Koate-DVI

Each vial 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 mL of fresh pooled human plasma. The final product when reconstituted as directed contains polyethylene glycol (PEG) not more than (NMT) 1500 mcg/mL, glycine NMT 0.05 M, polysorbate 80 NMT 25 mcg/mL, tri-n-butyl phosphate (TNBP) NMT 5 mcg/g, calcium NMT 3mM, aluminum NMT 1 mcg/mL, histidine NMT 0.06 M, and albumin (human) NMT 10 mg/mL.
Koate-DVI, 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 hrs. 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 Pappenhagen. 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 IV route.

Pharmacology: 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. 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).
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-1 (human immunodeficiency virus type 1) were studied only at these 2 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 eg, 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. (See Table 1.)

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Similar studies have shown that a terminal 80°C heat incubation for 72 hrs inactivates non-lipid enveloped viruses eg, hepatitis A and canine parvovirus in vitro, as well as lipid enveloped viruses eg, hepatitis C.
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.
Pharmacokinetics: A 2-stage clinical study using Koate-DVI was performed in individuals with hemophilia A who have been previously treated with other plasma-derived AHF concentrates. In Stage I 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 10 min after infusion of Koate-DVI was 1.9% iu/kg (Koate-HP 1.82% iu/kg). Mean biologic half-life of Koate-DVI was 16.12 hrs (Koate-HP 16.13 hrs). In Stage II of the study, participants received Koate-DVI treatments for 6 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.
Clinical Studies: The objective of clinical studies with Koate-DVI was to establish bioequivalence with its predecessor product, Koate-HP, a product that has been used safely and effectively since 1989. The manufacturing processes and product parameters for Koate-HP are equivalent to those of Koate-DVI, except that Koate-HP has no terminal heating step.
Nineteen subjects with severe hemophilia A (<2% plasma FVIII) were randomly assigned to receive either Koate-DVI or Koate-HP. After a wash-out period of 4-7 days, the subjects received an infusion of the other product. FVIII levels and corresponding activated Partial Thromboplastin Time (aPTT) levels were obtained at prescribed intervals over a 48-hr period after each infusion. Dosages ranged between 44.8 and 55.1 iu/kg.
There were no significant differences between the pharmacokinetic parameters of Koate-DVI and Koate-HP (see Table 2), demonstrating that the 80°C heating step has not altered the biological activity of the product.
In an extension to the pharmacokinetic study, Koate-DVI was administered to 17 HIV-negative patients with severe hemophilia A (<2% FVIII) as prophylaxis for bleeding episodes over a 6-month period. Eleven of the 17 patients had fewer than 10 bleeding episodes. In a total of 168 bleeding episodes, 137 (86.7%) required no more than 1 or 2 treatments. Of the 69 adverse events observed in the course of 972 infusions administered, only 1 was deemed to be related (remotely) to Koate-DVI. None of the adverse events were considered severe or life-threatening. There was no evidence of inhibitor formation throughout the 26 weeks of therapy (mean exposure days 55.06±20.35) as evidenced by the absence of any detectable inhibitors on Bethesda assay, and by the stability of the in vivo recoveries over time.

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Treatment of Bleeding Episodes: Nineteen previously treated subjects with severe hemophilia A, who had participated in the pharmacokinetic study described previously were provided with Koate-DVI as their sole AHF source of home therapy for a period of 6 months. Infusions at a minimum dose level of 20-30 iu/kg had to be administered at least twice weekly. Following this schedule, each subject experienced approximately 50 exposure days during the 6-month study period. Throughout the study, subjects maintained home diaries to document AHF usage. At weeks 8, 17 and 26, subjects returned to the clinic for an interim history; physical examination; laboratory studies, including a 10-min FVIII recovery study, hematologic tests, and serum chemistry tests; and a Bethesda assay for inhibitor detection. At the end of the study, a 48-hr pharmacokinetic study with Koate-DVI was repeated, along with clinical and laboratory studies.
Over the study period, the 19 subjects experienced 152 bleeding episodes. A single treatment was effective in >90% of bleeding episodes, and 2 treatments were sufficient in another 6.6% of cases. Koate-DVI was well tolerated, with 29 adverse events (2.75%) observed in the course of 1053 infusions.
Only 10 of the adverse reactions related to 7 infusions were considered to be related to Koate-DVI, and all were mild to moderate. Koate-DVI therefore provides an effective and safe treatment for bleeding episodes.
Neoantigenicity: No evidence of inhibitor formation was observed in 19 previously treated patients after approximately 50 treatment days in the study described previously. This is supported by the absence of detectable inhibitors on repeat Bethesda assays, the stability of in vivo recovery of FVIII and the reproducibility of the pharmacokinetic parameters before and after the 26-week study. Therefore, the terminal heat treatment step in the manufacture of Koate-DVI is not shown to alter the molecule in any way that would increase the evidence of FVIII inhibitor formation.

