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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) . . . . . . Page 3
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
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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.
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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.
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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.
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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.
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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.
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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.
As with all plasma-derived
therapeutics, the potential to
transmit infectious agents cannot
be totally eliminated. Please see
accompanying Koate®-DVI
Full Prescribing Information.
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