Israel - English - Ministry of Health
The format of this leaflet was determined by the Ministry of Health and its content was
checked and approved by it in March 2009.
Antihemophilic Factor (Human)
Double Viral Inactivation
Solvent/Detergent Treated and Heated in Final Container at 80ºC
Antihemophilic Factor (Human), Koãte®-DVI, is a sterile, stable, purified, dried concentrate of
human Antihemophilic Factor (AHF, factor VIII) 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. Koãte®-DVI is intended for use in therapy of classical hemophilia (hemophilia A).
Koãte-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, Koãte-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.
Koãte-DVI must be administered by
the intravenous route.
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 Factor VIII 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 Koãte-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
The removal and inactivation of spiked relevant and model enveloped and non-enveloped viruses
during the manufacturing process for Koãte-DVI have been validated in laboratory studies at
Grifols Therapeutics Inc. 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,
Immunodeficiency Virus Type 1) 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 large enveloped DNA viruses) was
Table I. Summary of In Vitro Log
Viral Reduction Studies
Enveloped Model Viruses
Non-enveloped Model Viruses
HAV and viruses
resistant to chemical
and physical agents
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.
Koãte-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 Koãte-DVI was performed in individuals with hemophilia A who
had been previously treated with other plasma-derived Factor VIII concentrates. In Stage 1 of the
pharmacokinetic study with 19 individuals, statistical comparisons demonstrated that Koãte-DVI is
bioequivalent to the unheated product, Koãte®-HP. The incremental in vivo recovery ten minutes
after infusion of Koãte-DVI was 1.90% IU/kg (Koãte-HP 1.82% IU/kg). Mean biologic half-life of
Koãte-DVI was 16.12 hours (Koãte-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 52 days (range 23-94). No
evidence of inhibitor formation was observed, either in the clinical study or in the preclinical
INDICATIONS AND USAGE
Koãte-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. Koãte-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.
Koãte-DVI contains naturally occurring von Willebrand's factor, which is co-purified as part of the
Koãte-DVI has not been investigated for efficacy in the treatment of von Willebrand's disease, and
hence is not approved for such usage.
Koãte-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 these measures, because this product is made from human blood, it may carry a risk
of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD)
agent. 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 Grifols Therapeutics Inc. [1-800-520-
2807].The physician should discuss the risks and benefits of this product with the patient, before
prescribing or administering 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.
A vaccination is also recommended for hemophilic patients who are hepatitis A seronegative.
1. Koãte-DVI is intended for treatment of bleeding disorders
arising from a deficiency in factor VIII. This deficiency should
be proven prior to administering Koãte-DVI.
2. Administer within 3 hours after reconstitution. Do not
refrigerate after reconstitution.
Administer only by the intravenous route.
4. Filter needle should be used prior to administering.
5. Koãte-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 Koãte-DVI product in
accordance with biohazard procedures.
Pregnancy Category C
Animal reproduction studies have not been conducted with Koãte-DVI. It is also not known
whether Koãte-DVI can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Koãte-DVI should be given to a pregnant woman only if clearly needed.
Antihemophilic Factor (Human), has been used extensively in pediatric patients.
Spontaneous adverse event reports with Koãte-HP and Koãte-DVI for pediatric use were within the
experience of those reports for adult use.
Information for Patients
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 and immune-
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)
Ten adverse reactions related to 7 infusions were observed during a total of 1053 infusions
performed during the clinical study of Koãte-DVI, for a frequency of 0.7% infusions associated
with adverse reactions. All reactions were mild and included paraesthesia, vision blurred, headache,
nausea, abdominal pain, and feeling jittery.
DOSAGE AND ADMINISTRATION
Each bottle of Koãte-DVI has the Factor VIII content in international units per bottle stated on the
label of the bottle. The reconstituted product must be administered intravenously by either direct
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 Koãte-DVI required for hemostasis must be individualized according to the needs of the
patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors,
and the factor VIII level desired. It is often critical to follow the course of therapy with factor VIII
The clinical effect of Koãte-DVI is the most important element in evaluating the effectiveness of
treatment. It may be necessary to administer more Koãte-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 Antihemophilic Factor (Human) 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, 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 Factor VIII concentrate administered frequently on a predetermined schedule may result in
eradication of the Factor VIII inhibitor.
Most successful regimens have employed high doses of
Factor VIII 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 (percent of normal) can be estimated by
multiplying the dose of Antihemophilic Factor (Human) 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:
Expected % factor VIII increase (% of normal) = # units administered × 2%/IU/kg
body weight (kg)
Example for a 70 kg adult: 1400 IU × 2%/IU/kg = 40%
Dosage required(IU) =
body weight (kg)×desired % factor VIII increase
(% of normal)
Example for a 15 kg child: 15 kg × 100% = 750 IU required
The dosage necessary to achieve hemostasis depends upon the type and severity of the bleeding
episode, according to the following general guidelines:
Mild superficial or early hemorrhages may respond to a single dose of 10 IU per 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.
