ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
KOGENATE Bayer 250 IU powder and solvent for solution for injection.
2.
2.1 General description
Each vial contains nominally 250 IU human coagulation factor VIII (octocog alfa).
Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster
kidney cells containing the human factor VIII gene.
2.2 Qualitative and quantitative composition
One ml of KOGENATE Bayer contains approximately 100 IU (250 IU / 2.5 ml) of human coagulation
factor VIII (octocog alfa) after reconstitution.
The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard
which was calibrated against WHO standard in International Units (IU).
The specific activity of KOGENATE Bayer is approximately 4000 IU/mg protein.
Solvent: water for injections.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
Powder: dry white to slightly yellow powder or cake.
Solvent: water for injection, a clear, colourless solution.
The reconstituted medicinal product is a clear and colourless solution.
4.
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII
deficiency).
This preparation does not contain von Willebrand factor and is therefore not indicated in von
Willebrand's disease.
Treatment should be initiated under the supervision of a physician experienced in the treatment of
haemophilia.
Posology
The number of units of factor VIII administered is expressed in International Units (IU), which are
related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is
expressed either as a percentage (relative to normal human plasma) or in International Units (relative
to the International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII
activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation
2
of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU)
factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal
activity. The required dose is determined using the following formulae:
I.
Required IU = body weight (kg) × desired factor VIII rise (% of normal) × 0.5
II. Expected factor VIII rise (% of normal) =
2 × administered IU
body weight (kg)
On demand treatment
The dose, frequency and duration of the substitution therapy must be individualised according to the
patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the
bleeding, the presence of inhibitors, and the factor VIII level desired).
The following table provides a guide for factor VIII minimum blood levels. In the case of the
haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of
normal) in the corresponding period:
Degree of haemorrhage/
Type of surgical procedure
Factor VIII level
required (%) (IU/dl)
Frequency of doses (hours)/
Duration of therapy (days)
Haemorrhage
20 - 40
Early haemarthrosis, muscle
bleed or oral bleed
Repeat every 12 to 24 hours. At
least 1 day, until the bleeding
episode as indicated by pain is
resolved or healing is achieved.
More extensive haemarthrosis,
muscle bleed or haematoma
30 - 60
Repeat infusion every 12 - 24 hours
for 3 - 4 days or more until pain and
disability are resolved.
Life threatening bleeds such as
intracranial bleed, throat bleed,
severe abdominal bleed
60 - 100
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
30 - 60
Minor
including tooth extraction
Every 24 hours, at least 1 day, until
healing is achieved.
Major
80 - 100
(pre- and
postoperative)
a) By bolus infusions
Repeat infusion every 8 - 24 hours
until adequate wound healing
occurs, then continue with therapy
for at least another 7 days to
maintain a factor VIII activity of
30% to 60%
b) By continuous infusion
Raise factor VIII activity pre-
surgery with an initial bolus
infusion and immediately follow
with continuous infusion (in
IU/Kg/h) adjusting according to
patient’s daily clearance and desired
factor VIII levels for at least 7 days.
The amount to be administered and the frequency of administration should always be adapted
according to the clinical effectiveness in the individual case. Under certain circumstances larger
amounts than those calculated may be required, especially in the case of the initial dose.
3
During the course of treatment, appropriate determination of factor VIII levels is advised in order to
guide the dose to be administered and the frequency at which to repeat the infusions. In the case of
major surgical interventions in particular, precise monitoring of the substitution therapy by means of
coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in
their response to factor VIII, achieving different levels of
in vivo
recovery and demonstrating different
half-lives.
Continuous Infusion
It has been shown in a clinical study performed with adult haemophilia A patients who undergo a
major surgery that KOGENATE Bayer can be used for continuous infusion in surgeries (pre-, during
and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as
with any other long term intravenous infusions. For the calculation of the initial infusion rate,
clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average
population value (3.0-3.5 ml/h/kg) and then adjust accordingly.
Infusion rate (in IU/kg/h) = Clearance (in ml/h/kg) × desired factor VIII level (in IU/ml)
For continuous infusion, clinical and
in vitro
stability has been demonstrated using ambulatory pumps
with a PVC reservoir. KOGENATE Bayer contains low level of polysorbate-80 as an excipient, which
is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride
(PVC) materials. This should be considered for a continuous infusion administration.
Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are
20 to 40 IU of KOGENATE Bayer per kg body weight at intervals of 2 to 3 days.
In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.
Paediatric population
Data have been obtained from clinical studies in 61 children under 6 years of age and non-
interventional studies in children of all ages.
Patients with inhibitors
Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma
factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an
assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at
levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation
factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with
KOGENATE Bayer. However, in the presence of an inhibitor the doses required are variable and must
be adjusted according to clinical response and monitoring of plasma factor VIII activity. In patients
with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin
complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be
considered. These therapies should be directed by physicians with experience in the care of patients
with haemophilia.
Method of administration
For intravenous use.
KOGENATE Bayer should be injected intravenously over several minutes. The rate of administration
should be determined by the patient’s comfort level (maximal rate of infusion: 2 ml/min).
Continuous infusion
KOGENATE Bayer can be infused by continuous infusion. The infusion rate should be calculated
based on the clearance and the desired FVIII level.
Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg
to achieve a FVIII level of 100%. For calculation of ml/hour, multiply infusion rate in IU/h/kg by kg
bw/concentration of solution (IU/ml).
