Antihemophilic Factor (Human), Koate®-DV,I is a sterile, stable, purified, dried concentrate of human Antihemophilic Factor (AHF, factor VIII, AHG) which has been treated with tri-n-butyl phosphate (TNBP) and polysorbate 80 and heated in lyophilized form in the final container at 80°C for 72 hours. Koate-DVI is intended for use in therapy of classical hemophilia (hemophilia A).

Koate-DVI is purified from the cold insoluble fraction of pooled fresh-frozen plasma by modification and refinements of the methods first described by Hershgold, Pool, and Pappanhagen. 1 Koate-DVI contains purified and concentrated factor VIII. The factor VIII is 300-1000 times purified over whole plasma. Part of the fractionation may be performed by another licensed manufacturer. When reconstituted as directed, Koate-DVI contains approximately 50-150 times as much factor VIII as an equal volume of fresh plasma. The specific activity, after addition of Albumin (Human), is in the range of 9-22 IU/mg protein. Koate-DVI must be administered by the intravenous route.

Each bottle of Koate-DVI contains the labeled amount of antihemophilic factor activity in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of AHF found in 1.0 mL of fresh pooled human plasma. The final product when reconstituted as directed contains not more than (NMT) 1500 µg/mL polyethylene glycol (PEG). NMT 0.05 M glycine, NMT 25 µg/mL polysorbate 80, NMT 5 µg/g tri-n-butyl phosphate (TNBP), NMT 3 mM calcium, NMT 1 µg/mL aluminum, NMT 0.06 M histidine, and NMT 10 mg/mL Albumin (Human).

Hemophilia A is a hereditary bleeding disorder characterized by deficient coagulant activity of the specific plasma protein clotting factor, factor VIII. In afflicted individuals, hemorrhages may occur spontaneously or after only minor trauma. Surgery on such individuals is not feasible without first correcting the clotting abnormality. The administration of Koate-DVI provides an increase in plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients.

After infusion of Antihemophilic Factor (Human), there is usually an instantaneous rise in the coagulant level followed by an initial rapid decrease in activity, and then a subsequent much slower rate of decrease in activity. 2-4 The early rapid phase may represent the time of equilibration with the extravascular compartment, and the second or slow phase of the survival curve presumably is the result of degradation and reflects the true biologic half-life of the infused Antihemophilic Factor (Human). 3

The removal and inactivation of spiked relevant and model enveloped and non-enveloped viruses during the manufacturing process for Koate-DVI have been validated in laboratory studies at Bayer Corporation. Studies performed with the model enveloped viruses indicated that the greatest reduction was achieved by TNBP/polysorbate 80 treatment and 80°C heat. For this reason, VSV (Vesicular Stomatitis Virus, model for RNA enveloped viruses) and HIV-I (Human Immunodeficiency Virus Type I) were studied only at these two steps of the manufacturing process. The efficacy of the dry heat treatment was studied using all of the viruses, including BVDV (Bovine Viral Diarrheal Virus, model for hepatitis C virus) and Reo (Reovirus Type 3, model for viruses resistant to physical and chemical agents, such as hepatitis A), and the effect of moisture content on the inactivation of HAV (Hepatitis A Virus), PPV (Porcine Parvovirus, model for parvovirus B19), and PRV (Pseudorabies Virus, model for hepatitis B virus) was investigated.

Table I. Summary of In Vitro Log 10 Viral Reduction Studies
 
Enveloped Model Viruses Non-enveloped Model Viruses
 
HIV-I BVDV PRV VSV Reo HAV PPV
Model for
HIV-1/2 HCV HBV RNA enveloped viruses HAV and viruses resistant to chemical and physical agents HAV B19
9.4 10.3 9.5 10.9 9 4.5 3.7

Similar studies have shown that a terminal 80°C heat incubation for 72 hours inactivates non-lipid enveloped viruses such as hepatitis A and canine parvovirus in vitro, as well as lipid enveloped viruses such as hepatitis C. 7

Koate-DVI is purified by a gel permeation chromatography step serving the dual purpose of reducing the amount of TNBP and polysorbate 80 as well as increasing the purity of the factor VIII.

A two-stage clinical study using Koate-DVI was performed in individuals with hemophilia A who had been previously treated with other plasma-derived AHF concentrates. In Stage 1 of the pharmacokinetic study with 19 individuals, statistical comparisons demonstrated that Koate-DVI is bioequivalent to the unheated product, Koate®-HP. The incremental in vivo recovery ten minutes after infusion of Koate-DVI was 1.90% IU/kg (Koate-HP 1.82% IU/kg). Mean biologic half-life of Koate-DVI was 16.12 hours (Koate-HP 16.13 hours). In Stage II of the study, participants received Koate-DVI treatments for six months on home therapy with a median of 54 days (range 24-93). No evidence of inhibitor formation was observed, either in the clinical study or in the preclinical investigations. 2

Koate-DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII. Koate-DVI provides a means of temporarily replacing the missing clotting factor in order to control or prevent bleeding episodes, or in order to perform emergency and elective surgery on individuals with hemophilia.

