product monograph - jeff traister · plasma. the resulting injection volume is small,allowing...

Key Scientific Information

Product Monograph

Talecris is a leader in pathogen safety,

specializing in plasma-derived therapies.

Koate®-DVI – effective treatment, commitment

to supply.

As with all plasma-derived therapeutics, the potential to transmit infectiousagents cannot be totally eliminated. Because this product is made from humanblood it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. Hepatitis B vaccinationis essential for patients with hemophilia A; vaccination is recommended at birthor at the time of diagnosis. Hepatitis A vaccination is also recommended forhemophilia patients who are hepatitis A seronegative. Please see accompanying Koate®-DVI Full Prescribing Information.

Ko–ate®-DVI(Double Viral Inactivation)

Infusion of more than 2 billion IUsworldwide with no confirmed cases of

viral transmission.*

* Ko–ate®-DVI and Ko–ate®-HP

HISTORY OF HEMOPHILIA CARE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page ii

1. STRUCTURE AND FUNCTION OF FACTOR VIII (FVIII) . . . . . . . . . . . . . . . . . . . . . . . Page 1

2. MANUFACTURE OF KOATE®-DVI, ANTIHEMOPHILIC FACTOR (HUMAN) . . . . . .

3. PATHOGEN SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 5• Plasma Donor Screening and Selection• Plasma Donation Testing• Plasma Inventory Hold and Look Back• Plasma Manufacturing Pool Testing• Pathogen Removal and Inactivation During Koate®-DVI Manufacturing• Post-market Surveillance

4. PRODUCT CHARACTERISTICS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13• Composition and Clotting Activity• Specific Activity• Protein Composition• Storage

5. CLINICAL STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 15• Pharmacokinetics• Treatment of Bleeding Episodes• Neoantigenicity

6. DOSING AND ADMINISTRATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 17• General Approach to Treatment and Assessment of Treatment Efficacy• Calculation of Dosage

7. PRESCRIBING INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Back Cover• Package Insert

i

TABLE OF CONTENTS

Koate®-DVI (Double Viral Inactivation)

Trusted by patients worldwide, more than 2 billion IUs have been infused with no

confirmed cases of viral transmission.

Koate®-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.

Factor VIII in the Management of Hemophilia A

Hemophilia A, a blood coagulation disorder, is an inherited genetic disease linked to

the X chromosome. The disease is characterized by a defect or deficiency of the blood

coagulation factor VIII (FVIII), which leads to spontaneous, as well as traumatically

induced, bleeding episodes in affected patients.

The original therapy for hemophilia A provided FVIII replacement with whole plasma or

cryoprecipitate. This approach was only partially effective, because of the large volume

of plasma and the large amounts of protein that were needed to achieve only partial

and transient hemostasis. An additional drawback of replacement therapy with plasma

was the required hospitalization of the patient.

High-purity FVIII products are concentrated up to one thousand-fold in comparison to

plasma. The resulting injection volume is small, allowing convenient home treatment

of bleeding episodes. These advances in treatment have dramatically improved the

quality of life for hemophilia patients. Now patients can undergo surgery when needed,

treat most bleeding episodes at home, and live a more normal lifestyle with fewer

days lost from work or school.

The following chapters of this monograph describe the production, safety and efficacy

of Koate®-DVI, Antihemophilic Factor (Human).

The Strength of Talecris

Talecris Biotherapeutics is a new company with a long history of innovation. Talecris

carries on a tradition of developing life-saving therapies derived from human plasma

that began in the 1940s through our affiliation with Cutter Laboratories and Bayer

Biological Products (Miles in the U.S.). Koate®-DVI is manufactured with U.S.-sourced

plasma at the Clayton, North Carolina, USA, facility.

Talecris specializes in a variety of plasma-derived therapies.

As with all plasma-derived

therapeutics, the potential to

transmit infectious agents cannot

be totally eliminated. Please see

accompanying Koate®-DVI

Full Prescribing Information.

ii

HISTORY OF HEMOPHILIA CARE

In the cell, the FVIII molecule (antihemophilic factor, AHF) is initially synthesized

as a 2,351 amino acid, single-chain precursor protein. A 19-amino acid peptide is

cleaved from the amino-terminal portion during passage through the cytoplasm.

Therefore, the secreted protein consists of 2,332 amino acids with a calculated

molecular weight of approximately 265,000 daltons. Carbohydrates are bound to the

protein backbone at approximately 25 sites, bringing the effective molecular weight

closer to 300,000 daltons.

