KOATE DVI 1000

Israel - English - Ministry of Health

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Active ingredient:
FACTOR VIII (HUMAN)
Available from:
PERRIGO ISRAEL AGENCIES LTD, ISRAEL
ATC code:
B02BD02
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJECTION
Composition:
FACTOR VIII (HUMAN) 1000 IU/VIAL
Administration route:
I.V
Prescription type:
Required
Manufactured by:
GRIFOLS THERAPEUTICS LLC., USA
Therapeutic group:
COAGULATION FACTOR VIII
Therapeutic area:
COAGULATION FACTOR VIII
Therapeutic indications:
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.
Authorization number:
117 90 29931 00
Authorization date:
2015-02-28

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)

__________________________________________________________________

Koãte®-DVI

__________________________________________________________________

Double Viral Inactivation

Solvent/Detergent Treated and Heated in Final Container at 80ºC

DESCRIPTION

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

purified

from

cold

insoluble

fraction

pooled

fresh-frozen

plasma

modification

refinements

methods

first

described

Hershgold,

Pool,

Pappanhagen.

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.

Each

bottle

Koãte-DVI

contains

labeled

amount

antihemophilic

factor

activity

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).

CLINICAL 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 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

(Human).

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,

(Vesicular

Stomatitis

Virus,

model

enveloped

viruses)

HIV-1

(Human

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

investigated.

Table I. Summary of In Vitro Log

Viral Reduction Studies

Enveloped Model Viruses

Non-enveloped Model Viruses

HIV-1

Model for

HIV-1/2

large

enveloped

viruses

enveloped

viruses

HAV and viruses

resistant to chemical

and physical agents

Global

Reduction

Factor

≥9.4

≥10.3

≥9.3

≥10.9

≥4.5

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.

5,6,7

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

investigations.

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

manufacturing process.

Koãte-DVI has not been investigated for efficacy in the treatment of von Willebrand's disease, and

hence is not approved for such usage.

CONTRAINDICATIONS

None known.

WARNINGS

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.

8,9

Hepatitis

A vaccination is also recommended for hemophilic patients who are hepatitis A seronegative.

PRECAUTIONS

General

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.

Pediatric Use

Koãte-DVI

been

studied

pediatric

patients.

Koãte-HP,

solvent/detergent

treated

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-

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 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

syringe

injection

drip

infusion.

product

must

administered

within

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 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

level assays.

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.

13,14

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%

70 kg

or

Dosage required(IU) =

body weight (kg)×desired % factor VIII increase

(% of normal)

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,

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.

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 Antihemophilic Factor (Human), dose of 40-50 IU per kg

and a maintenance dose of 20-25 IU per kg every 8-12 hours.

17,18

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 hemostasis.

18,19

Prophylaxis

Factor VIII concentrates may also be administered on a regular schedule for prophylaxis of

bleeding, as reported by Nilsson et al.

Reconstitution

Vacuum Transfer

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

(25˚C, 77˚F).

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

dry.

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.

HOW SUPPLIED

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

NDC Number

Activity

Diluent

Carton (kit)

13533-675-20

250 IU

5 mL

13533-675-30

500 IU

5 mL

13533-675-50

1000 IU

10 mL

STORAGE

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.

Rx only

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

. 1966; 67(1):23-32.

2. Data on file.

3. Aronson DL: Factor VIII (antihemophilic globulin).

Semin Thromb Hemostas

1979; 6(1):12-27.

4. Britton M, Harrison J, Abildgaard CF: Early treatment of hemophilic hemarthroses with minimal

dose of new factor VIII concentrate.

J Pediatr

. 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.

1990; 30(1):50-2.

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

.1994; 67(4):345-50.

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

at http://www.hemophilia.org.

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]

Ann

Intern Med

. 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.

Blood

. 1979;

53(5):1012-3.

12. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors.

Ann NY Acad Sci.

1991;

614:97-105.

13. Mariani G, Hilgartner M, Thompson AR, et al: Immune Tolerance to Factor VIII: International

Registry Data.

Adv Exp Med Biol

. 1995;386:201-8.

14. DiMichele D: Hemophilia 1996, New Approach to an Old Disease.

Pediatr Clin North Am

1996 Jun; 43:(3) 709-36.

Abildgaard

Simone

Corrigan

al:.

Treatment

hemophila

with

glycine-

precipitated factor VIII.

N Engl J Med

. 1966;275(9):471-5.

16. . Abildgaard CF: current concepts

in the

management of

hemophilia.

Semin Hematol

1975;12(3):223-32.

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

management of

haemophilia.

Clin Haematol

1985;14(2):489-512.

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

. 1992;232(1):25-32.

Manufacturer: Grifols Therapeutics Inc, USA

Importer: Perrigo Agencies Ltd.

03.2015

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