4
Example for calculation of infusion rate for continous infusion after initial bolus injection
Desired plasma
FVIII level
Infusion rate
IU/h/kg
Infusion rate for 75 kg patient
ml/h
Clearance:
3 ml/h/kg
Concentrations of rFVIII solution
100 IU/ml 200 IU/ml 400 IU/ml
100 % (1 IU/ml)
3.0
2.25 1.125 0.56
60 % (0.6 IU/ml)
1.8
1.35 0.68 0.34
40 % (0.4 IU/ml)
1.2
0.9 0.45 0.225
Higher infusion rates may be required in conditions with accelerated clearance during major bleedings
or extensive tissue damage during surgical interventions.
After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using
the steady state equation with the measured FVIII level and the rate of infusion using the following
equation:
clearance = infusion rate/actual FVIII level.
During continuous infusion, infusion bags should be changed every 24 hours.
For instructions on reconstitution of the medicinal product before administration, see section 6.6 and
the package leaflet.
-
Known hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity reactions
As with any intravenous protein product, allergic type hypersensitivity reactions are possible.
Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild
hypotension and nausea during infusion can constitute an early warning for hypersensitivity and
anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as
appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped
immediately and the patient should contact their physician
.
In case of shock, the current medical
standards for shock treatment should be observed.
Antibodies (inhibitors)
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the
management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins
directed against the factor VIII procoagulant activity, which are quantified in Modified Bethesda Units
(BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-
haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20
exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant
factor VIII product to another in previously treated patients with more than 100 exposure days who
have a history of inhibitor development.
Patients treated with recombinant coagulation factor VIII should be carefully monitored for the
development of inhibitors by appropriate clinical observations and laboratory tests. (see also section
4.8)
Continuous infusion
In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent
thrombophlebitis at the infusion site as with any other long term intravenous infusions.
5
-
Known allergic reactions to mouse or hamster protein.
Registration
In the interest of the patients, it is recommended that, whenever possible, every time that KOGENATE
Bayer is administered to them, the name and the batch number of the product is registered.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium
free”.
No interactions of KOGENATE Bayer with other medicinal products are known.
Animal reproduction studies have not been conducted with KOGENATE Bayer.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of
KOGENATE Bayer during pregnancy and breast-feeding is not available. Therefore, KOGENATE
Bayer should be used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
KOGENATE Bayer has no influence on the ability to drive or to use machines.
The most commonly reported adverse drug reaction occurring is the formation of neutralising
antibodies (prevalent in previously untreated or minimally treated patients).
The frequencies of adverse reactions reported with KOGENATE Bayer are summarized in the table
below. Within each frequency group, undesirable effects are presented in order of decreasing
seriousness. Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon
(≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).
MeDRa Standard
System Organ Class
Common
Uncommon
Rare
Blood and the
Lymphatic System
Disorders
Inhibitor
Formation to
FVIII
(Reported in PUP
and minimally
treated patients in
clinical trials)*
Inhibitor
Formation to
FVIII
(Reported in
PTP in clinical
trials and Post
Marketing
Studies)
*
General Disorders and
Administration Site
Conditions
Infusion site
reaction
Infusion related febrile reaction
(pyrexia)
Immune System
Disorders
Skin associated
hypersensitivity
reactions,
(pruritus, urticaria
and rash)
Systemic Hypersensitivity
reactions (including one
anaphylactic reaction, nausea,
blood pressure abnormal and,
dizziness)
* see section below
6
Description of selected adverse reactions
The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the
management of individuals with haemophilia A. In studies with recombinant factor VIII preparations,
development of inhibitors is predominantly observed in previously untreated haemophiliacs. Patients
should be carefully monitored for the development of inhibitors by appropriate clinical observations
and laboratory tests.
In clinical studies, KOGENATE Bayer has been used in the treatment of bleeding episodes in 37
previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as
having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP
patients treated with KOGENATE Bayer developed inhibitors: Overall, 9 out of 60 (15%) developed
inhibitors, 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU.
The median number of exposure days at the time of inhibitor detection in these patients was 9 days
(range 3 - 18 days).
The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five
patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more
than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The
fifth patient was lost to follow-up.
In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure
days), followed over four years, no de-novo inhibitors were observed.
In extensive post-registration studies with KOGENATE Bayer, involving more than 1000 patients the
following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as
having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.
During studies, no patient developed clinically relevant antibody titres against the trace amounts of
mouse protein and hamster protein present in the preparation. However, the possibility of allergic
reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in
certain predisposed patients (see section 4.3 and 4.4).
No case of overdose with recombinant coagulation factor VIII has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.
The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and
vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII
binds to vWF in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor
IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts
prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of
factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either
spontaneously or as a results of accidental or surgical trauma. By replacement therapy the plasma
levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency
and correction of the bleeding tendencies.
Determination of activated partial thromboplastin time (aPTT) is a conventional
in vitro
assay method
for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree and
7
duration of aPTT normalisation observed after administration of KOGENATE Bayer is similar to that
achieved with plasma-derived factor VIII.
5.2 Pharmacokinetic properties
The analysis of all recorded
in vivo
recoveries in previously treated patients demonstrated a mean rise
of 2 % per IU/kg body weight for KOGENATE Bayer. This result is similar to the reported values for
factor VIII derived from human plasma.
After administration of KOGENATE Bayer, peak factor VIII activity decreased by a two-phase
exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-
derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional
pharmacokinetic parameters for KOGENATE Bayer for bolus injection are: mean residence time
[MRT (0-48)] of about 22 hours and clearance of about 160 ml/h. Mean baseline clearance for 14 adult
patients undergoing major surgeries with continuous infusion are 188 ml/h corresponding to 3.0
ml/h/kg (range 1.6-4.6 ml/h/kg).