Figure 1

In plasma, the FVIII molecule is cleaved to produce two peptides, an amino-terminal

heavy chain (domains A1, A2, B) and a carboxy-terminal light chain (A3, C1, C2). The

protein circulates as a dimer, with calcium ions binding the chains together by linking

the A and C domains.

When activated by thrombin, the heavy chain is cleaved, expelling the carbohydrate-

rich B domain, which is not required for coagulant activity. Several additional cleavage

steps generate 50, 43 and 73 kd peptides, producing maximal coagulant activity.

Further cleavage inactivates the coagulant activity of the FVIII protein.

By itself, FVIII is a highly reactive unstable molecule. It is stabilized in plasma by

binding to von Willebrand factor (vWF).

THE INTACTPRECURSORMOLECULE

The intact precursor molecule

comprises three types of domains

and two smaller linker regions, as

shown in Figure 1:

• A domains: three A segments

(A1, A2, A3), each approximately

330 amino acids

• B domain: a unique middle segment

(B) consisting of 980 amino acids,

to which most of the carbohydrates

are bound

• C domains: two C segments

(C1, C2) of 150 amino acids each

1

1. STRUCTURE AND FUNCTION OF FACTOR VI I I (FVI I I )

A1

FVIII PRECURSOR

FVIII IN PLASMA

Secretion

Thrombin Activation

Inactivation

heavy chain200 kd

90 kd

50 kd 43 kd

45 kd

light chain 80 kd

80 kd

73 kd

73 kd

A2 B A3 C1 C2

A1 A2 B A3 C1 C2

A1 A2 B A3 C1 C2

A1 A2 A3 C1 C2

25 kd

Manufacturing Process of Koate®-DVI Flow Diagram

Figure 2







2

Cryo-Separation1.

2. Adsorption andPEG Precipitation

3. Glycine/NaClPrecipitation

4. Solvent/DetergentTreatment

6. Formulation

10. Dry Heat Treatment80˚C 72 hrs

9. Freeze Drying

Plasma Pooling

5. GelChromatography

7. Sterile Filtration

8. Filling

Final Product

ViralInactivationStep

Factor VIIICvon Willebrand Concentrate

AHF Precipitate

AHF Filtrate

Cryoprecipitate

Viral Inactivation Step

Manufacturing Process of Koate®-DVI

Koate®-DVI is manufactured at Talecris’ biological products production facility in

Clayton, North Carolina, USA. The manufacturing process is outlined in the flow

diagram in Figure 2 and described below.

1. Cryo-Separation. Frozen plasma is thawed and centrifuged to collect

the cryoprecipitate.

2. Adsorption and PEG Precipitation. The cryoprecipitate is solubilized in water.

Aluminum hydroxide and polyethylene glycol (PEG) are added to precipitate the

non-AHF proteins. The precipitate is removed by centrifugation or filtration and

the AHF filtrate is collected. This step removes non-product-related plasma

proteins while retaining AHF, bound and stabilized by von Willebrand Factor.

3. Glycine/Sodium Chloride Precipitation. AHF is precipitated by the addition of

glycine/sodium chloride and the precipitate is collected by centrifugation.

4. Solvent/Detergent Treatment. A solvent/detergent solution consisting of

TNBP (tri-n-butyl phosphate) and polysorbate 80 (Tween-80) is added to the

AHF and the suspension is incubated for six hours. This step is included in the

manufacturing process specifically to inactivate enveloped viruses by disrupting

their lipid-soluble envelopes.

5. Gel Chromatography. The AHF solution is passed through a gel chromatography

column that removes low molecular weight compounds. This step serves a dual

purpose: 1) removal of the TNBP and polysorbate 80; and 2) further purification of

the AHF, the larger FVIII molecules associated with their protective von Willebrand

Factor proteins and impurities. The resulting FVIII solution is 300 to 1,000 times

purified over whole plasma.

6. Formulation. The purified AHF solution is collected and diluted, as needed, for

filtration and filling. Pasteurized Albumin (Human), USP, which is often used to

stabilize plasma-derived and recombinant proteins in pharmaceutical

preparations, is added to preserve AHF activity.

7. Sterile Filtration. The solution is passed through a sterilizing filter to remove any

bacterial contaminants.

8. Filling. The solution is dispensed aseptically into the final vial.

9. Freeze Drying. Vials containing the final AHF formulation are freeze-dried

and stoppered.