Koate-DVI contains naturally occurring von Willebrand' factor, which is co-purified as part of the manufacturing process.

Koate-DVI has not been investigated for efficacy in the treatment of von Willebrand' disease, and hence is not approved for such usage.

CONTRAINDICATIONS

None known.

Koate-DVI is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite those measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Bayer Corporation [1-888-765-3203]. The physician should discuss the risks and benefits of this product with the patient, before prescribing it to a patient.

Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. It is emphasized that hepatitis B vaccination is essential for patients with hemophilia and it is recommended that this be done at birth or diagnosis. 8,9 Hepatitis A vaccination is also recommended for hemophilic patients who are hepatitis A seronegative.

PRECAUTIONS

General

  1. Koate-DVI is intended for treatment of bleeding disorders arising from a deficiency in factor VIII. This deficiency should be proven prior to administering Koate-DVI.
  2. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.
  3. Administer only by the intravenous route.
  4. Filter needle should be used prior to administering.
  5. Koate-DVI contains levels of blood group isoagglutinins which are not clinically significant when controlling relatively minor bleeding episodes. When large or frequently repeated doses are required, patients of blood groups A, B, or AB should be monitored by means of hematocrit for signs of progressive anemia, as well as by direct Coombs' tests.
  6. Product administration and handling of the infusion set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.
    Place needles in sharps container after single use. Discard all equipment including any reconstituted Koate-DVI product in accordance with biohazard procedures.

Pregnancy Cateogry C

Animal reproduction studies have not been conducted with Koate-DVI. It is also not known whether Koate-DVI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Koate-DVI should be given to a pregnant woman only if clearly needed.

Pediatric Use

Koate-DVI has not been studied in pediatric patients. Koate-HP, solvent/detergent treated Antihemophilic Factor (Human), has been used extensively in pediatric patients.

Spontaneous adverse event reports with Koate-HP for pediatric use were within the experience of those reports for adult use.

Information for Patient

Some viruses, such as parvovirus B19), or hepatitis A, are particularly difficult to remove or inactivate at this time. parvovirus B19), most seriously affects pregnant women, or immune-compromised individuals.

Symptoms of parvovirus B19), infection include fever, drowsiness, chills and runny nose followed about 2 weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and pain in the belly. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear.

ADVERSE REACTIONS

Allergic-type reactions may result from the administration of Antihemophilic Factor (Human) preparations. 10,11

Ten adverse reactions related to 7 infusions were observed during a total of 1053 infusions performed during the clinical study of Koate-DVI, for a frequency of 0.7% infusions associated with adverse reactions. All reactions were mild and included tingling in the arm, ear, and face, blurred vision, headache, nausea, stomach ache, and jittery feeling. 2

DOSAGE AND ADMINISTRATION

Each bottle of Koate-DVI has the AHF(H) content in international units per bottle stated on the label of the bottle. The reconstituted product must be administered intravenously by either direct syringe injection or drip infusion. The product must be administered within 3 hours after reconstitution.

General Approach to Treatment and Assessment of Treatment Efficacy

The dosages described below are presented as general guidance. It should be emphasized that the dosage of Koate-DVI required for hemostatis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrrhage, the presence of inhibitors, and the factor VIII level desired. It is often critical to follow the course of therapy with factor VIII level assays.

The clinical effect of Koate-DVI is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more Koate-DVI than would be estimated in order to attain satisfactory clinical results. If the calculated dose fails to attain the expected factor VIII levels, or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests.

When an inhibitor is present, the dosage requirement for AHF(H) is extremely variable and the dosage can be determined only by the clinical response. Some patients with low titer inhibitors, (10 Bethesda units) can be successfully treated with factor VIII without a resultant anamnestic rise in inhibitor titer. 12 Factor VIII levels and clinical response to treatment must be assessed to insure adequate response. Use of alternative treatment products, such as Factor IX Complex concentrates, Antihemophilic Factor (Porcine) or Anti-Inhibitor Coagulant Complex, may be necessary for patients with high titer inhibitors. Immune tolerance therapy using repeated doses of FVIII concentrate administered frequently on a predetermined schedule may result in eradication of the FVIII inhibitor. 13,14 Most successful regimens have employed high doses of FVIII administered at least once daily, but no single dosage regimen has been universally accepted as the most effective. Consultation with a hemophilia expert experienced with the management of immune tolerance regimens is also advisable.

