Helixate NexGen

1 

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Helixate NexGen 250 IU powder and solvent for solution for injection 
Helixate NexGen 500 IU powder and solvent for solution for injection 
Helixate NexGen 1000 IU powder and solvent for solution for injection 
Helixate NexGen 2000 IU powder and solvent for solution for injection 
Helixate NexGen 3000 IU powder and solvent for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 250/500/1000/2000/3000 IU human coagulation factor VIII (INN: 
octocog alfa). 
Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster 
kidney cells containing the human factor VIII gene.  
 
 One mL Helixate NexGen 250 IU contains approximately 100 IU (250 IU / 2.5 mL) of 

recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water 
for injections. 

 One mL Helixate NexGen 500 IU contains approximately 200 IU (500 IU / 2.5 mL) of 
recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water 
for injections. 

 One mL Helixate NexGen 1000 IU contains approximately 400 IU (1000 IU / 2.5 mL) of 
recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water 
for injections. 

 One mL Helixate NexGen 2000 IU contains approximately 400 IU (2000 IU / 5 mL) of 
recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water 
for injections. 

 One mL Helixate NexGen 3000 IU contains approximately 600 IU (3000 IU / 5 mL) of 
recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water 
for injections. 

 
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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection.  
 
Powder: dry white to slightly yellow powder or cake.  
Solvent: water for injection, a clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



3 

 
This product is indicated for adults, adolescents and children of all ages. 
 
4.2 Posology and method of administration 
 
Treatment should be 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.  
 
On demand treatment 
 
The calculation 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) 
 
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).  
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



4 

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: 
 
Table 1: Guide for dosing in bleeding episodes and surgery 

Degree of haemorrhage/  
Type of surgical procedure 

Factor VIII level 
required (%) (IU/dl) 

Frequency of doses (hours)/ 
Duration of therapy (days)  

Haemorrhage 
 
Early haemarthrosis, muscle 
bleed or oral bleed  

 
 

20 - 40 

 
 
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 haemorrhages 
(such as intracranial bleed, 
throat bleed, severe abdominal 
bleed) 

60 - 100 Repeat infusion every 8 to 24 hours 
until threat is resolved 

Surgery 
 
Minor 
including tooth extraction 

 
 

30 - 60 

 
 
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% (IU/dl). 
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.  
 
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, demonstrating different half-lives and recoveries. 
 
Continuous infusion 
 
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.  
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



5 

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.  
 
Special populations 
 
Paediatric population 
The safety and efficacy of Helixate NexGen in children of all ages have been established. 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 
 
Intravenous use. 
 
Helixate NexGen should be injected intravenously over 2 to 5 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).  
 
Me

dic
ina

l p
rod

uc
t n

o l
on

ge
r a

uth
ori

se
d



6 

Table 2: Example for calculation of infusion rate for continuous 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. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
- Known allergic reactions to mouse or hamster protein. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity  
 
Allergic type hypersensitivity reactions are possible with Helixate NexGen. The product contains 
traces of mouse and hamster proteins and human proteins other than factor VIII (see section 5.1). 
 
If symptoms of hypersensitivity occur, patients should be advised to discontinue the use of the 
medicinal product immediately and contact their physician. 
 
Patients should be informed of the early signs of hypersensitivity reactions including hives, nausea, 
generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.  
In case of shock, standard medical treatment for shock should be implemented. 
 
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 Bethesda Units (BU) 
per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the 
severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 
20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.  
 
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII 
product to another in previously treated patients with more than 100 exposure days who have a 
previous history of inhibitor development. Therefore, it is recommended to monitor all patients 
carefully for inhibitor occurrence following any product switch. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



7 

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre 
inhibitors which are transiently present or remain consistently low titre posing less risk of insufficient 
clinical response than high titre inhibitors. 
 
In general, all patients treated with coagulation factor VIII products should be carefully monitored for 
the development of inhibitors by appropriate clinical observations and laboratory tests.  
If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with 
an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with 
high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should 
be considered. Management of such patients should be directed by physicians with experience in the 
care of haemophilia and factor VIII inhibitors. 
 
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. 
 
Sodium content 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium 
free”. 
 
