ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen 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. Helixate NexGen 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 Helixate NexGen 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 Helixate
NexGen. 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.
Helixate NexGen 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
Helixate NexGen 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 patients 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 Helixate
NexGen 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 Helixate NexGen with other medicinal products are known.
Animal reproduction studies have not been conducted with Helixate NexGen.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate
NexGen during pregnancy and breast-feeding is not available. Therefore, Helixate NexGen should be
used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
Helixate NexGen 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 Helixate NexGen 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, Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen, 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 sections 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 Helixate NexGen 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 Helixate NexGen. This result is similar to the reported values for
factor VIII derived from human plasma.
After administration of Helixate NexGen, 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 Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen, since no mutagenic
potential could be detected
in vitro
or
in vivo
for the predecessor product of Helixate NexGen.
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 administration sets can be used 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 vials 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 top of 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 Helixate NexGen contains:
•
one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber
blend stopper and aluminium seal)
•
one vial with solvent (6 ml clear glass type 1 vial with latex-free grey chlorobutyl rubber blend
stopper and aluminium seal)
•
an additional package with:
- 1 filter transfer device 20/20 [Mix2Vial]
- 1 venipuncture set
- 1 disposable 5 ml syringe
- 2 sterile alcohol swabs for single use
6.6 Special precautions for disposal and other handling
Detailed instructions for preparation and administration are contained in the package leaflet provided
with Helixate NexGen.
Helixate NexGen powder should only be reconstituted with the supplied solvent (2.5 ml water for
injections) using the supplied sterile Mix2Vial filter transfer device. 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 Helixate
NexGen if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn through the Mix2Vial filter transfer device into the sterile
disposable syringe (both supplied).
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
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/00/144/001
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.
Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen 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. Helixate NexGen 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 Helixate NexGen 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 Helixate
NexGen. 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.
Helixate NexGen 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
Helixate NexGen 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 patients 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 Helixate
NexGen 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 Helixate NexGen with other medicinal products are known.
Animal reproduction studies have not been conducted with Helixate NexGen.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate
NexGen during pregnancy and breast-feeding is not available. Therefore, Helixate NexGen should be
used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
Helixate NexGen 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 Helixate NexGen 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, Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen, 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 sections 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 Helixate NexGen 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 Helixate NexGen. This result is similar to the reported values for
factor VIII derived from human plasma.
After administration of Helixate NexGen, 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 Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen, since no mutagenic
potential could be detected
in vitro
or
in vivo
for the predecessor product of Helixate NexGen.
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 administration sets can be used 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 vials 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 top of 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 Helixate NexGen contains:
•
one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber
blend stopper and aluminium seal)
•
one vial with solvent (6 ml clear glass type 1 vial with latex-free grey chlorobutyl rubber blend
stopper and aluminium seal)
•
an additional package with:
- 1 filter transfer device 20/20 [Mix2Vial]
- 1 venipuncture set
- 1 disposable 5 ml syringe
- 2 sterile alcohol swabs for single use
6.6 Special precautions for disposal and other handling
Detailed instructions for preparation and administration are contained in the package leaflet provided
with Helixate NexGen.
Helixate NexGen powder should only be reconstituted with the supplied solvent (2.5 ml water for
injections) using the supplied sterile Mix2Vial filter transfer device. 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 Helixate
NexGen if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn through the Mix2Vial filter transfer device into the sterile
disposable syringe (both supplied).
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
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/00/144/002
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.
Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen 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. Helixate NexGen 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 Helixate NexGen 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 Helixate
NexGen. 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.
Helixate NexGen 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
Helixate NexGen 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 patients 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 Helixate
NexGen 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 Helixate NexGen with other medicinal products are known.
Animal reproduction studies have not been conducted with Helixate NexGen.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate
NexGen during pregnancy and breast-feeding is not available. Therefore, Helixate NexGen should be
used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available.
Helixate NexGen 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 Helixate NexGen 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, Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen, 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 sections 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 Helixate NexGen 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 Helixate NexGen. This result is similar to the reported values for
factor VIII derived from human plasma.