10. Dry Heat Treatment. The final freeze-dried product is then heated at 80˚C

for 72 hours. The second viral inactivation step, the combined freeze dry/

dry heat treatment (steps 9 and 10), inactivates many enveloped and

non-enveloped viruses.

MANUFACTURE OF KOATE®-DVI,ANTIHEMOPHILICFACTOR (HUMAN)

Koate®-DVI is a FVIII concentrate

for the treatment of hemophilia A.

The product is prepared from

human plasma from healthy

donors collected at FDA-licensed

commercial plasma centers that

meet Talecris’ specifications.

Individual units of plasma are

tested, frozen rapidly, and

quarantined for 60 days before

use (60-day Plasma Inventory

Hold and Lookback) as described

in Section 3 (Pathogen Safety).

3

2. MANUFACTURE OF KOATE®-DVI ,ANTIHEMOPHILIC FACTOR (HUMAN)

Two Independent Viral Inactivation Steps:

Solvent/Detergent Step1, 2

Disrupts the viral lipid coat and inactivates enveloped viruses such as HIV and

hepatitis B and C viruses.

Freeze Dry/Dry Heat Treatment Step1, 2

Freeze drying followed by 80˚C 72-hour heating under controlled moisture conditions

denatures virus proteins and inactivates enveloped and non-enveloped viruses such as

parvovirus B19 and hepatitis A virus.

Figure 3

1. Horowitz et al. Viral safety of solvent/detergent-treated blood products. Blood Coagulation and Fibrinolysis.1994; 5 (suppl 3): 21-28.

2. Horowitz et al. Inactivation of lipid-enveloped viruses by tri (n-butyl) phosphate detergent combination.Transfusion. 1985; 25:516-522.







4

Inventory Hold and Lookback

Adsorption and Precipitation

Koate®-DVI

The use of plasma products is not without risk. Human plasma may contain

pathogenic agents capable of transmitting Acquired Immunodeficiency Disease

Syndrome (AIDS), CJD, hepatitis and other diseases. In order to ensure the safety of

Koate®-DVI and minimize the risk from pathogen contamination, Talecris has

implemented a multi-layered system of overlapping safety measures that include

Plasma Donor Screening and Selection, Plasma Donation Testing, Plasma Inventory

Hold and Lookback, Plasma Manufacturing Pool Testing, and Validated Viral Reduction

Steps within the Manufacturing Process.

PLASMA DONOR SCREENING AND SELECTION

The viral safety of Koate®-DVI begins with high-quality source material: carefully

screened and tested human plasma collected exclusively from approved plasma

suppliers in the USA. All plasma suppliers must be US FDA-licensed collection centers

with Clinical Laboratory Improvement Amendments (CLIA) certification, Plasma Protein

Therapeutics Association (PPTA) certification, and International Quality Plasma Program

(IQPP) certification. The centers must be regularly inspected and deemed acceptable

by the US FDA, US Department of Health and Human Services Health Care Finance

Administration (HCFA), and other federal, state and local authorities as required.

In addition, all facilities, procedures and records at each center must be inspected

regularly by Talecris Quality Operations (QO).

Talecris enforces careful plasma donor qualification and screening standards at every

point in the plasma procurement process that includes identification and residency

checks, a detailed medical history, and a physical examination. During the screening

interview, very specific and direct questions are asked about risk factors and donors

who are unsuitable to donate plasma are excluded at this step. In accordance with

current US FDA regulatory requirements3 to reduce the theoretical risk of transmission

of transmissible spongiform encephalopathies (TSE), such as Creutzfeldt-Jakob

disease (CJD), the following prospective donors are excluded from donating plasma:

donors who have been diagnosed with variant CJD or any other form of CJD, donors

at increased risk for CJD (e.g., family history), donors at potential risk for CJD

(e.g., residence in the UK for no less than three months during 1980 to 1996), donors

who received blood transfusions in the UK and donors who have injected bovine

insulin since 1980.

3. Guidance for Industry, Revised Preventive Measures to Reduce the Possible Risk of Transmission ofCreutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and BloodProducts, January 2002

PLASMA TESTINGPlasma testing must be performed

by a testing facility that meets

all regulatory and licensing

requirements and has been

pre-approved by Talecris.