Cardiovascular events 
 
Haemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop 
cardiovascular events as non-haemophilic patients when clotting has been normalised by treatment 
with FVIII. Elevation of FVIII levels following administration, in particular with existing 
cardiovascular risk factors, might put a patient into the same risk for vessel closure or myocardial 
infarction as for the non-haemophilic population. Consequently, patients should be evaluated and 
monitored for cardiac risk factors. 
 
Catheter-related complications 
 
If a central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Documentation 
 
It is strongly recommended that every time that Helixate NexGen is administered to a patient, the 
name and batch number of the product are recorded in order to maintain a link between the patient and 
the batch of the medicinal product. 
 
Paediatric population  
 
The listed warnings and precautions apply both to adults and children. 
 
4.5 Interactions with other medicinal products and other forms of interaction 
 
No interactions of Helixate NexGen with other medicinal products have been reported. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with Helixate NexGen. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



8 

Pregnancy and breast-feeding 
 
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. 
 
Fertility 
 
There are no fertility data available. 
 
4.7 Effects on ability to drive or use machines 
 
Helixate NexGen has no influence on the ability to drive or to use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the 
infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, 
restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed 
with recombinant factor VIII products and may in some cases progress to severe anaphylaxis 
(including shock). In particular the skin related reactions may occur commonly, whereas a progress to 
severe anaphylaxis (including shock) is considered to be rare. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with Helixate NexGen.  If such inhibitors occur, the condition will manifest 
itself as an insufficient clinical response. In such cases, it is recommended that a specialised 
haemophilia centre be contacted. 
 
Tabulated list of adverse reactions  
 
The table presented below is according to the MedDRA system organ classification (SOC and 
Preferred Term Level).  
 
Frequencies have been evaluated according to the following convention: very common: (1/10), 
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare 
(<1/10,000), not known (cannot be estimated from the available data). 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



9 

Table 3: Frequency of adverse drug reactions 
MedDRA 
Standard 
System Organ 
Class 

Frequency 
Very common Common Uncommon Rare Very 

Rare / not 
known 

Blood and the 
Lymphatic 
System 
Disorders 

 FVIII 
Inhibition 
(PUPs)* 

  FVIII 
Inhibition 
(PTPs)* 

  

General 
Disorders and 
Administratio
n Site 
Conditions 

 Infusion site 
reaction 

 Infusion related 
febrile reaction 
(pyrexia) 

 

Immune 
System 
Disorders 

 Skin associated 
hypersensitivity 
reactions, 
(pruritus, 
urticaria and 
rash) 

 Systemic 
Hypersensitivit
y reactions 
(including 
anaphylactic 
reaction, 
nausea, blood 
pressure 
abnormal and, 
dizziness) 

 

Nervous 
System 
Disorders 

    Dysgeusia 

* Frequency is based on studies with all FVIII products which included patients with severe 
haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Paediatric population 
Frequency, type and severity of adverse reactions in children are expected to be the same as in all 
population groups except for the inhibitor formation. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
No case of overdose with recombinant coagulation factor VIII has been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



10 

Mechanism of action 
 
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 result 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. 
 
Pharmacodynamic effects 
 
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 
duration of aPTT normalisation observed after administration of Helixate NexGen is similar to that 
achieved with plasma-derived factor VIII. 
 
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. 
 
Hypersensitivity 
 
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). 
 
Immune Tolerance Induction (ITI) 
 
Data on Immune Tolerance Induction have been collected in patients with haemophilia A who had 
developed inhibitors to FVIII. A retrospective review has been done on 40 patients, and 39 patients 
were included in a prospective investigator-initiated clinical study. Data show that Helixate NexGen 
has been used to induce immune tolerance. In patients where immune tolerance was achieved the 
bleedings could be prevented or controlled with Helixate NexGen again, and the patients could 
continue with prophylactic treatment as maintenance therapy. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
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. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



11 

Distribution and elimination 
 
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. PHARMACEUTICAL PARTICULARS 
 
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 recombinant coagulation factor VIII adsorption to the internal surfaces of some 
infusion equipment. 
 
