Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified, is a sterile, nonpyrogenic, dried preparation of antihemophilic factor (Factor VIII, Factor VIII:C, AHF) in concentrated form with a specific activity range of 2 to 15 AHF International Units/mg of total protein. When reconstituted with the appropriate volume of diluent, it contains approximately 12.5 mg/mL Albumin (Human), 1.5 mg/mL polyethylene glycol (3350), 0.055 M histidine and 0.030 M glycine as stabilizing agents. In the absence of the added Albumin (Human), the specific activity is approximately 2,000 AHF International Units/mg of protein. It also contains, per AHF International Unit, not more than 0.1 ng mouse protein, 18 ng organic solvent (tri-n-butyl phosphate) and 50 ng detergent (octoxynol 9). See Clinical Pharmacology .
Hemofil M AHF is prepared by the Method M process from pooled human plasma by immunoaffinity chromatography utilizing a murine monoclonal antibody to Factor VIII:C, followed by an ion exchange chromatography step for further purification. Source material may be provided by other US licensed manufacturers. Hemofil M AHF also includes an organic solvent (tri-n-butyl phosphate) and detergent (octoxynol 9) virus inactivation step designed to reduce the risk of transmission of hepatitis and other viral diseases. However, no procedure has been shown to be totally effective in removing viral infectivity from coagulation factor products.
Each bottle of Hemofil M AHF is labeled with the AHF activity expressed in International Units per bottle, which is referenced to the WHO International Standard.
Hemofil M AHF is to be administered only intravenously.
Antihemophilic factor (AHF) is a protein found in normal plasma which is necessary for clot formation.
The administration of Hemofil M AHF provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect of patients with hemophilia A (classical hemophilia). The administration of Hemofil M AHF will also correct deficiencies caused by circulating inhibitors when the inhibitor level does not exceed 10 Bethesda Units per mL.
The half-life of Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified, administered to Factor VIII deficient patients has been shown to be 14.8 ± 3.0 hours.
Use of an organic solvent (tri-n-butyl phosphate; TNBP) in the manufacture of Antihemophilic Factor (Human) has little or no effect on AHF activity, while lipid enveloped viruses, such as hepatitis B and human immunodeficiency virus (HIV) are inactivated. 1 Prince, et al , report inactivation of at least 10,000 Chimpanzee Infectious Doses (CID-50) of hepatitis B virus, 10,000 CID-50 of hepatitis non A, non B virus, and 30,000 Tissue Culture Infectious Doses of HIV with TNBP/detergent treatment during manufacture of an Antihemophilic Factor (Human) concentrate 2
In vitro studies demonstrate that the Hemofil M AHF, manufacturing process provides for significant viral reduction. These studies, summarized in Table 1, demonstrate virus clearance during the Hemofil M AHF manufacturing process using Human Immunodeficiency virus, Type 1 (HIV-1); Bovine Viral Diarrhea virus (BVD), a model for lipid enveloped RNA viruses, such as hepatitis C virus (HCV); Pseudorabies virus (PRV), a model for lipid enveloped DNA viruses, such as herpes; Porcine Parvovirus (PPV), a model for non-lipid enveloped DNA viruses, such as human parvovirus B19 and hepatitis A virus (HAV), a model for non-lipid enveloped RNA viruses. These reductions are achieved through a combination of process chemistry, partitioning and/or inactivation during solvent/detergent treatment, immunoaffinity chromatography, Q-Sepharose column chromatography and lyophilization.
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Hemofil M AHF was administered to 11 patients previously untreated with Antihemophilic Factor (Human). They have shown no signs of hepatitis or HIV infection following three to nine months of evaluation.
A study of 25 patients treated with Hemofil M AHF, and monitored for three to six months has demonstrated no evidence of antibody response to mouse protein. More than 1,000 infusions of Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified, have been administered during the clinical trials with no significant reactions. Reported events included a single episode each of chest tightness, fuzziness and dizziness, and one patient reported an unusual taste after each infusion.
The use of Hemofil M AHF is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes.
Hemofil M AHF can be of significant therapeutic value in patients with acquired Factor VIII inhibitors not exceeding 10 Bethesda Units per mL. 3 However, in such uses, the dosage should be controlled by frequent laboratory determinations of circulating AHF.