Calculation of Dosage

The in vivo percent elevation in factor VIII can be estimated by multiplying the dose of AHF(H) per kilogram of body weight (IU/kg) by 2%. This method of calculation is based on clinical findings by Abildgaard et al, 15 and is illustrated in the following examples:

# units administered × 2%/IU/kg
body weight (kg)
Example for a 70 kg adult:
I 400 IU × 2%/IU/kg = 40%
70 kg
or
Dosage required (IU) =
body weight (kg) × desired % factor VIII increase
2%/IU/kg
Example for a 15 kg child:
       15 kg × 100% = 750 IU required
2%/IU/kg          

The dosage necessary to achieve hemostasis depends upon the type and severity of the bleeding episode, according to the following general guidelines:

Mild Hemorrhage

Mild superficial or early hemorrhages may respond to a single dose of 10 IU per kg, 16 leading to an in vivo rise of approximately 20% in the factor VIII level. Therapy need not be repeated unless there is evidence of further bleeding.

Moderate Hemorrhage

For more serious bleeding episodes (e.g., definite hemarthroses, known trauma), the factor VIII level should be raised to 30%-50% by administering approximately 15-25 IU per kg. If further therapy is required, repeated doses of 10-15 IU per kg every 8-12 hours may be given. 17

Severe Hemorrhage

In patients with life-threatening bleeding or possible hemorrhage involving vital structures (e.g., central nervous system, retropharyngeal and retroperitoneal spaces, iliopsoas sheath), the factor VIII level should be raised to 80%-100% of normal in order to achieve hemostasis. This may be achieved in most patients with an initial AHF [Antihemophilic Factor (Human), Koate®-DVI] dose of 40-50 IU per kg and a maintenance dose of 20-25 IU per kg every 8-12 hours. 18,19 For major surgical procedures, Factor VIII levels should be checked throughout the perioperative course to ensure adequate replacement therapy.

Surgery

For major surgical procedures, the factor VIII level should be raised to approximately 100% by giving a preoperative dose of 50 IU/kg. The factor VIII level should be checked to assure that the expected level is achieved before the patient goes to surgery in order to maintain hemostatic levels, repeat infusions may be necessary every 6 to 12 hours initially, and for a total of 10 to 14 days until healing is complete. The intensity of factor VIII replacement therapy required depends on the type of surgery and postoperative regimen employed. For minor surgical procedures, less intensive treatment schedules may provide adequate hemostatis. 18,19

Prophylaxis

Factor VIII concentrates may also be administered on a regular schedule for prophylaxis of bleeding, as reported by Nilsson et al. 20

Incorrect diagnosis, inappropriate dosage, method of administration, and biological differences in individual patients, could reduce the efficacy of this product or even result in an ill effect following its use. It is important that this product be stored properly, the directions for use be followed carefully during use, the risk of transmitting viruses be carefully weighed before the product is prescribed, and that plasma factor VIII levels be measured in initial treatment situations or if clinical response appears inadequate.

Reconstitution

Vacuum Transfer

  1. Warm the unopened diluent and the concentrate to room temperature (NMT 37°C, 99°F).
  2. After removing the plastic flip-top caps (Fig. A), aseptically cleanse the rubber stoppers of both bottles.
  3. Remove the protective cover from the plastic transfer-needle cartridge with tamper-proof seal and penetrate the stopper of the diluent bottle (Fig. B).
  4. Remove the remaining portion of the plastic cartridge, invert the diluent bottle and penetrate the rubber seal on the concentrate bottle (Fig. C) with the needle at an angle.
    Alternate method of transferring sterile water: With a sterile needle and syringe, withdraw the appropriate volume of diluent and transfer to the bottle of lyophilized concentrate.
  5. The vacuum will draw the diluent into the concentrate bottle. Hold the diluent bottle at an angle to the concentrate bottle in order to direct the jet of diluent against the wall of the concentrate bottle (Fig. C). Avoid excessive foaming.
  6. After removing the diluent bottle and transfer needle (Fig. D), swirl vigorously until completely dissolved without creating excessive foaming (Fig. E).
  7. After the concentrate powder is completely dissolved, withdraw solution into the syringe through the filter needle which is supplied in the package (Fig. F). Replace the filter needle with the administration set provided and inject intravenously.
  8. If a patient is to receive more than one bottle, the contents of two bottles may be drawn into the same syringe; a separate unused filter needle should be used for each bottle, then the needle for intravenous injection should be attached to the syringe.

images/70/59707001.jpg

Rate of Administration

The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 5 to 10 minutes is generally well-tolerated.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Koate-DVI is supplied in the following single dose bottles with the total units of factor VIII activity stated on the label of each bottle. A suitable volume of Sterile Water for Injection, USP, is a sterile double-ended transfer needle, a sterile filter needle, and a sterile administration set are provided.