6.3 Shelf-life 
 
30 months. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. If 
not used immediately, in-use storage times and conditions prior to use are the responsibility of the 
user. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



12 

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". After reconstitution, the chemical and 
physical in-use stability has been demonstrated for 3 hours in in vitro studies. 
 
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. 
 
Within its overall shelf life of 30 months the product when kept in its outer carton, may be stored at 
ambient room temperature (up to 25°C) for a limited period of 12 months. In this case, the product 
expires at the end of this 12-month period or the expiration date on the product vial, whichever is 
earlier. The new expiry date must be noted on the top of the outer carton. 
 
For storage conditions after reconstitution of the 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 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. 
 
The reconstituted medicinal product is a clear and colourless solution. 
Helixate NexGen powder should only be reconstituted with the supplied solvent (2.5 mL (for 250 IU, 
500 IU and 1000 IU) or 5 mL (for 2000 IU and 3000 IU) water for injections) using the supplied 
sterile Mix2Vial filter transfer device. For infusion, the product must be prepared under aseptic 
conditions. If any component of the package is opened or damaged, do not use this component. 
Gently rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Parenteral 
drug products should be inspected visually for particulate matter and discoloration prior to 
administration. 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). Helixate NexGen should be reconstituted and administered with 
the components provided with each package. 
 
The reconstituted product must be filtered prior to administration to remove potential particulate 
matter in the solution. Filtering is achieved by using the Mix2Vial adapter. 
 
For single use only. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



13 

 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/00/144/001 - Helixate NexGen 250 IU 
EU/1/00/144/002 - Helixate NexGen 500 IU 
EU/1/00/144/003 - Helixate NexGen 1000 IU 
EU/1/00/144/004 - Helixate NexGen 2000 IU 
EU/1/00/144/005 - Helixate NexGen 3000 IU 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 August 2000 
Date of latest renewal: 06 August 2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURERRESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



15 

A MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance 
 
Bayer Corporation (license holder) 
Bayer HealthCare LLC 
800 Dwight Way 
Berkeley, CA 94710 
USA 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Bayer HealthCare Manufacturing S.r.l. 
Via delle Groane 126 
20024 Garbagnate Milanese (MI) 
Italy 
 
 
B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic Safety Update Reports  
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



18 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Helixate NexGen 250 IU powder and solvent for solution for injection 
Helixate NexGen 500 IU powder and solvent for solution for injection 
Helixate NexGen 1000 IU powder and solvent for solution for injection 
Helixate NexGen 2000 IU powder and solvent for solution for injection 
Helixate NexGen 3000 IU powder and solvent for solution for injection 
 
Recombinant coagulation factor VIII (octocog alfa) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S)
 
Helixate NexGen  250 IU contains (250 IU / 2.5 mL) = 100 IU octocog alfa per mL after 
reconstitution. 
Helixate NexGen 500 IU contains (500 IU / 2.5 mL) = 200 IU octocog alfa per mL after 
reconstitution. 
Helixate NexGen 1000 IU contains (1000 IU / 2.5 mL) = 400 IU octocog alfa per mL after 
reconstitution. 
Helixate NexGen 2000 IU contains (2000 IU / 5 mL) = 400 IU octocog alfa per mL after 
reconstitution. 
Helixate NexGen 3000 IU contains (3000 IU / 5 mL) = 600 IU octocog alfa per mL after 
reconstitution. 
 
 
3. LIST OF EXCIPIENTS 
 
Glycine, sodium chloride, calcium chloride, histidine, polysorbate 80, sucrose. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 vial with powder for solution for injection. 
1 vial with 2.5 mL water for injections. 
1 vial with 5 mL water for injections. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use, single dose administration only. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



19 

8. EXPIRY DATE, 
 
EXP 
EXP (End of the 12 month period, if stored at room temperature): ........... 
Do not use after this date. 
 
May be stored at temperatures up to 25°C for up to 12 months within the expiry date indicated on the 
label. Note the new expiry date on the top of the carton. After reconstitution, the product must be used 
within 3 hours. Do not refrigerate after reconstitution. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C - 8°C). Do not freeze.  
 