5.3 Preclinical safety data
Even doses several fold higher than the recommended clinical dose (related to body weight) failed to
demonstrate any acute or subacute toxic effects for KOGENATE Bayer in laboratory animals (mouse,
rat, rabbit, and dog).
Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and
carcinogenicity were not performed with octocog alfa due to the immune response to heterologous
proteins in all non-human mammalian species.
No studies were performed on the mutagenic potential of KOGENATE Bayer, since no mutagenic
potential could be detected
in vitro
or
in vivo
for the predecessor product of KOGENATE Bayer.
6.
6.1 List of excipients
Powder
Glycine
Sodium chloride
Calcium chloride
Histidine
Polysorbate 80
Sucrose
Solvent
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6..
Only the provided components (powder vial with Bio-Set device, pre-filled syringe containing solvent
and venipuncture set) should be used for reconstitution and injection because treatment failure can
occur as a consequence of human coagulation factor VIII adsorption to the internal surfaces of some
infusion equipment.
8
6.3 Shelf-life
30 months.
After reconstitution, the product should be used immediately.
However, during
in vitro
studies, the chemical and physical in-use stability has been demonstrated for
24 hours at 30°C in PVC bags for continuous infusion".
Do not refrigerate after reconstitution.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial and the pre-filled syringe in the outer
carton in order to protect from light.
The product when kept in its outer carton may be stored at ambient room temperature (up to 25°C) for
a limited period of 3 months. In this case, the product expires at the end of this 3-month period; the
new expiry date must be noted on the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container and special equipment for use, administration or
implantation
Each package of KOGENATE Bayer contains:
•
one vial plus Bio-Set device, containing powder (10 ml clear glass type 1 vial with latex-free
grey halogenobutyl rubber blend stopper plus transfer device with protective cap [Bio-Set])
•
one pre-filled syringe with 2.5 ml solvent (clear glass cylinder type 1 with latex-free grey
bromobutyl rubber blend stopper)
•
syringe plunger rod
•
two sterile alcohol swabs for single use
•
two dry swabs
•
two plasters
6.6 Special precautions for disposal and other handling
Detailed instructions for preparation and administration are contained in the package leaflet provided
with KOGENATE Bayer.
KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 ml water for
injections) in the prefilled syringe and the integrated transfer device (Bio-Set). Reconstitution should
be performed in accordance with good practices rules, particularly with attention to asepsis. Gently
rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Do not use
KOGENATE Bayer if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn back into the syringe.
Use the provided venipuncture set for intravenous injection.
For continuous infusion, the product must be prepared under aseptic conditions.
For single use only. Any unused solution must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
9
•
one venipuncture set
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/00/143/004
9.
Date of first authorisation: 04 August 2000
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
10
1.
KOGENATE Bayer 500 IU powder and solvent for solution for injection.
2.
2.1 General description
Each vial contains nominally 500 IU human coagulation factor VIII (octocog alfa).
Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster
kidney cells containing the human factor VIII gene.
2.2 Qualitative and quantitative composition
One ml of KOGENATE Bayer contains approximately 200 IU (500 IU / 2.5 ml) of human coagulation
factor VIII (octocog alfa) after reconstitution.
The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard
which was calibrated against WHO standard in International Units (IU).
The specific activity of KOGENATE Bayer is approximately 4000 IU/mg protein.
Solvent: water for injections.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
Powder: dry white to slightly yellow powder or cake.
Solvent: water for injection, a clear, colourless solution.
The reconstituted medicinal product is a clear and colourless solution.
4.
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII
deficiency).
This preparation does not contain von Willebrand factor and is therefore not indicated in von
Willebrand's disease.
Treatment should be initiated under the supervision of a physician experienced in the treatment of
haemophilia.
Posology
The number of units of factor VIII administered is expressed in International Units (IU), which are
related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is
expressed either as a percentage (relative to normal human plasma) or in International Units (relative
to the International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII
activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation
11
of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU)
factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal
activity. The required dose is determined using the following formulae:
I.
Required IU = body weight (kg) × desired factor VIII rise (% of normal) × 0.5
II. Expected factor VIII rise (% of normal) =
2 × administered IU
body weight (kg)
On demand treatment
The dose, frequency and duration of the substitution therapy must be individualised according to the
patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the
bleeding, the presence of inhibitors, and the factor VIII level desired).
The following table provides a guide for factor VIII minimum blood levels. In the case of the
haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of
normal) in the corresponding period:
Degree of haemorrhage/
Type of surgical procedure
Factor VIII level
required (%) (IU/dl)
Frequency of doses (hours)/
Duration of therapy (days)
Haemorrhage
20 - 40
Early haemarthrosis, muscle
bleed or oral bleed
Repeat every 12 to 24 hours. At
least 1 day, until the bleeding
episode as indicated by pain is
resolved or healing is achieved.
More extensive haemarthrosis,
muscle bleed or haematoma
30 - 60
Repeat infusion every 12 - 24 hours
for 3 - 4 days or more until pain and
disability are resolved.
Life threatening bleeds such as
intracranial bleed, throat bleed,
severe abdominal bleed
60 - 100
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
30 - 60
Minor
including tooth extraction
Every 24 hours, at least 1 day, until
healing is achieved.
Major
80 - 100
(pre- and
postoperative)
a) By bolus infusions
Repeat infusion every 8 - 24 hours
until adequate wound healing
occurs, then continue with therapy
for at least another 7 days to
maintain a factor VIII activity of
30% to 60%
b) By continuous infusion
Raise factor VIII activity pre-
surgery with an initial bolus
infusion and immediately follow
with continuous infusion (in
IU/Kg/h) adjusting according to
patient’s daily clearance and desired
factor VIII levels for at least 7 days.