After administration of Helixate NexGen, 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 Helixate NexGen 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 Helixate NexGen 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 Helixate NexGen, since no mutagenic
potential could be detected
in vitro
or
in vivo
for the predecessor product of Helixate NexGen.
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 administration sets can be used 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 vials 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 top of 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 Helixate NexGen contains:
•
one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber
blend stopper and aluminium seal)
•
one vial with solvent (6 ml clear glass type 1 vial with latex-free grey chlorobutyl rubber blend
stopper and aluminium seal)
•
an additional package with:
- 1 filter transfer device 20/20 [Mix2Vial]
- 1 venipuncture set
- 1 disposable 5 ml syringe
- 2 sterile alcohol swabs for single use
6.6 Special precautions for disposal and other handling
Detailed instructions for preparation and administration are contained in the package leaflet provided
with Helixate NexGen.
Helixate NexGen powder should only be reconstituted with the supplied solvent (2.5 ml water for
injections) using the supplied sterile Mix2Vial filter transfer device. 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 Helixate
NexGen if you notice visible particulate matter or turbidity.
After reconstitution, the solution is drawn through the Mix2Vial filter transfer device into the sterile
disposable syringe (both supplied).
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
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/00/144/003
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 Helixate NexGen 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 Helixate NexGen 3000 IU looks like and content of the pack
Helixate NexGen 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 Helixate NexGen 3000 IU.
Marketing Authorisation Holder
Bayer Schering Pharma AG
13342 Berlin
Germany
Manufacturer
Bayer HealthCare Manufacturing S.r.l.
Via delle Groane 126
20024 Garbagnate Milanese (MI)
Italy
106
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België / Belgique / Belgien
CSL Behring N.V.
Tél/Tel: +32-(0)16 38 80 80
Luxembourg / Luxemburg
CSL Behring N.V.
Tél/Tel: +32-(0)16 38 80 80
Česká republika
IBP medica s.r.o.
Tel: +42-02-222560723
Malta
AM Mangion Ltd.
Phone: +356 2397 6000/6412
Danmark
CSL Behring AB
Tlf: +46-(0)8-54496670
Nederland
CSL Behring BV
Tel: +31-(0)76 523 60 45
Deutschland
CSL Behring GmbH
Tel: +49-(0)69-30584437
Norge
CSL Behring AB
Tlf: +46-(0)8-54496670
Eesti
CSL Behring AB
Tel: +46-(0)8-54496670
Österreich
CSL Behring GmbH
Tel: +43-(0)1-80101-0
Ελλάδα
CSL Behring ΜΕΠΕ,
Τηλ: +30-210 7255 660
Polska
Imed Poland sp. z.o.o.
Tel. +48 22 663 43 10
+30-210 7255 661
España
CSL Behring, S. A.
Tel: +34 93 367 1870
Portugal
CSL Behring Unipessoal, Lda.
Tel. +351-21-7826230
France
CSL Behring S.A.
Tél: +33-(0)1-53585400
România
Prisum International Trading srl
Tel. +40 21 322.01.71
Ireland
CSL Behring UK Limited
Tel: +44-(0)1444 447400
Slovenija
MediSanus d.o.o.
Tel: +386 1 25 71 496
Ísland
CSL Behring AB
Simi: +46-(0)8-54496670
Slovenská republika
TIMED, s.r.o.
Tel.: +421 2 482 095 20
Italia
CSL Behring S.p.A.
Tel: +39-02-349641
Suomi/Finland
CSL Behring AB
Puh/Tel: +46-(0)8-54496670
Κύπρος
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ ΛΤΔ
Τηλ. +357-22677038
Sverige
CSL Behring AB
Tel: +46-(0)8-54496670
Latvija
CSL Behring AB
Tel: +46-(0)8-54496670
United Kingdom
CSL Behring UK Limited
Tel: +44-(0)1444 447400
Lietuva
CSL Behring AB
Tel. +46-(0)8-54496670
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
107
България
Novimed Ltd.
Teл. + 359 2 958 84 68
Magyarország
Plazmed Kft.
Tel: +36-28-59 10 00
Source: European Medicines Agency
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