Keep the vials in the outer carton in order to protect from light.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused solution must be discarded. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/144/001 - Helixate NexGen 250 IU 
EU/1/00/144/002 - Helixate NexGen 500 IU 
EU/1/00/144/003 - Helixate NexGen 1000 IU 
EU/1/00/144/004 - Helixate NexGen 2000 IU 
EU/1/00/144/005 - Helixate NexGen 3000 IU 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



20 

16. INFORMATION IN BRAILLE 
 
Helixate NexGen 250 
Helixate NexGen 500 
Helixate NexGen 1000 
Helixate NexGen 2000 
Helixate NexGen 3000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



21 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL WITH POWDER FOR SOLUTION FOR INJECTION 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Helixate NexGen 250 IU powder for solution for injection 
Helixate NexGen 500 IU powder for solution for injection 
Helixate NexGen 1000 IU powder for solution for injection 
Helixate NexGen 2000 IU powder for solution for injection 
Helixate NexGen 3000 IU powder for solution for injection 
 
Recombinant coagulation factor VIII (octocog alfa) 
 
Intravenous use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
250 IU (octocog alfa) (100 IU/mL after reconstitution). 
500 IU (octocog alfa) (200 IU/mL after reconstitution). 
1000 IU (octocog alfa) (400 IU/mL after reconstitution). 
2000 IU (octocog alfa) (400 IU/mL after reconstitution). 
3000 IU (octocog alfa) (600 IU/mL after reconstitution). 
 
 
6. OTHER 
 
 Me

dic
ina

l p
rod

uc
t n

o l
on

ge
r a

uth
ori

se
d



22 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL WITH 2.5 mL or 5 mL WATER FOR INJECTIONS 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF 

ADMINISTRATION 
 
Water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
For reconstitution of Helixate NexGen, see package leaflet. Use entire content. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2.5 mL [for reconstitution of strengths 250/500/1000 IU] 
5 mL [for reconstitution of strengths 2000/3000 IU] 
 
 
6. OTHER 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



24 

Package Leaflet: Information for the user 
 

Helixate NexGen 250 IU powder and solvent for solution for injection 
Helixate NexGen 500 IU powder and solvent for solution for injection 

Helixate NexGen 1000 IU powder and solvent for solution for injection 
Helixate NexGen 2000 IU powder and solvent for solution for injection 
Helixate NexGen 3000 IU powder and solvent for solution for injection 

Recombinant coagulation factor VIII (octocog alfa) 
 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or your pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Helixate NexGen is and what it is used for 
2. What you need to know before you use Helixate NexGen 
3. How to use Helixate NexGen 
4. Possible side effects 
5. How to store Helixate NexGen 
6. Contents of the pack and other information 
 
 
1. What Helixate NexGen is and what it is used for 
 
Helixate NexGencontains the active substance human recombinant coagulation factor VIII (octocog 
alfa). 
 
Helixate NexGen is used for treatment and prophylaxis of bleeding adults, adolescents and children of 
all ages with haemophilia A (congenital factor VIII deficiency). 
This preparation does not contain von Willebrand factor and is therefore not to be used in von 
Willebrand's disease. 
 
The vial contains a dry white to slightly yellow powder or cake, as well as water for injections to be 
used to reconstitute the contents of the vial. 
 
 
2. What you need to know before you use Helixate NexGen 
 
Do not use Helixate NexGen  

 if you are allergic to octocog alfa or to any of the other ingredients of this medicine (listed in 
section 6 and end of section 2). 

 if you are allergic to mouse or hamster protein. 
If you are unsure about this, ask your doctor. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



25 

Warnings and precautions 
Take special care with Helixate NexGen  and talk to your doctor or pharmacist if: 

 you experience tightness in the chest, feeling dizzy, feeling sick or faint, or experience 
dizziness on standing, you may be experiencing a rare severe sudden allergic reaction (a so-
called anaphylactic reaction) to this medicine. If this occurs, stop administering the product 
immediately and seek medical advice. 

 your bleeding is not being controlled with your usual dose of this medicine. The formation of 
inhibitors (antibodies) is a known complication that can occur during treatment with all Factor 
VIII medicines. These inhibitors, especially at high levels, stop the treatment working properly 
and you or your child will be monitored carefully for the development of these inhibitors. If 
your or your child’s bleeding is not being controlled with Helixate NexGen, tell your doctor 
immediately. 

 you have previously developed a factor VIII inhibitor and you switch factor VIII products, 
you may be at risk of your inhibitor coming back. 

 you have been told you have heart disease or are at risk for heart disease. 
 you require a central venous access device (CVAD) for the administration of Helixate 

NexGen. You may be at risk of CVAD-related complications including local infections, 
bacteria in the blood (bacteremia) and the formation of a blood clot in the blood vessel 
(thrombosis) where the catheter is inserted. 