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.
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 Antihemophilic Factor (Human), 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,
Factor VIII levels should be checked throughout the perioperative course to ensure adequate
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 hemostasis.
Factor VIII concentrates may also be administered on a regular schedule for prophylaxis of
bleeding, as reported by Nilsson et al.
Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into
contact with the product to be administered via the intravenous route should not come in contact
with any non-sterile surface. Any contaminated needles should be discarded by placing in a
puncture proof container, and new equipment should be used.
After removing all items from the box, warm the sterile water (diluent) to room temperature
Remove shrink band from product vial. If the shrink band is absent or shows signs of
tampering, do not use the product and notify Grifols Therapeutics Inc. immediately.
Remove the plastic flip tops from each vial (Fig. A). Clenae vial tops (grey stoppers) with
alcohol swab and allow surface to dry. After cleaning, do not allow anything to touch the
latex (rubber) stopper.
Carefully remove the plastic sheath from the short end of the transfer needle. .Insert the
exposed needle into the diluent vial to the hub. (Fig. B)
Carefully grip the sheath of the other end of the transfer needle and twist to remove it.
Invert the diluent vial and insert the attached needle into the vial of concentrate at a 45˚
angle (Fig. C). This will direct the stream of diluent against the wall of the concentrate vial
and minimize foaming. The vacuum will draw the diluent into the concentrate vial.**
Remove the diluent bottle and transfer needle (Fig. D).
Immediately after adding the diluent, agitate vigorously for 10-15 seconds. (Fig. E1) then
swirl continuously until completely dissolved (Fig. E2). Some foaming will occur, but
attempt to avoid excessive foaming. The vial should then be visually inspected for
particulate matter and discoloration prior to administration.
Clean the top of the vial of reconstituted Koate-DVI again with alcohol swab and let surface
Attach the filter needle (from the package) to a sterile syringe. Withdraw the Koate-DVI
solution into the syringe through the filter needle (Fig. F).
Remove the filter needle from the syringe and replace with an appropriate injection or
butterfly needle for administration. Discard filter needle into a puncture proof container.
If the same patient is using more than one vial of Koate-DVI, the contents of multiple vials
may be drawn into the same syringe through the filter needles provided.
**If vacuum is lost in the concentrate vial during reconstitution, use a sterile syringe and needle to
remove the sterile water from the diluent vial and inject it into the concentrate vial, directing the
stream of fluid against the wall of the vial.
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.
Koãte-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.
Approximate Factor VIII
Koãte-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.
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
. 1966; 67(1):23-32.
2. Data on file.
3. Aronson DL: Factor VIII (antihemophilic globulin).
Semin Thromb Hemostas
4. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal
dose of new factor VIII concentrate.
. 1974; 85(2):245-7.
5. Winkelman L, Feldman PA, Evan DR: Severe heat treatment of lyophilized coagulation factors.
Curr Stud Hematol Blood Transfus.
1989; 56: 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.
7. Hart HF, Hart WG, Crossley J, et al: Effect of terminal (dry) heat treatment on non-enveloped
viruses in coagulation factor concentrates.
8. National Hemophilia Foundation Medical and Scientific Advisory Council. MASAC
recommendations concerning products licensed for the treatment of hemophilia and other
bleeding disorders. Section F. (Document 205, November 2011), accessed 19 July 2012
9. CDC. Blood safety monitoring among persons with bleeding disorders - United States,
May 1998-June 2002. MMWR. 2003;51:1152-4
10. Eyster ME, Bowman HS, Haverstick JN: Adverse reactions to factor VIII infusions. [letter]
. 1977; 87(2):248.
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.
12. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors.
Ann NY Acad Sci.
13. Mariani G, Hilgartner M, Thompson AR, et al: Immune Tolerance to Factor VIII: International
Adv Exp Med Biol
14. DiMichele D: Hemophilia 1996, New Approach to an Old Disease.
Pediatr Clin North Am
1996 Jun; 43:(3) 709-36.
precipitated factor VIII.
N Engl J Med
16. . Abildgaard CF: current concepts
17. Hilgartner MW: Factor replacement therapy. In: Hilgartner MW, Pochedly C, eds.: Hemophilia
in the child and adult. New York : Raven Press; 1989, p. 1-26.
18. Kasper CK, Dietrich SL: Comprehensive
19. Nilsson IM, Berntorp E, Löfqvist T, et al: : Twenty five years' experience of prophylactic
treatment in severe haemophilia A and B.
J Intern Med
Manufacturer: Grifols Therapeutics Inc, USA
Importer: Perrigo Agencies Ltd.