Hemofil M AHF is not indicated in von Willebrand' disease.
Known hypersensitivity to mouse protein is a contraindication to the use of Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified.
Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified, 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 Baxter Healthcare Corporation, Hyland Immuno at 1-800-423-2862 (in the U.S.). The physician should discuss the risks and benefits of this product with the patient.
Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly non A, non B hepatitis. As indicated under Clinical Pharmacology , however, a group of such patients treated with Hemofil M AHF did not demonstrate signs or symptoms of non A, non B hepatitis over observation periods ranging from three to nine months.
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 (Human) (AHF), Hemofil M, Method M, Monoclonal Purified, is initiated.
No benefit may be expected from this product in treating other deficiencies.
The processing of Hemofil M AHF significantly reduces the presence of blood group specific antibodies in the final product.
Although no hypersensitivity reactions have been observed, because Hemofil M AHF contains trace amounts of mouse protein (less than 0.1 ng/AHF activity units), the possibility exists that patients treated with this product may develop hypersensitivity to the mouse proteins.
The pulse rate should be determined before and during administration of Hemofil M AHF. Should a significant increase occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.
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 two 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.
Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis, and 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 AHF content of the patient' plasma fails to reach expected levels or if bleeding is not controlled after apparently adequate dosage, the presence of inhibitor should be suspected. By appropriate laboratory procedures, the presence of inhibitor can be demonstrated and quantified in terms of AHF units neutralized by each mL of plasma or by the total estimated plasma volume. If the inhibitor is at low levels (i.e., <10 Bethesda Units/mL), after administration of sufficient AHF units to neutralize the inhibitor, additional AHF units will elicit the predicted response.
Pregnancy Category C. Animal reproduction studies have not been conducted with Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified. It is not known whether Hemofil M AHF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Hemofil M AHF should be given to a pregnant woman only if clearly needed.
Allergic reactions may be encountered from the use of Antihemophilic Factor (Human) preparations. See Information for Patients .
The protein in greatest concentration in Hemofil M AHF is Albumin (Human). Reactions associated with albumin are extremely rare, although nausea, fever, chills or urticaria have been reported.
Each bottle of Antihemophilic Factor (Human) (AHF), Hemofil M AHF, Method M, Monoclonal Purified, is labeled with the AHF activity expressed in IU per bottle. This potency assignment is referenced to the World Health Organization International Standard.
The high purity of Hemofil M AHF has been thought to influence the difficulty of producing an accurate potency measurement. 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 AHF level, expressed as IU/dL of plasma or % (percent) of normal, can be calculated by multiplying the dose administered per kg body weight (IU/kg) by two. This calculation is based on the clinical finding by Abildgaard, et al , 4 which is supported by data from the collaborative study of in vivo recovery and survival with 15 different lots of Hemofil M AHF on 56 hemophiliacs that demonstrated a mean peak recovery point above the mean pre-infusion baseline of about 2.0 IU/dL per infused IU/kg body weight. 5
Example:
Note: Do not refrigerate after reconstitution.
Administer at room temperature.
Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified, should be administered not more than three hours after reconstitution.
Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.
Plastic syringes are recommended for use with this product. The ground glass surface of all-glass syringes tend to stick with solutions of this type.
Preparations of Hemofil M AHF 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 Hemofil M AHF. Should a significant increase occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.
Hemofil M AHF is available as single dose bottles. Each bottle is labeled with the potency in International Units, and is packaged together with 10 mL of Sterile Water for Injection, USP, a double-ended needle, and a filter needle.
Store Antihemophilic Factor (Human) (AHF), Hemofil M, Method M, Monoclonal Purified at 2-8°C (36-46°F) until the expiration date noted on the package. Within this period (indicated by the expiration date), the product may be stored at room temperature, not to exceed 30°C (86°F), for up to twelve months. Avoid freezing to prevent damage to the diluent bottle.
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. 6
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Baxter, Hyland Immuno, and Hemofil are trademarks of Baxter International, Inc.
Baxter and Hemofil are registered in the U.S. Patent and Trademark office.
Baxter Healthcare Corporation
Hyland Immuno
Glendale, CA 91203 USA
U.S. License No. 140
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Printed in USA
Part No. 7260
Revised February 2000
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