 
Your doctor may carry out tests to ensure that your current dose of this medicine provides adequate 
factor VIII levels. 
 
Other medicines and Helixate NexGen 
Interactions with other medicines are not known. However, please tell your doctor or pharmacist if 
you are taking, have recently taken or might take any other medicines. 
 
Children and adolescents 
The listed warnings and precautions apply to patients of all ages, adults and children. 
 
Pregnancy, breast-feeding and fertility 
Experience regarding fertility or the use of Helixate NexGen during pregnancy and breast-feeding is 
not available. Therefore, if you are pregnant or breast-feeding, think you may be pregnant or are 
planning to have a baby, ask your doctor for advice before using this medicine. 
Helixate NexGen is not likely to affect the fertility in male or female patients, as the active substance 
is naturally occurring in the body. 
 
Driving and using machines 
No effects on ability to drive or use machines have been observed. 
 
Helixate NexGen contains sodium 
This medicinal product contains less than 1 mmol (23 mg) sodium per vial and is therefore considered 
essentially “sodium-free”. 
 
Documentation 
It is recommended that every time that you use Helixate NexGen, the name and batch number of the 
product are documented. 
 
 
3. How to use Helixate NexGen 
 
Always use this medicine exactly as described in this leaflet or as your doctor or pharmacist has told 
you. Check with your doctor, pharmacist or nurse if you are not sure. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



26 

Treatment of bleeding 
Your doctor will calculate the dose of this medicine and how frequently you should use it to get the 
necessary level of factor VIII activity in your blood. The doctor should always adjust the dose and the 
frequency of administration according to your individual needs. How much Helixate NexGen you 
should use and how often you should use it depends on many factors such as:  

 your weight 
 the severity of your haemophilia 
 where the bleed is and how serious it is 
 whether you have inhibitors and how high the inhibitor titre is 
 the factor VIII level that is needed. 

 
Prevention of bleeding 
If you are using Helixate NexGen to prevent bleeding (prophylaxis), your doctor will calculate the 
dose for you. This will usually be in the range of 20 to 40 IU of octocog alfa per kg of body weight, 
given every 2 to 3 days. However, in some cases, especially for younger patients, shorter dose 
intervals or higher doses may be necessary.  
 
Laboratory tests 
It is strongly recommended that appropriate laboratory tests be performed on your plasma at suitable 
intervals to ensure that adequate factor VIII levels have been reached and are maintained. For major 
surgery in particular, close monitoring of the substitution therapy by means of coagulation analysis 
must be carried out. 
 
Use in children and adolescents 
Helixate NexGen can be used in children of all ages. 
 
If bleeding is not controlled 
If the factor VIII level in your plasma fails to reach expected levels, or if bleeding is not controlled 
after apparently adequate dose, you may have developed factor VIII inhibitors. This must be checked 
by an experienced doctor. 
If you have the impression that the effect of this medicine is too strong or too weak, talk to your 
doctor.  
 
Patients with inhibitors 
If you have been told by your doctor that you have developed factor VIII inhibitors you may need to 
use a larger amount of this medicine to control bleeding. If this dose does not control your bleeding 
your doctor may consider giving you an additional product, factor VIIa concentrate or (activated) 
prothrombin complex concentrate.  
These treatments should be prescribed by doctors with experience in the care of patients with 
haemophilia A. Speak to your doctor if you would like further information on this. 
Do not increase your dose of medicine you use to control your bleeding without consulting your 
doctor. 
 
Duration of treatment 
Your doctor will tell you, how often and at what intervals this medicine is to be administered. 
Usually, the substitution therapy with Helixate NexGen is a life-time treatment. 
 