In addition, plasma intended for

use by Talecris must meet the

following virus safety criteria:

5

3. PATHOGEN SAFETY

Test Type Test Requirement

HBsAg Non-reactive

Anti-HIV-1/2 Non-reactive

Anti-HCV Non-reactive

HCV NAT Negative

HIV-1 NAT Negative

HBV NAT Negative

Parvovirus B19 NAT Non-elevated

PLASMA DONATION TESTING

Only plasma units from qualified repeat donors are used. To become qualified, all

applicant donors must have two consecutive acceptable sets of viral marker test

results and screening interviews within a period of six months. If an applicant donor

does not return within six months, his or her unit of plasma is destroyed, regardless

of test results, and any qualified donor who has donated at a different center or has

allowed more than six months to elapse before donating must be re-qualified.

Each plasma donation must undergo serological testing and must be found non-

reactive or negative for antibodies against human immunodeficiency virus types 1 or 2

(anti-HIV-1/2) and hepatitis C virus (anti-HCV) and non-reactive for hepatitis B virus

surface antigen (HBsAg). Because it takes time for a body to develop antibodies in

response to a viral infection and time for virus particles to reach concentrations that

are high enough to be detected by conventional serological methods, testing by nucleic

acid technologies (NAT) is also performed. NAT tests have significantly improved the

safety of plasma-derived products by enabling reliable, early, direct detection of

minute concentrations of pathogens in plasma and are performed to detect HBV, HCV

and HIV and elevated levels of parvovirus B19. During the tests, selected regions of

viral genetic material are amplified and, because NAT is so sensitive, testing can be

performed in a mini-pool format rather than on each individual unit of plasma.

Plasma donors testing positive/reactive for HBsAg, anti-HIV-1/2, anti-HCV, HBV by NAT,

HCV by NAT or HIV-1 by NAT are notified, permanently deferred from donating plasma,

and entered into the National Donor Deferral Registry (NDDR). The NDDR is a

centralized database, maintained by the American Blood Resources Association, which

lists all plasma donors in North America who have been permanently rejected due to

viral testing. All potential donors must be checked against the registry to prevent the

use of units from deferred donors. Because of the nature of parvovirus B19 infections,

the notification and deferral of plasma donors with elevated B19 NAT test results

would provide little or no public health benefit and, therefore, are not performed.







6

PLASMA INVENTORY HOLD AND LOOKBACK

Each plasma unit is assigned a unique identification number and all documentation

that accompanies the unit (e.g., viral marker and NAT test results) must contain this

unique identifier. As a result, there is complete traceability of every single plasma unit.

Each unit of plasma is held in inventory for at least 60 days to ensure they have been

tested and donation records have been verified. This also allows time to see if donors

develop any infections since they donated the plasma. If new information on a donor’s

health status becomes available or if any potential problems are identified, a lookback

procedure is initiated to trace and destroy previous donations from that individual.

PLASMA MANUFACTURING POOL TESTING

All acceptable units are pooled at the manufacturing facility and then a second round

of viral marker and NAT testing is performed on the plasma manufacturing pool. The

only pools that are further processed are those that test negative/non-reactive for

HBsAg, anti-HIV-1/2, anti-HCV, HBV by NAT, HCV by NAT, HIV-1 by NAT and are non-

elevated for parvovirus B19 by NAT. Thus, only the highest-quality plasma is used in

producing Koate®-DVI.

PATHOGEN REMOVAL AND INACTIVATION

DURING KOATE®-DVI MANUFACTURING

The safety of Koate®-DVI is further enhanced by the incorporation of virus inactivation/

removal steps into the manufacturing process. Studies to evaluate various steps of the

manufacturing process for their capacity to clear pathogens have been conducted in

accordance with regulatory guidelines4, 5.

The steps investigated in the Koate®-DVI production process were:

1. Removal of cryoprecipitate from thawed pooled plasma (“cryo removal”)

2. Aluminum hydroxide adsorption and polyethylene glycol precipitation of

solubilized cryoprecipitate (“adsorption + precipitation”)

3. Treatment of soluble AHF with TNBP/polysorbate 80 (“solvent/detergent”)

4. Freeze drying, followed by 72 hours 80˚C dry heat treatment of AHF

4. CPMP Note for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of StudiesValidating the Inactivation and Removal of Viruses. CPMP/BWP/268/95 (1996).

5. CPMP Note for Guidance on Plasma-derived Medicinal Products. CPMP/BWP/269/95 rev. 3 (2001).

7

CJD clearance, using an experimental model agent of TSE, was investigated. These

studies provide reasonable assurance that low levels of CJD/variant CJD infectivity, if

present in plasma, would be reduced during the Koate®-DVI manufacturing process6.