The amount to be administered and the frequency of administration should always be adapted
according to the clinical effectiveness in the individual case. Under certain circumstances larger
amounts than those calculated may be required, especially in the case of the initial dose.
12
During the course of treatment, appropriate determination of factor VIII levels is advised in order to
guide the dose to be administered and the frequency at which to repeat the infusions. In the case of
major surgical interventions in particular, precise monitoring of the substitution therapy by means of
coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in
their response to factor VIII, achieving different levels of
in vivo
recovery and demonstrating different
half-lives.
Continuous Infusion
It has been shown in a clinical study performed with adult haemophilia A patients who undergo a
major surgery that KOGENATE Bayer can be used for continuous infusion in surgeries (pre-, during
and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as
with any other long term intravenous infusions. For the calculation of the initial infusion rate,
clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average
population value (3.0-3.5 ml/h/kg) and then adjust accordingly.
Infusion rate (in IU/kg/h) = Clearance (in ml/h/kg) × desired factor VIII level (in IU/ml)
For continuous infusion, clinical and
in vitro
stability has been demonstrated using ambulatory pumps
with a PVC reservoir. KOGENATE Bayer contains low level of polysorbate-80 as an excipient, which
is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride
(PVC) materials. This should be considered for a continuous infusion administration.
Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are
20 to 40 IU of KOGENATE Bayer per kg body weight at intervals of 2 to 3 days.
In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.
Paediatric population
Data have been obtained from clinical studies in 61 children under 6 years of age and non-
interventional studies in children of all ages.
Patients with inhibitors
Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma
factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an
assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at
levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation
factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with
KOGENATE Bayer. However, in the presence of an inhibitor the doses required are variable and must
be adjusted according to clinical response and monitoring of plasma factor VIII activity. In patients
with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin
complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be
considered. These therapies should be directed by physicians with experience in the care of patients
with haemophilia.
Method of administration
For intravenous use.
KOGENATE Bayer should be injected intravenously over several minutes. The rate of administration
should be determined by the patient’s comfort level (maximal rate of infusion: 2 ml/min).
Continuous infusion
KOGENATE Bayer can be infused by continuous infusion. The infusion rate should be calculated
based on the clearance and the desired FVIII level.
Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg
to achieve a FVIII level of 100%. For calculation of ml/hour, multiply infusion rate in IU/h/kg by kg
bw/concentration of solution (IU/ml).
13
Example for calculation of infusion rate for continous infusion after initial bolus injection
Desired plasma
FVIII level
Infusion rate
IU/h/kg
Infusion rate for 75 kg patient
ml/h
Clearance:
3 ml/h/kg
Concentrations of rFVIII solution
100 IU/ml 200 IU/ml 400 IU/ml
100 % (1 IU/ml)
3.0
2.25 1.125 0.56
60 % (0.6 IU/ml)
1.8
1.35 0.68 0.34
40 % (0.4 IU/ml)
1.2
0.9 0.45 0.225
Higher infusion rates may be required in conditions with accelerated clearance during major bleedings
or extensive tissue damage during surgical interventions.
After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using
the steady state equation with the measured FVIII level and the rate of infusion using the following
equation:
clearance = infusion rate/actual FVIII level.
During continuous infusion, infusion bags should be changed every 24 hours.
For instructions on reconstitution of the medicinal product before administration, see section 6.6 and
the package leaflet.
-
Known hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity reactions
As with any intravenous protein product, allergic type hypersensitivity reactions are possible.
Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild
hypotension and nausea during infusion can constitute an early warning for hypersensitivity and
anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as
appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped
immediately and the patient should contact their physician
.
In case of shock, the current medical
standards for shock treatment should be observed.
Antibodies (inhibitors)
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the
management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins
directed against the factor VIII procoagulant activity, which are quantified in Modified Bethesda Units
(BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-
haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20
exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant
factor VIII product to another in previously treated patients with more than 100 exposure days who
have a history of inhibitor development.
Patients treated with recombinant coagulation factor VIII should be carefully monitored for the
development of inhibitors by appropriate clinical observations and laboratory tests. (see also section
4.8)
Continuous infusion
In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent
thrombophlebitis at the infusion site as with any other long term intravenous infusions.
14
-
Known allergic reactions to mouse or hamster protein.
Registration
In the interest of the patients, it is recommended that, whenever possible, every time that KOGENATE
Bayer is administered to them, the name and the batch number of the product is registered.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium
free”.
No interactions of KOGENATE Bayer with other medicinal products are known.
Animal reproduction studies have not been conducted with KOGENATE Bayer.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of
KOGENATE Bayer during pregnancy and breast-feeding is not available. Therefore, KOGENATE
Bayer should be used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
KOGENATE Bayer has no influence on the ability to drive or to use machines.
The most commonly reported adverse drug reaction occurring is the formation of neutralising
antibodies (prevalent in previously untreated or minimally treated patients).
The frequencies of adverse reactions reported with KOGENATE Bayer are summarized in the table
below. Within each frequency group, undesirable effects are presented in order of decreasing
seriousness. Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon
(≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).