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's 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's disease, and hence, is not approved for such usage.

Each vial of Koate-DVI has the AHF(H) content in iu/vial stated on the label of the vial. The reconstituted product must be administered IV by either direct syringe injection or drip infusion. Koate-DVI must be administered within 3 hrs after reconstitution.
General Approach to Treatment and Assessment of Treatment Efficacy: The dosages described as follows are presented as general guidance. It should be emphasized that the dosage of Koate-DVI required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency and hemorrhage, 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. Factor VIII levels and clinical response to treatment must be assessed to insure adequate response. Use of alternative treatment products eg, 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. 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 level 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, and is illustrated in the following examples: See equations.

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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/kg, 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 (eg, definite hemarthroses, known trauma), the factor VIII level should be raised to 30-50% by administering approximately 15-25 iu/kg. If further therapy is required, repeated doses of 10-15 iu/kg every 8-12 hrs may be given.
Severe Hemorrhage: In patients with life-threatening bleeding or possible hemorrhage involving vital structures (eg, 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/kg and a maintenance dose of 20-25 iu/kg every 8-12 hrs. 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 6-12 hrs initially, and for a total of 10-14 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 hemostasis.
Prophylaxis: Factor VIII concentrates may also be administered on a regular schedule for prophylaxis of bleeding, as reported by Nilsson et al.
Incorrect diagnosis, inappropriate dosage, method of administration, and biological differences in individual patients, could reduce the efficacy of Koate-DVI or even result in an ill effect following its use. It is important that Koate-DVI 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:
Warm the unopened diluent and the concentrate to room temperature (not more than 37°C, 99°F).
After removing the plastic flip-top caps, aseptically cleanse the rubber stoppers of both bottles.
Remove the protective cover from the plastic transfer-needle cartridge with tamperproof seal and penetrate the stopper of the diluent bottle.
Remove the remaining portion of the plastic cartridge, invert the diluent bottle and penetrate the rubber seal on the concentrate bottle 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.
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. Avoid excessive foaming.
After removing the diluent bottle and transfer needle, swirl vigorously until completely dissolved without creating excessive foaming.
After the concentrate powder is completely dissolved, withdraw solution into the syringe through the filter needle which is supplied in the package. Replace the filter needle with the administration set provided and inject IV.
If a patient is to receive >1 vial, the contents of 2 vials may be drawn into the same syringe; a separate unused filter needle should be used for each bottle, then the needle for IV injection should be attached to the syringe.
Rate of Administration: Should be adapted to the response of the individual patient, but administration of the entire dose in 5-10 min is generally well tolerated.

None known.

Koate-DVI is made from human plasma. Products made from human plasma may contain infectious agents eg, 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.
The physician should discuss the risks and benefits of Koate-DVI 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 upon diagnosis. Hepatitis A vaccination is also recommended for hemophilic patients who are hepatitis A seronegative.

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.
Administer within 3 hrs after reconstitution. Do not refrigerate after reconstitution.
Administer only by IV route.
Filter needle should be used prior to administering.
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.
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.
Information for Patients: Some viruses eg, 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.
Use in pregnancy: Pregnancy Category 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.
Use in children: 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.

Use in pregnancy: Pregnancy Category 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.

Allergic-type reactions may result from the administration of antihemophilic factor (human) preparations. 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, stomachache and jittery feeling.

Store 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 eg, 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.

Haemostatics

B02BD02 - coagulation factor VIII ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.

P₁S₁S₃