) ^TM has been thought to influence the difficulty of producing an accurate potency measurement in vitro.

Experiments have shown that, to achieve accurate activity levels, such a potency assay should be conducted using plastic test tubes and pipets as well as substrate containing normal levels of von Willebrand Factor.

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 b.d. weight (IU/kg) by two. This calculation is based on the clinical findings of Abildgaard et al⁸ 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 preinfusion baseline of approximately 2.0 IU/dL per IU/kg b.d. weight.

Example (Assuming patients baseline AHF level is at < 1%):

1. A dose of 1750 IU AHF administered to a 70 kg patient, i.e. 25 IU/kg (1 750/70), should be expected to cause a peak postinfusion 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. 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 (pre- and post- operative)	80-100	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 patients plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained. Other dosage regimens have been proposed s.c. as that of Schimpf, et al, which describes continuous maintenance therapy.⁹

Reconstitution

Use Aseptic Technique

1. Bring Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) ^TM, (dry concentrate) and Sterile Water for Injection, USP, (diluent) to room temperature.
2. Remove caps from concentrate and diluent bottles to expose central portion of rubber stoppers.
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 diluent stopper.
5. Remove protective covering from other end of double-ended needle. Invert diluent bottle over the upright Bioclate (antihemophilic factor) ^TM bottle, then rapidly insert free end of the needle through the Bioclate (antihemophilic factor) ^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 Bioclate (antihemophilic factor) ^TM bottle. Swirl gently until all material is dissolved. Be sure that Bioclate (antihemophilic factor) ^TM is completely dissolved, otherwise active material will be removed by the filter.

NOTE: Do not refrigerate after reconstitution. See Administration.

Administration

Use Aseptic Technique

Administer at room temperature. Bioclate (antihemophilic factor) ^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), Bioclate (antihemophilic factor) ^TM.

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

1. Attach filter needle to a disposable syringe and draw back plunger to admit air into syringe.
2. Insert needle into reconstituted Bioclate (antihemophilic factor) ^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 Bioclate (antihemophilic factor) ^TM, the contents of multiple bottles may be drawn into the same syringe by drawing up each bottle through a separate unused filter needle. This practice lessens the loss of Bioclate (antihemophilic factor) ^TM. Please note, filter needles are intended to filter the contents of a single bottle of Bioclate (antihemophilic factor) ^TM only.

Rate of Administration

Preparations of Bioclate (antihemophilic factor) ^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 Bioclate (antihemophilic factor) ^TM. 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

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

STORAGE

Bioclate (antihemophilic factor) ^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 320:1 66-1 70, 1989
2. Kessler CM: An Introduction to Factor VIII Inhibitors: The Detection and Quantitation. Am J Med 91 (Suppl 5A): 1 S-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 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 Vlll: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 CE, 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, Rothmann 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 EM: The Natural History of Factor VIII Inhibitors in Patients With Hemophilia A. Hoyer LW (ed), Factor VIII lnhtbitors, N.Y., AR Liss, 1984, pp 19-29
11. RasiV, 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 Previously Unexposed to Factor VIIIC Concentrates. Seminars in Hematology 27:1-7, 1990

 

Side Effects & Drug Interactions

SIDE EFFECTS

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 the 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) Bioclate (antihemophilic factor) 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 PATIENT INFORMATION.

 

DRUG INTERACTIONS

 

Warnings & Precautions

WARNINGS

No information provided.

PRECAUTIONS

General

Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) ^TM 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 anti-bodies 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 Bioclate (antihemophilic factor) ^TM rAHF. Of this group 12 individuals developed detectable inhibitor and of these, 3 patients showed a titer greater than 10 B.U. The true immunogenicity of Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) ^TM is uncertain at this time. 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 Antihemophilic Factor (Recombinant), Bioclate (antihemophilic factor) ^TM contains trace amounts of mouse protein (maximum of 0.1 ng/IU rAHF), hamster protein (maximum of 1 ng CHO protein/IU rAHF), and bovine protein (maximum of 1 ng BSNIU rAHF), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Information for Patients

Although allergic type hypersensitivity reactions were not observed in any patient receiving Bioclate (antihemophilic factor) ^TM 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.

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 patients plasma at suitable intervals to assure that adequate AHF levels have been reached and are maintained.

If the patients 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 adthtional AHF may neutralize the inhibitor. Thereafter the administra tion 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

Bioclate (antihemophilic factor) † 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

Bioclate (antihemophilic factor) ^TM 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).

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.

 

Overdosage & Contraindications

OVERDOSE

No infrormation provided.

 

CONTRAINDICATIONS

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

 

Clinical Pharmacology

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 Bioclate (antihemophilic factor) † 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^ÒM, (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^ÒM 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 in 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 totalling 437,126 IU rAHF. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.

 

Medication Guide

PATIENT INFORMATION

Although allergic type hypersensitivity reactions were not observed in any patient receiving Bioclate (antihemophilic factor) † 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.