MeDRa Standard
System Organ Class
Common
Uncommon
Rare
Blood and the
Lymphatic System
Disorders
Inhibitor
Formation to
FVIII
(Reported in PUP
and minimally
treated patients in
clinical trials)*
Inhibitor
Formation to
FVIII
(Reported in
PTP in clinical
trials and Post
Marketing
Studies)
*
General Disorders and
Administration Site
Conditions
Infusion site
reaction
Infusion related febrile reaction
(pyrexia)
Immune System
Disorders
Skin associated
hypersensitivity
reactions,
(pruritus, urticaria
and rash)
Systemic Hypersensitivity
reactions (including one
anaphylactic reaction, nausea,
blood pressure abnormal and,
dizziness)
* see section below
15
Description of selected adverse reactions
The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the
management of individuals with haemophilia A. In studies with recombinant factor VIII preparations,
development of inhibitors is predominantly observed in previously untreated haemophiliacs. Patients
should be carefully monitored for the development of inhibitors by appropriate clinical observations
and laboratory tests.
In clinical studies, KOGENATE Bayer has been used in the treatment of bleeding episodes in 37
previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as
having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP
patients treated with KOGENATE Bayer developed inhibitors: Overall, 9 out of 60 (15%) developed
inhibitors, 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU.
The median number of exposure days at the time of inhibitor detection in these patients was 9 days
(range 3 - 18 days).
The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five
patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more
than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The
fifth patient was lost to follow-up.
In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure
days), followed over four years, no de-novo inhibitors were observed.
In extensive post-registration studies with KOGENATE Bayer, involving more than 1000 patients the
following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as
having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.
During studies, no patient developed clinically relevant antibody titres against the trace amounts of
mouse protein and hamster protein present in the preparation. However, the possibility of allergic
reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in
certain predisposed patients (see section 4.3 and 4.4).
No case of overdose with recombinant coagulation factor VIII has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.
The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and
vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII
binds to vWF in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor
IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts
prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of
factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either
spontaneously or as a results of accidental or surgical trauma. By replacement therapy the plasma
levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency
and correction of the bleeding tendencies.
Determination of activated partial thromboplastin time (aPTT) is a conventional
in vitro
assay method
for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree and
16
duration of aPTT normalisation observed after administration of KOGENATE Bayer is similar to that
achieved with plasma-derived factor VIII.
5.2 Pharmacokinetic properties
The analysis of all recorded
in vivo
recoveries in previously treated patients demonstrated a mean rise
of 2 % per IU/kg body weight for KOGENATE Bayer. This result is similar to the reported values for
factor VIII derived from human plasma.
After administration of KOGENATE Bayer, peak factor VIII activity decreased by a two-phase
exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-
derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional
pharmacokinetic parameters for KOGENATE Bayer for bolus injection are: mean residence time
[MRT (0-48)] of about 22 hours and clearance of about 160 ml/h. Mean baseline clearance for 14 adult
patients undergoing major surgeries with continuous infusion are 188 ml/h corresponding to 3.0
ml/h/kg (range 1.6-4.6 ml/h/kg).
5.3 Preclinical safety data
Even doses several fold higher than the recommended clinical dose (related to body weight) failed to
demonstrate any acute or subacute toxic effects for KOGENATE Bayer in laboratory animals (mouse,
rat, rabbit, and dog).
Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and
carcinogenicity were not performed with octocog alfa due to the immune response to heterologous
proteins in all non-human mammalian species.
No studies were performed on the mutagenic potential of KOGENATE Bayer, since no mutagenic
potential could be detected
in vitro
or
in vivo
for the predecessor product of KOGENATE Bayer.
6.
6.1 List of excipients
Powder
Glycine
Sodium chloride
Calcium chloride
Histidine
Polysorbate 80
Sucrose
Solvent
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6..
Only the provided components (powder vial with Bio-Set device, pre-filled syringe containing solvent
and venipuncture set) should be used for reconstitution and injection because treatment failure can
occur as a consequence of human coagulation factor VIII adsorption to the internal surfaces of some
infusion equipment.
17
6.3 Shelf-life
30 months.
After reconstitution, the product should be used immediately.
However, during
in vitro
studies, the chemical and physical in-use stability has been demonstrated for
24 hours at 30°C in PVC bags for continuous infusion".
Do not refrigerate after reconstitution.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial and the pre-filled syringe in the outer
carton in order to protect from light.
The product when kept in its outer carton may be stored at ambient room temperature (up to 25°C) for
a limited period of 3 months. In this case, the product expires at the end of this 3-month period; the
new expiry date must be noted on the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container and special equipment for use, administration or
implantation
Each package of KOGENATE Bayer contains:
•
one vial plus Bio-Set device, containing powder (10 ml clear glass type 1 vial with latex-free
grey halogenobutyl rubber blend stopper plus transfer device with protective cap [Bio-Set])
•
one pre-filled syringe with 2.5 ml solvent (clear glass cylinder type 1 with latex-free grey
bromobutyl rubber blend stopper)
•
syringe plunger rod
•
two sterile alcohol swabs for single use
•
two dry swabs
•
two plasters
6.6 Special precautions for disposal and other handling
Detailed instructions for preparation and administration are contained in the package leaflet provided
with KOGENATE Bayer.
KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 ml water for
injections) in the prefilled syringe and the integrated transfer device (Bio-Set). Reconstitution should
be performed in accordance with good practices rules, particularly with attention to asepsis. Gently
rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Do not use
KOGENATE Bayer if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn back into the syringe.
Use the provided venipuncture set for intravenous injection.
For continuous infusion, the product must be prepared under aseptic conditions.
For single use only. Any unused solution must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
18
•
one venipuncture set
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/00/143/005
9.
Date of first authorisation: 04 August 2000
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
19
1.
KOGENATE Bayer 1000 IU powder and solvent for solution for injection.
2.
2.1 General description
Each vial contains nominally 1000 IU human coagulation factor VIII (octocog alfa).
Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster
kidney cells containing the human factor VIII gene.
2.2 Qualitative and quantitative composition
One ml of KOGENATE Bayer contains approximately 400 IU (1000 IU / 2.5 ml) of human
coagulation factor VIII (octocog alfa) after reconstitution.
The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard
which was calibrated against WHO standard in International Units (IU).
The specific activity of KOGENATE Bayer is approximately 4000 IU/mg protein.
Solvent: water for injections.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
Powder: dry white to slightly yellow powder or cake.
Solvent: water for injection, a clear, colourless solution.
The reconstituted medicinal product is a clear and colourless solution.
4.
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII
deficiency).
This preparation does not contain von Willebrand factor and is therefore not indicated in von
Willebrand's disease.
Treatment should be initiated under the supervision of a physician experienced in the treatment of
haemophilia.
Posology
The number of units of factor VIII administered is expressed in International Units (IU), which are
related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is
expressed either as a percentage (relative to normal human plasma) or in International Units (relative
to the International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII
activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation
20
of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU)
factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal
activity. The required dose is determined using the following formulae:
I.
Required IU = body weight (kg) × desired factor VIII rise (% of normal) × 0.5
II. Expected factor VIII rise (% of normal) =
2 × administered IU
body weight (kg)
On demand treatment
The dose, frequency and duration of the substitution therapy must be individualised according to the
patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the
bleeding, the presence of inhibitors, and the factor VIII level desired).
The following table provides a guide for factor VIII minimum blood levels. In the case of the
haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of
normal) in the corresponding period:
Degree of haemorrhage/
Type of surgical procedure
Factor VIII level
required (%) (IU/dl)
Frequency of doses (hours)/
Duration of therapy (days)
Haemorrhage
20 - 40
Early haemarthrosis, muscle
bleed or oral bleed
Repeat every 12 to 24 hours. At
least 1 day, until the bleeding
episode as indicated by pain is
resolved or healing is achieved.
More extensive haemarthrosis,
muscle bleed or haematoma
30 - 60
Repeat infusion every 12 - 24 hours
for 3 - 4 days or more until pain and
disability are resolved.
Life threatening bleeds such as
intracranial bleed, throat bleed,
severe abdominal bleed
60 - 100
Repeat infusion every 8 to 24 hours
until threat is resolved
Surgery
30 - 60
Minor
including tooth extraction
Every 24 hours, at least 1 day, until
healing is achieved.
Major
80 - 100
(pre- and
postoperative)
a) By bolus infusions
Repeat infusion every 8 - 24 hours
until adequate wound healing
occurs, then continue with therapy
for at least another 7 days to
maintain a factor VIII activity of
30% to 60%
b) By continuous infusion
Raise factor VIII activity pre-
surgery with an initial bolus
infusion and immediately follow
with continuous infusion (in
IU/Kg/h) adjusting according to
patient’s daily clearance and desired
factor VIII levels for at least 7 days.
The amount to be administered and the frequency of administration should always be adapted
according to the clinical effectiveness in the individual case. Under certain circumstances larger
amounts than those calculated may be required, especially in the case of the initial dose.
21
During the course of treatment, appropriate determination of factor VIII levels is advised in order to
guide the dose to be administered and the frequency at which to repeat the infusions. In the case of
major surgical interventions in particular, precise monitoring of the substitution therapy by means of
coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in
their response to factor VIII, achieving different levels of
in vivo
recovery and demonstrating different
half-lives.
Continuous Infusion
It has been shown in a clinical study performed with adult haemophilia A patients who undergo a
major surgery that KOGENATE Bayer can be used for continuous infusion in surgeries (pre-, during
and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as
with any other long term intravenous infusions. For the calculation of the initial infusion rate,
clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average
population value (3.0-3.5 ml/h/kg) and then adjust accordingly.
Infusion rate (in IU/kg/h) = Clearance (in ml/h/kg) × desired factor VIII level (in IU/ml)
For continuous infusion, clinical and
in vitro
stability has been demonstrated using ambulatory pumps
with a PVC reservoir. KOGENATE Bayer contains low level of polysorbate-80 as an excipient, which
is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride
(PVC) materials. This should be considered for a continuous infusion administration.
Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are
20 to 40 IU of KOGENATE Bayer per kg body weight at intervals of 2 to 3 days.
In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.
Paediatric population
Data have been obtained from clinical studies in 61 children under 6 years of age and non-
interventional studies in children of all ages.
Patients with inhibitors
Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma
factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an
assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at
levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation
factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with
KOGENATE Bayer. However, in the presence of an inhibitor the doses required are variable and must
be adjusted according to clinical response and monitoring of plasma factor VIII activity. In patients
with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin
complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be
considered. These therapies should be directed by physicians with experience in the care of patients
with haemophilia.
Method of administration
For intravenous use.
KOGENATE Bayer should be injected intravenously over several minutes. The rate of administration
should be determined by the patient’s comfort level (maximal rate of infusion: 2 ml/min).
Continuous infusion
KOGENATE Bayer can be infused by continuous infusion. The infusion rate should be calculated
based on the clearance and the desired FVIII level.
Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg
to achieve a FVIII level of 100%. For calculation of ml/hour, multiply infusion rate in IU/h/kg by kg
bw/concentration of solution (IU/ml).
