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.
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Antihemophilic Factor (Human), Koate®-HP, 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 is intended for use in therapy of classical hemophilia (hemophilia A).
Koate-HP 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 Pappenhagen. 1 Koate-HP 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-HP 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-HP must be administered by the intravenous route.
Each bottle of Koate-HP 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) 5 units heparin/mL, NMT 1500 ppm polyethylene glycol (PEG), NMT 0.05 M glycine, NMT 25 ppm polysorbate 80, NMT 5 ppm tri-n-butyl phosphate (TNBP), NMT 3 mM calcium chloride, NMT 1 ppm 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-HP provides an increase in plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients.
After infusion of Koate-HP, 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 Studies with Koate-HP in hemophilic patients have demonstrated a biologic half-life of approximately 9 to 14 hours. 2
In 1984, Prince, et al 5 described the susceptibility of hepatitis B virus (HBV) and the Hutchinson strain of non-A, non-B hepatitis virus to inactivation by ether and polysorbate 80. This method is known to disrupt lipid-containing enveloped viruses. Subsequently, others 6.7 using tri-n-butyl phosphate as an alternative organic solvent to the hazardous ethyl ether in combination with a number of different detergents including polysorbate 80, sodium deoxycholate, sodium cholate, or Triton x-100, showed these forms of chemical treatment to be rapidly effective in inactivating certain lipid-enveloped viruses. These viruses included vesicular stomatitis virus (VSV), sindbis virus, and sendai virus 6 as well as, in a later study, 7 human immunodeficiency virus (HIV), HBV and non-A, non-B virus. Similar studies undertaken at Bayer Corporation using TNBP and polysorbate 80 treatment of factor VIII concentrate immediately prior to a gel permeation chromatography purifying/concentrating procedure have confirmed the inactivation of VSV, visna, and sindbis viruses.
Antihemophilic Factor (Human), Koate®-HP is purified by virtue of a gel permeation chromatography step serving the dual purpose of removing the TNBP and polysorbate 80 as well as increasing the purity of the Factor VIII. Recently, concerns have been expressed concerning alterations to immune function occurring in asymptomatic hemophiliacs, 8 - 15 with some of the abnormalities being independent of HIV exposure. It has been suggested that the underlying mechanisms might include repeated exposure to viral agents, repeated allostimulation and/or possible contaminants in factor VIII preparations (e.g., lgG aggregates). More highly purified preparations which have minimized risks of viral transmission may therefore be desirable. 6
Koate-HP 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-HP provides a means of temporarily replacing the missing clotting factor in order to correct or prevent bleeding episodes, or in order to perform emergency and elective surgery on hemophiliacs.
Koate-HP has not been investigated for efficacy in the treatment of von Willebrand' disease, and hence is not approved for such usage.
None known.
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Koate-HP 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 these 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 or administering it to the 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. 16,17 Hepatitis A vaccination is also recommended for hemophilic patients who are hepatitis A seronegative. |
No studies of CD4 cell count surveillance have been done in HIV seropositive patients treated exclusively with Koate-HP; however, there have been several reports of increased rates of CD4 cell count decline in HIV seropositive hemophilia patients treated with conventionally purified FVIII concentrates compared to those treated with immunoaffinity purified products. 18-20 The clinical significance of these CD4 cell count findings remains uncertain.
Animal reproduction studies have not been conducted with Koate-HP. It is also not known whether Koate-HP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Koate-HP should be given to a pregnant woman only if clearly needed.
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.
Allergic-type reactions may result from the administration of Antihemophilic Factor (Human) preparations. 21,22
Each bottle of Koate-HP has the Antihemophilic Factor (Human) 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.
Shanbrom et al, 23 based upon studies in hemophiliacs, have suggested a linear dose-response relation with an approximate rise of 2.5% in Factor VIII activity for each unit of Antihemophilic Factor (Human) transfused per kg of body weight. Abildgaard et al, 24 in work with hemophilic children 8 months to 14 years of age, reported a response factor of 0.5 units/kg. Clinical experience with Koate-HP has demonstrated a similar dose-response relationship. 2 The following formulas can provide a guide for dosage calculations:
All efforts should be made to follow the course of therapy with factor VIII level assays. It may be dangerous to assume any certain level has been reached unless direct evidence is obtained.
The level of factor VIII required to prevent spontaneous hemorrhage is approximately 5% of normal, while a level of 30% of normal is the minimum required for hemostasis following trauma and surgery. 25-27 Mild superficial or early hemorrhages may respond to a single dose of 10 IU per kg, 4,28 leading to an in vivo rise of approximately 20% in the factor VIII level. In patients with early hemarthrosis (mild pain, minimal or no swelling, erythema, warmth, and minimal or no joint limitation), if treated promptly, even smaller doses may be adequate. 28-30
In cases of mild hemorrhage, therapy need not be repeated unless there is evidence of further bleeding.
For more serious hemorrhages and for minor surgical procedures, the patient' plasma factor VIII level should be raised to 30%-50% of normal for optimum hemostasis. 28,31 This usually requires an initial dose of 15-25 IU per kg; and if further therapy is required, a maintenance dose of 10-15 IU per kg every 8-12 hours.
In patients with life-threatening bleeding, or hemorrhage involving vital structures (central nervous system, retropharyngeal and retroperitoneal spaces, iliopsoas sheath), it may be desirable to raise the factor VIII level to 80%-100% of normal in order to achieve hemostasis. 28,31-33 This may be achieved with an initial Antihemophilic Factor (Human) Koate®-HP dose of 40-50 IU per kg and a maintenance dose of 20-25 IU per kg every 8-12 hours.
For major surgical procedures, Kasper 31 recommends that a dose of Antihemophilic Factor (Human) sufficient to achieve a level of 80%-100% of normal be given an hour before the procedure. It is recommended that the factor VIII level be checked prior to going to surgery to assure the expected level is achieved. A second dose, half the size of the priming dose, should be given about 5 hours after the first dose. The factor VIII level should be maintained at a daily minimum of at least 30% for a healing period of 10-14 days, depending on the nature of the operative procedure.
The above discussion is presented as a reference and a guideline. It should be emphasized that the dosage of Antihemophilic Factor (Human), Koate®-HP required for normalizing hemostasis must be individualized according to the needs of the patient. Factors to be considered include the weight of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors, and the factor VIII level desired. All efforts should be made to follow the course of therapy with factor VIII level assays.
The clinical effect of Koate-HP is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more Koate-HP 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 adequate calculated dosage, the presence of a factor VIII inhibitor should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory procedure. When an inhibitor is present, the dosage requirement for Koate-HP is extremely variable and the dosage can be determined only by the clinical response.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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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.
Antihemophilic Factor (Human), Koate®-HP 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, a sterile double-ended transfer needle, a sterile filter needle, and a sterile administration set are provided.
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Antihemophilic Factor (Human) Koate®-HP 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.
U.S. federal law prohibits dispensing without prescription.
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 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.