The Koate®-DVI viral validation studies were performed using relevant or model

viruses. HIV-1 and hepatitis A virus (HAV) were chosen as relevant blood-borne

pathogens, while bovine viral diarrhea (BVDV) and porcine parvovirus (PPV) were

chosen to model HCV and human parvovirus B19, respectively. Pseudorabies virus

(PRV) was used as a surrogate for HBV and the human herpes viruses. Vesicular

stomatitis virus (VSV) was utilized as an additional model enveloped virus and Reovirus

type 3 (Reo) was included as another model non-enveloped virus. As shown in Table 1

on page 11, the viruses used in the studies were very different in their structure and

composition and represented a wide range of physico-chemical challenges to the

manufacturing process.

Table 2 on page 12 shows the viral reduction of each test virus across the individual

manufacturing steps7. The greatest reduction in virus load was achieved by the two

very different inactivation steps, steps 3 and 4, with approximately 4 log10 or more

reduction obtained per step for each virus. Having multiple steps with independent

mechanisms of viral reduction improves safety because viruses that survive one step

would be less likely to survive a subsequent step and a single step with a large effect

(e.g., 4 log10 virus reduction) should provide more safety than several less effective

steps. The overall reduction in virus infectivity was used as a measure of the virus

reduction capacity of the manufacturing process and was calculated by adding all

individual reduction factors that were greater than 1 log10 and that employed different

mechanisms of viral reduction8. The data shows that the Koate®-DVI manufacturing

process is capable of reducing a variety of viral challenges from both enveloped

and non-enveloped viruses and provides a high margin of safety against the risk

of viral transmission.







8

POST-MARKET SURVEILLANCE

Although the safety of plasma-derived products is achieved using a controlled,

step-by-step process, the ultimate proof of product safety comes from a consistent

record of safe use.

In 1989, Koate®-HP, Antihemophilic Factor (Human), a plasma-derived AHF product

which incorporated a solvent/detergent treatment step in its manufacturing process,

was introduced. A second viral inactivation step (freeze dry/80˚C dry heat treatment)

was added to the manufacturing process for Koate®-HP to develop Koate®-DVI (double

viral inactivation) and to provide an even greater margin of safety. History has shown

that the removal by adsorption and precipitation and the double viral inactivation by

solvent/detergent and by freeze dry/80˚C dry heat are capable of removing a variety of

challenges. Over 2 billion IUs of Koate®-DVI and Koate®-HP have been used throughout

the world without any confirmed transmission of HBV, HCV, HIV or TSE6, 9.

As with all plasma-derived therapeutics, the potential to transmit infectious agents

cannot be totally eliminated. 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. Hepatitis B vaccination is essential for patients

with hemophilia A; vaccination is recommended at birth or at the time of diagnosis.

Hepatitis A vaccination is also recommended for hemophilia patients who are hepatitis

A seronegative. Please see accompanying Koate®-DVI Full Prescribing Information.

6. Data on File, Antihemophilic Factor (Human), Assessment of SE Safety. T.02.61-04, valid from 11/21/05.

7. Data on file, Antihemophilic Factor (Human), Clearance Potential of the Purification for Viruses. T.20.31-03,valid from 05/03/01.

8. 1994. Joint Announcement of the Federal Health Agency and the Paul Ehrlich Institute Federal Office forSera and Vaccines: Requirements for Validation Studies to Demonstrate the Virus Safety of Drugs Derivedfrom Human Blood or Plasma. Federal Gazette 84:1-11.

9. Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack oftransmission of hepatitis B and C viruses and HIV type 1. Transfusion 1999; 39: 1160-1168.

9

Solvent/Detergent Treatment Step Destroys Viral Infectivity

• Chemical process that disrupts the lipid envelope structure and removes the

receptor proteins that are critical for virus attachment to the host cell

• Enveloped viruses such as HIV, HBV and HCV are rendered non-infectious

Freeze Dry/Dry Heat Treatment Step Inactivates Viruses

• Freeze dry/80˚C dry heat treatment for 72 hours with moisture control denatures

critical viral proteins

• Enveloped viruses (e.g., HIV, HBV, HCV) and non-enveloped viruses (e.g., parvovirus

B19, HAV) are inactivated







10

• Enveloped Virus • Solvent Detergent step disruptsthe viral lipid coat and inactivatesenveloped viruses

• Enveloped and non-envelopedviruses

• Heat Treatment inactivatesenveloped and non-envelopedviruses

Viral DNAor RNA

Lipid envelope

Receptorbinding proteins

Protein spikes

Viral DNA or RNA

Characteristics of Viruses used in Viral Validation Studies

Table 1

Table 1 shows that the viruses used in viral validation studies vary greatly in their

structure and composition. Demonstrating effective removal/inactivation of such a

diverse panel of viruses provides assurance that the manufacturing process is capable

of clearing any unknown or emerging pathogen that could potentially contaminate the

plasma pools.