22
Example for calculation of infusion rate for continous infusion after initial bolus injection
Desired plasma
FVIII level
Infusion rate
IU/h/kg
Infusion rate for 75 kg patient
ml/h
Clearance:
3 ml/h/kg
Concentrations of rFVIII solution
100 IU/ml 200 IU/ml 400 IU/ml
100 % (1 IU/ml)
3.0
2.25 1.125 0.56
60 % (0.6 IU/ml)
1.8
1.35 0.68 0.34
40 % (0.4 IU/ml)
1.2
0.9 0.45 0.225
Higher infusion rates may be required in conditions with accelerated clearance during major bleedings
or extensive tissue damage during surgical interventions.
After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using
the steady state equation with the measured FVIII level and the rate of infusion using the following
equation:
clearance = infusion rate/actual FVIII level.
During continuous infusion, infusion bags should be changed every 24 hours.
For instructions on reconstitution of the medicinal product before administration, see section 6.6 and
the package leaflet.
-
Known hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity reactions
As with any intravenous protein product, allergic type hypersensitivity reactions are possible.
Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild
hypotension and nausea during infusion can constitute an early warning for hypersensitivity and
anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as
appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped
immediately and the patient should contact their physician
.
In case of shock, the current medical
standards for shock treatment should be observed.
Antibodies (inhibitors)
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the
management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins
directed against the factor VIII procoagulant activity, which are quantified in Modified Bethesda Units
(BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-
haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20
exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant
factor VIII product to another in previously treated patients with more than 100 exposure days who
have a history of inhibitor development.
Patients treated with recombinant coagulation factor VIII should be carefully monitored for the
development of inhibitors by appropriate clinical observations and laboratory tests. (see also section
4.8)
Continuous infusion
In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent
thrombophlebitis at the infusion site as with any other long term intravenous infusions.
23
-
Known allergic reactions to mouse or hamster protein.
Registration
In the interest of the patients, it is recommended that, whenever possible, every time that KOGENATE
Bayer is administered to them, the name and the batch number of the product is registered.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium
free”.
No interactions of KOGENATE Bayer with other medicinal products are known.
Animal reproduction studies have not been conducted with KOGENATE Bayer.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of
KOGENATE Bayer during pregnancy and breast-feeding is not available. Therefore, KOGENATE
Bayer should be used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
KOGENATE Bayer has no influence on the ability to drive or to use machines.
The most commonly reported adverse drug reaction occurring is the formation of neutralising
antibodies (prevalent in previously untreated or minimally treated patients).
The frequencies of adverse reactions reported with KOGENATE Bayer are summarized in the table
below. Within each frequency group, undesirable effects are presented in order of decreasing
seriousness. Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon
(≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).
MeDRa Standard
System Organ Class
Common
Uncommon
Rare
Blood and the
Lymphatic System
Disorders
Inhibitor
Formation to
FVIII
(Reported in PUP
and minimally
treated patients in
clinical trials)*
Inhibitor
Formation to
FVIII
(Reported in
PTP in clinical
trials and Post
Marketing
Studies)
*
General Disorders and
Administration Site
Conditions
Infusion site
reaction
Infusion related febrile reaction
(pyrexia)
Immune System
Disorders
Skin associated
hypersensitivity
reactions,
(pruritus, urticaria
and rash)
Systemic Hypersensitivity
reactions (including one
anaphylactic reaction, nausea,
blood pressure abnormal and,
dizziness)
* see section below
24
Description of selected adverse reactions
The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the
management of individuals with haemophilia A. In studies with recombinant factor VIII preparations,
development of inhibitors is predominantly observed in previously untreated haemophiliacs. Patients
should be carefully monitored for the development of inhibitors by appropriate clinical observations
and laboratory tests.
In clinical studies, KOGENATE Bayer has been used in the treatment of bleeding episodes in 37
previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as
having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP
patients treated with KOGENATE Bayer developed inhibitors: Overall, 9 out of 60 (15%) developed
inhibitors, 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU.
The median number of exposure days at the time of inhibitor detection in these patients was 9 days
(range 3 - 18 days).
The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five
patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more
than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The
fifth patient was lost to follow-up.
In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure
days), followed over four years, no de-novo inhibitors were observed.
In extensive post-registration studies with KOGENATE Bayer, involving more than 1000 patients the
following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as
having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.
During studies, no patient developed clinically relevant antibody titres against the trace amounts of
mouse protein and hamster protein present in the preparation. However, the possibility of allergic
reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in
certain predisposed patients (see section 4.3 and 4.4).
No case of overdose with recombinant coagulation factor VIII has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.
The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and
vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII
binds to vWF in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor
IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts
prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of
factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either
spontaneously or as a results of accidental or surgical trauma. By replacement therapy the plasma
levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency
and correction of the bleeding tendencies.
Determination of activated partial thromboplastin time (aPTT) is a conventional
in vitro
assay method
for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree and
25
duration of aPTT normalisation observed after administration of KOGENATE Bayer is similar to that
achieved with plasma-derived factor VIII.
5.2 Pharmacokinetic properties
The analysis of all recorded
in vivo
recoveries in previously treated patients demonstrated a mean rise
of 2 % per IU/kg body weight for KOGENATE Bayer. This result is similar to the reported values for
factor VIII derived from human plasma.
After administration of KOGENATE Bayer, peak factor VIII activity decreased by a two-phase
exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-
derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional
pharmacokinetic parameters for KOGENATE Bayer for bolus injection are: mean residence time
[MRT (0-48)] of about 22 hours and clearance of about 160 ml/h. Mean baseline clearance for 14 adult
patients undergoing major surgeries with continuous infusion are 188 ml/h corresponding to 3.0
ml/h/kg (range 1.6-4.6 ml/h/kg).