NDC Number Approximate Factor VIII
Activity
Diluent
0026-0665-20 250 IU 5 mL
0026-0665-30 500 IU 5 mL
0026-0665-50 1000 IU  10 mL 

STORAGE

Koate-DVI should be stored under refrigeration (2-8°C; 36-46°F). Storage of lyophilized powder at room temperature (up to 25°C or 77°F) for 6 months, such as in home treatment situations, may be done without loss of factor VIII activity. Freezing should be avoided as breakage of the diluent bottle might occur.

CAUTION

Rx only

U.S. federal law prohibits dispensing without prescription.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these risk factors, it is important that this product be stored properly, that the directions be followed carefully during use, and that the risk of transmitting viruses be carefully weighed before the product is prescribed.

No warranty, express or implied, including any warranty of merchantability or fitness is made. Representatives of the Company are not authorized to vary the terms or the contents of the printed labeling, including the package insert for this product, except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

  1. Hershgold EJ, Pool JG, Pappenhagen AR: The potent antihemophilic globulin concentrate derived from a cold insoluble fraction of human plasma: characterization and further data on preparation and clinical trial. J Lab Clin Med 67(1):23-32, 1966.
  2. Data on file at Bayer Corporation.
  3. Aronson DL: Factor VIII (antihemophilic globulin). Semin Thromb Hemostas 6(1):12-27, 1979.
  4. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal dose of new factor VIII concentrate. J Pediatr 85(2):245-7, 1974.
  5. Winkelman L, Feldman PA, Evan DR: Severe heat treatment of lyophilized coagulation factors in Virus Inactivation in Plasma Products. Curr Stud Hematol Blood Transfus , Morgenthaler J-J (ed.). Basel, Karger, 1989 No 56, pp. 55-69.
  6. Skidmore SJ, Pasi KJ, Mawson SJ, et al: Serological evidence that dry heating of clotting factor concentrates prevents transmission of non-A, non-B hepatitis. J. Med Virol 30(1):50-2, 1990.
  7. Hart HF, Hart WG, Crossley J, et al: Effect of terminal (dry) heat treatment on non-enveloped viruses in coagulation factor concentrates. Vox Sang 67(4):345-50, 1994.
  8. National Hemophilia Foundation Medical and Scientific Advisory Council. Hemophilia Information; Exchange--AIDS Update: Recommendations concernng AIDS and the treatment of hemophilia HIV infection. Section I.G. (Rev. Jan, 1988).
  9. Safety of therapeutic products used for hemophilia patients. MMWR 37(29):441-4, 449-50, 1988.
  10. Eyster ME, Bowman HS, Haverstick JN: Adverse reactions to factor VIII infusions. [letter] Ann Intern Med 87(2):248, 1977.
  11. Prager D, Djerassi I, Eyster ME, et al: Pennsylvania state-wide hemophilia program: summary of immediate reactions with the use of factor VIII and factor IX concentrate. Blood 53(5):1012-3, 1979.
  12. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors. Ann NY Acad Sci 614:97-105, 1991.
  13. Mariani G, Hilgartner M, Thompson AR, et al: Immune Tolerance to Factor VIII: International Registry Data. Adv Exp Med Biol 386:201-8, 1995.
  14. DiMichele D: Hemophilia 1996, New Approach to an Old Disease. Pediatr Clin North Am 43:(3) 709-35, Jun 1995.
  15. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophila with glycine-precipitated factor VIII. N Engl J Med 275(9):471-5, 1966.
  16. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal dose of new factor VIII concentrate. J Pediatr 85(2):245-7, 1974.
  17. Abildgaard CF: current concepts in the management of hemophilia. Semin Hematol 12(3):223-32, 1975.
  18. Hilgartner MW: Factor replacement therapy. In: Hilgartner MW, Pochedly C, eds.: Hemophilia in the child and adult. New York, Raven Press, 1989, pp 1-26.
  19. Kasper CK, Dietrich SL: Comprehensive management of haemophilia. Clin Haematol 14(2):489-512, 1985.
  20. Nilsson IM, Berntorp E, Löfquist T, et al: Twenty five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 232(1):25-32, 1992.

Bayer Corporation

Pharmaceutical Division

Elkhart, IN 46515 USA

U.S. License No. 8

        14-7665-000

(Issued May 1999)