11

VIRUS*

Model for:

Genome

Enveloped

Size/Diameter, nm

Resistance tophysicochemicaltreatment

HIV: Human Immunodeficiency VirusBVDV: Bovine Viral Diarrhea VirusPRV: Pseudorabies VirusVSV: Vesicular Stomatitis VirusReo: Reovirus Type 3HAV: Hepatitis A VirusPPV: Porcine Parvovirus

HCV: Hepatitis C VirusHBV: Hepatitis B VirusCMV: CytomegalovirusHSV: Herpes Virus*Viruses recommended by the European Agency for the Evaluation of Medicinal Products (CPMP/BWP/268/95)

C

HIV-1

HIV-1,HIV-2

RNA

yes

80–100

low

BVDV

HCV

RNA

yes

40–60

low

PRV

HBV, CMV,Epstein-Barr

virus,HHV-1, 2, 6, 7

DNA

yes

120–200

medium

VSV

Envelopedviruses

RNA

yes

45–100

medium

Reo

Non-enveloped

viruses

RNA

no

60–80

high

HAV

HAV

RNA

no

27–30

high

PPV

Parvo B19

DNA

no

18–26

very high

Viral Reduction Factors (log10) for Koate®-DVI Production Process

Table 2

Table 2 shows that the manufacturing process is capable of reducing a variety of viral

challenges by both enveloped and non-enveloped viruses. Therefore, the Koate®-DVI

manufacturing process provides a reasonable margin of safety against the risk of viral

transmission. It is relevant to emphasize again that viral reduction and inactivation

steps have been incorporated into the manufacturing process as added safety

procedures. Virus safety begins with careful donor screening, plasma testing and

plasma hold measures to minimize the risk of infectious agents from entering the

plasma pool prior to fractionation and product manufacture.







12

PURIFICATION STEP

Cryo removal

Adsorption + Precipitation

Solvent/Detergent

Freeze Dry/80˚C Dry Heat

Global Reduction Factor*

V

HIV-1

N/S

N/S

4.1

5.3

9.4

BVDV

0.0

0.2

5.3

5.0

10.3

PRV

1.1

0.4

4.5

3.9

9.5

VSV

N/S

N/S

4.9

6.0

10.9

Reo

1.0

2.7

N/A

5.3

9.0

HAV

N/S

N/S

N/A

4.5

4.5

PPV

N/S

N/S

N/A

3.7

3.7

N/S – Not StudiedN/A – Not Applicable

*Only steps that employ different mechanisms of viral reduction may be added. Steps that provide less than 1 log10 reduction are not included in calculating the global reduction factor.

COMPOSITION AND CLOTTING ACTIVITY

When reconstituted as directed, Koate®-DVI, Antihemophilic Factor (Human), contains

approximately 50-150 times as much factor VIII as an equal volume of fresh plasma.

Each bottle 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 1.0 mL of fresh-pooled human plasma. Each lot of Koate®-DVI is tested for

AHF activity using the aPTT coagulation assay. This test measures the ability of

Koate®-DVI to correct clotting time in factor VIII-deficient human plasma.

The final product also contains inert additives to facilitate solubility, freeze-drying and

stabilization. When reconstituted as directed, each vial contains NMT (not more than)

1,500 ppm polyethylene glycol (PEG), NMT 0.05 M glycine, NMT 25 ppm polysorbate

80, NMT 5 ppm tri-n-butyl phosphate (TNBP), NMT 3mM calcium chloride, NMT

1mg/mL aluminum, NMT 0.06 M histidine and NMT 10 mg/ML Albumin (Human).

SPECIFIC ACTIVITY

Specific activity refers to the quantity of the desired protein as a fraction of total

protein in a mixture. In the case of factor VIII products, specific activity is referred to as

“purity” and is measured as the amount of clotting activity per mg of total protein in

the product. The Koate®-DVI production process includes multiple steps that remove

extraneous non-AHF proteins, including acid precipitation, adsorption with Al(OH)3, and

polyethylene glycol (PEG) precipitation. In addition, the AHF is gel-filtered to achieve an

approximate one hundred-fold purification of FVIII from the starting cryoprecipitate.