5.3 Preclinical safety data
Even doses several fold higher than the recommended clinical dose (related to body weight) failed to
demonstrate any acute or subacute toxic effects for KOGENATE Bayer in laboratory animals (mouse,
rat, rabbit, and dog).
Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and
carcinogenicity were not performed with octocog alfa due to the immune response to heterologous
proteins in all non-human mammalian species.
No studies were performed on the mutagenic potential of KOGENATE Bayer, since no mutagenic
potential could be detected
in vitro
or
in vivo
for the predecessor product of KOGENATE Bayer.
6.
6.1 List of excipients
Powder
Glycine
Sodium chloride
Calcium chloride
Histidine
Polysorbate 80
Sucrose
Solvent
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6..
Only the provided components (powder vial with Bio-Set device, pre-filled syringe containing solvent
and venipuncture set) should be used for reconstitution and injection because treatment failure can
occur as a consequence of human coagulation factor VIII adsorption to the internal surfaces of some
infusion equipment.
26
6.3 Shelf-life
30 months.
After reconstitution, the product should be used immediately.
However, during
in vitro
studies, the chemical and physical in-use stability has been demonstrated for
24 hours at 30°C in PVC bags for continuous infusion".
Do not refrigerate after reconstitution.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial and the pre-filled syringe in the outer
carton in order to protect from light.
The product when kept in its outer carton may be stored at ambient room temperature (up to 25°C) for
a limited period of 3 months. In this case, the product expires at the end of this 3-month period; the
new expiry date must be noted on the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container and special equipment for use, administration or
implantation
Each package of KOGENATE Bayer contains:
•
one vial plus Bio-Set device, containing powder (10 ml clear glass type 1 vial with latex-free
grey halogenobutyl rubber blend stopper plus transfer device with protective cap [Bio-Set])
•
one pre-filled syringe with 2.5 ml solvent (clear glass cylinder type 1 with latex-free grey
bromobutyl rubber blend stopper)
•
syringe plunger rod
•
two sterile alcohol swabs for single use
•
two dry swabs
•
two plasters
6.6 Special precautions for disposal and other handling
Detailed instructions for preparation and administration are contained in the package leaflet provided
with KOGENATE Bayer.
KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 ml water for
injections) in the prefilled syringe and the integrated transfer device (Bio-Set). Reconstitution should
be performed in accordance with good practices rules, particularly with attention to asepsis. Gently
rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Do not use
KOGENATE Bayer if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn back into the syringe.
Use the provided venipuncture set for intravenous injection.
For continuous infusion, the product must be prepared under aseptic conditions.
For single use only. Any unused solution must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
27
•
one venipuncture set
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/00/143/006
9.
Date of first authorisation: 04 August 2000
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
28
1.
FURTHER INFORMATION
What KOGENATE Bayer 3000 IU contains
Powder
The
active
substance is human coagulation factor VIII (octocog alfa) produced by recombinant DNA
technology.
The
other
ingredients are glycine, sodium chloride, calcium chloride, histidine, polysorbate 80, and
sucrose (
see end of Section 2)
.
Solvent
Water for injections, sterilised.
What KOGENATE Bayer 3000 IU looks like and content of the pack
KOGENATE Bayer 3000 IU is provided as a powder and solvent for solution for injection and is a dry
white to slightly yellow powder or cake. After reconstitution the solution is clear. Medical devices for
reconstitution and administration are provided with each package of KOGENATE Bayer 3000 IU.
Marketing Authorisation Holder
Bayer Schering Pharma AG
13342 Berlin
Germany
220
Manufacturer
Bayer HealthCare Manufacturing S.r.l.
Via delle Groane 126
20024 Garbagnate Milanese (MI)
Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België / Belgique / Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Luxembourg / Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
България
Байер България ЕООД
Tел. + 359 02 81 401 01
Magyarország
Bayer Hungária Kft.
Tel.:+36-14 87-41 00
Česká republika
Bayer s.r.o.
Tel: +420 271 730 661
Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05
Danmark
Bayer A/S
Tlf: +45-45 23 50 00
Nederland
Bayer B.V., Bayer Schering Pharma
Tel: +31-(0)297-28 06 66
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Norge
Bayer AS
Tlf. +47 24 11 18 00
Eesti
Bayer OÜ
Tel: +372 655 85 65
Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 46-0
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30-210-618 75 00
Polska
Bayer Sp. z o.o.
Tel.: +48-22-572 35 00
España
Química Farmacéutica Bayer S.L.
Tel: +34-93-495 65 00
Portugal
Bayer Portugal S.A.
Tel: +351-21-416 42 00
France
Bayer Santé
Tél: +33 (0)3- 28 16 34 00
România
SC Bayer SRL
Tel: +40 21 528 59 00
Ireland
Bayer Limited
Tel: +353 1 299 93 13
Slovenija
Bayer d. o. o.
Tel.: +386-(0)1-58 14 400
Ísland
Icepharma hf.
Simi: +354 540 8000
Slovenská republika
Bayer, spol. s r.o.
Tel: +421 2 59 21 31 11
Italia
Bayer S.p.A.
Tel: +39-02-397 81
Suomi/Finland
Bayer Oy, Bayer Schering Pharma
Puh/Tel: +358- 20 785 21
Κύπρος
NOVAGEM Limited
Tηλ: +357 22 74 77 47
Sverige
Bayer AB
Tel: +46-(0)8 580 223 00
Latvija
SIA Bayer
Tel: +371 67 84 55 63
United Kingdom
Bayer plc
Tel: +44 (0)1 635-56 30 00
Lietuva
UAB Bayer
Tel. +370 5 23 36 868
221
This leaflet was last approved in
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
222
Source: European Medicines Agency
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