Since AHF is a reactive protein, prone to protease degradation, Albumin (Human) USP

is added back to the formulation before freeze-drying. Albumin has been used routinely

as a stabilizer for both native and recombinant proteins in pharmaceutical preparations.

The specific activity of Koate®-DVI was studied at various stages throughout the

production process. Average values for the starting material, the purified concentrate

before albumin addition, and the final heat-treated vial are shown in Table 3. The

average specific activity of Koate®-DVI prior to albumin addition is close to 50 IU/mg protein.

Specific Activity Through the Koate®-DVI Production Process

Table 3

PURITY AND SAFETY“Purity,” in the context of

coagulation concentrates, refers to

specific activity or the percentage

of the desired protein relative to

other proteins present. A solution

containing only FVIII is termed

“high purity,” while natural, whole

human blood with appropriate

concentrations of plasma proteins

would be considered very low

purity. Therefore “purity” is a

measure of protein concentration

and not a measure of safety.

The purity of FVIII concentrate is

related to its production process.

13

4. PRODUCT CHARACTERISTICS

Process Step

Cryo suspension (n=31)

Concentrate beforealbumin addition (n=4)

Final product (n=6)

S

Potency IU/mL

17.1 +/- 1.32

280.29 +/- 93.25

117 +/- 7.87

Specific ActivityIU/mg Protein

0.70 +/- 0.18

48.36 +/- 6.58

15.67 +/- 0.90

PROTEIN COMPOSITION

Of greater importance than the specific activity or the total concentration of protein

in Koate®-DVI is the nature of the non-AHF proteins. Data on the protein composition

of the cryo suspension starting material and the Koate®-DVI final product, assayed

by immunonephelometry, are shown in Table 4. This study demonstrates the very

substantial removal of non-AHF plasma proteins during the production process.

Non-AHF proteins in Koate®-DVI are primarily Albumin (Human) and a trace of

fibronectin. Other plasma proteins are below detection limits.

Protein Composition (IU/mg) Through the Koate®-DVI Production Process

Table 4

STORAGE

Koate®-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 six months, such as in-home

treatment situations, may be done without loss of factor VIII activity. Freezing should

be avoided.

Reconstituted concentrate should not be refrigerated and should be infused within

three hours after reconstitution.

14







Protein

A-1 Apolipoprotein

Albumin

Alpha1-acid glycoprotein

Alpha1-antitrypsin

ATIII

Ceruloplasmin

Fibrinogen

Fibronectin

Haptoglobin

IgA

IgE (IU/ml)

IgG

IgM

Transferrin

CryoSuspension

0.34

4.02

0.50

0.42

0.64

0.38

16.54

6.65

0.39

0.74

98.60

2.66

1.75

0.55

FinalProduct

ND*

5.27

ND*

ND*

ND*

ND*

ND*

0.05

ND*

ND*

ND*

ND*

ND*

ND*

DetectionLimit

0.05

0.02

0.05

0.03

0.03

0.02

0.15

0.02

0.07

0.07

1.68

0.004

0.05

0.08*ND = not detected

PHARMACOKINETICS

Nineteen hemophilia subjects, of which eighteen had 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 the corresponding activated Partial Thromboplastin Time (aPTT) levels

were obtained at prescribed intervals over a 48-hour period after each infusion.

Dosages ranged between 44.8 and 55.1 IU/kg. Mean biologic half-life of Koate®-DVI

was 16.12 hours.

In a second study after the first pharmacokinetics study, Koate®-DVI was administered

to 17 HIV-negative patients with severe hemophilia A (<2% FVIII) as prophylaxis for

bleeding episodes over a six-month period. Fifteen of the 17 patients had fewer than

10 bleeding episodes. In a total of 158 bleeding episodes, 137 (86.7%) required no

more than one or two treatments. Of the 69 adverse events observed in the course

of 972 infusions administered, only one 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.

TREATMENT OF BLEEDING EPISODES

Nineteen previously treated subjects with severe hemophilia A, 18 of whom had

participated in the pharmacokinetic study described above plus one other subject,

were provided with Koate®-DVI as their sole AHF source of home therapy for a

period of six 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 six-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-minute FVIII recovery study, hematologic tests, and

serum chemistry test, and a Bethesda assay for inhibitor detection. At the end of the

study, a 48-hour pharmacokinetic study with Koate®-DVI was repeated, along with

clinical and lab studies.

CLINICAL STUDIESThere 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.

15

5. CLINICAL STUDIES

Over the study period, the 19 subjects experienced 152 bleeding episodes (Figure 4).

A single treatment was effective in over 90% of bleeding episodes, and two 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 1,053 infusions. Only 10 of

the adverse reactions, related to seven infusions, were considered to be related to

Koate®-DVI, and all were mild. Koate®-DVI, therefore, provides an effective and safe

treatment for bleeding episodes.

Treatment of Bleeding Episodes with Koate®-DVI

Figure 4

NEOANTIGENICITY

No evidence of inhibitor formation was observed in 19 previously treated patients

after approximately 50 treatment days in the study described above. 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 incidence of FVIII inhibitor formation. von Willebrand factor may play a

role in reducing the risk of inhibitor formation.10, 11

10. Goudemand et al. Influence of the type factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with Hemophilia A. Blood. 2006; 107:46-51.

11. Gringeri et al. Occurrence of inhibitors in previously untreated or minimally treated patients withhaemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate.Haemophilia. 2006; 12:128-132.







16

1

90.1%

150

120

90

60

30

02

6.6%

3

0.7%

Number of Treatments Required

MildModerateSevere

Num

ber

ofEp

isod

es

4

1.3%

4+

1.3%

Each bottle of Koate®-DVI has the AHF(H) 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. The product must

be administered within three 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 Koate®-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 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 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, 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 FVIII concentrate administered frequently on a predetermined

schedule may result in eradication of the FVIII inhibitor. Consultation with a

hemophilia expert experienced with the management of immune tolerance

regimens is also advisable.

DOSING ANDADMINISTRATION

Each bottle of Koate®-DVI has the

AHF(H) 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. The product must be

administered within three hours

after reconstitution.

17

6. DOSING AND ADMINISTRATION

Administration is ConvenientApproximate Factor VIII

• Available in single-dose bottles

• Administer intravenously within three hours after reconstitution

• Administration in 5-10 minutes is generally well-tolerated

– Rate of administration should be adapted to the individual

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.12, and is illustrated in

the following examples:

• Dosage 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

Dosage Based on Severity of Bleeding

• Dosage varies based on severity of the deficiency and severity of the hemorrhage

12. Abildgaard et al. Treatment of hemophilia with glycine-precipitated factor VIII. N Engl J Med275(9):471–5, 1966.







18

Expected % factor VIII increase

Example for a 70 kg adult:

Dosage required (IU)

Example for a 15 kg child:

40%

750 IU required

1400 IU x 2%/IU/kg70 kg

15 kg x 100%2%/IU/kg

=

=

=

=

or

# units administered x 2%/IU/kgbody weight (kg)

body weight (kg) x desired % factor VIII increase2%/IU/kg

Mild Hemorrhage

Moderate Hemorrage

Severe Hemorrage

Dosage

10 IU/kg

15-25 IU/kg

40-50 IU/kg

Rise in Factor

20%

30-50%

80-100%

Maintenance

Single Dose

10-15 IU/kg every 8-12 hours

20-25 IU/kg every 8-12 hours

NDC Number

13533-0665-20

13533-0665-30

13533-0665-50

Activity

250 IU

500 IU

1000 IU

Diluent

5 mL

5 mL

10 mL

A

Talecris Biotherapeutics, Inc.Post Office Box 1105264101 Research Commons79T.W. Alexander DriveResearch Triangle Park, NC 27709

Visit our website at www.KoateDVI.comfor more information about Talecris and how Koate®-DVI can help you.

Contact our representatives to find out how we can serve your needs and earn your trust.

For customer service,call: 1-800-243-4153.For clinical and technical information,call: 1-800-520-2807 oremail: [email protected].

A new approach to a proud history of patient care.

For customer service,

call: 1-800-243-4153.

For clinical and

technical information,

call: 1-800-520-2807 or

email: [email protected].

www.KoateDVI.com

©2006 Talecris Biotherapeutics, Inc. All rights reserved. Printed in USA June 2006 KD11-0606

Talecris is a leader in pathogen safety, specializing in

plasma-derived therapies.

Koate®-DVI (Double Viral Inactivation)

Trusted by patients worldwide, more than 2 billion IUs have

been infused with no confirmed cases of viral transmission.*

Koate®-DVI – effective treatment, commitment to supply.

As with all plasma-derived therapeutics, the potential to transmit

infectious agents cannot be totally eliminated. Please see

accompanying Koate®-DVI Full Prescribing Information.

* Koate®-DVI and Koate®-HP

product monograph - jeff traister · plasma. the resulting injection volume is small,allowing...

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