How Helixate NexGen is given 
 
This medicine is intended for injection into a vein over 2 to 5 minutes depending on the total volume 
and your comfort level and should be used  within 3 hours after preparing the solution.  
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



27 

How Helixate NexGen is prepared for administration 
Use only the items that are provided with each package of this medicine. If these components cannot 
be used, please contact your doctor. If any component of the package is opened or damaged, do not 
use it. 
 
You must filter the reconstituted product before administration to remove any possible particles  in the 
solution. You are filtering by using the Mix2Vial adapter. 
 
This medicine must not be mixed with other infusion solutions. Do not use solutions containing 
visible particles or that are cloudy. Follow the directions given by your doctor closely and use the 
detailed instructions for reconstitution and administration provided at the end of this leaflet.  
 
If you use more Helixate NexGen than you should 
No cases of overdose with recombinant coagulation factor VIII have been reported.  
If you have used more Helixate NexGen than you should, please inform your doctor. 
 
If you forget to use Helixate NexGen 
• Proceed with your next dose immediately and continue at regular intervals as advised by your 

doctor.  
• Do not take a double dose to make up for a forgotten dose.  
 
If you want to stop using Helixate NexGen 
Do not stop using Helixate NexGen without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
The most serious side effects are hypersensitivity reactions or anaphylactic shock (rare side effect). 
If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately. 
Please consult your doctor immediately. 
 
For children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) 
may form very commonly (more than 1 in 10 patients); however patients who have received previous 
treatment with Factor VIII (more than 150 days of treatment) the risk is uncommon (less than 
1 in 100 patients). If this happens your or your child’s medicines may stop working properly and you 
or your child may experience persistent bleeding. If this happens, you should contact your doctor 
immediately. 
 
Other possible side effects: 
 
Common  may affect up to 1 in 10 users): 
• rash/itchy rash 
• local reactions where you injected the medication (e.g. burning sensation, temporary redness) 
 
Rare (may affect up to 1 in 1,000 users): 
• hypersensitivity reactions including severe sudden allergic reaction (which may include hives, 

nausea, urticaria, angioedema, chills, flushing, headache, lethargy, wheezing or difficulty 
breathing, restlessness, tachycardia, tingling or anaphylactic shock, e.g. tightness of the 
chest/general feeling of being unwell, dizziness and nausea and mildly reduced blood pressure, 
which may make you feel faint upon standing) 

• fever 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



28 

Not known (frequency cannot be estimated from the available data): 
• dysgeusia (strange taste) 
 
If you notice any of the following symptoms during injection/infusion: 
• chest tightness/general feeling of being unwell  
• dizziness 
• mild hypotension (mildly reduced blood pressure, which may make you feel faint upon 

standing) 
• nausea 
this can constitute an early warning for hypersensitivity and anaphylactic reactions.  
If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately. 
Please consult your doctor immediately.  
 
Hypersensitivity reactions 
During clinical studies, no patient developed clinically relevant antibody titres against the trace 
amounts of mouse protein and hamster protein present in the preparation. The possibility of allergic 
reactions to substances contained in this medication, e.g. trace amounts of mouse and hamster protein 
exists in certain predisposed patients. 
 
Reporting of side effects  
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects, you can help provide more information on the safety of this medicine. 
 
 
5. How to store Helixate NexGen 
 
Keep this medicine out of the sight and reach of children. 
 
Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vials in the outer carton in order to protect 
from light.  
 
Within the expiry date indicated on the label, this medicine when kept in its outer carton may be stored 
at ambient room temperature (up to 25°C) for a limited period of 12 months. In this case, this medicine 
expires at the end of this 12-month period or the expiration date on the product vial, whichever is 
earlier. The new expiry date must be noted on the outer carton. 
 
Do not refrigerate the solution after reconstitution. The reconstituted solution must be used within 3 
hours. This product is for single use only. Any unused solution must be discarded. 
 
Do not use this medicine after the expiry date which is stated on labels and cartons. The expiry date 
refers to the last day of that month. 
 
Do not use this medicine if you notice any particles or the solution is cloudy. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



29 

6. Contents of the pack and other information 
 
What Helixate NexGen contains 
 
Powder 
The active substance is human coagulation factor VIII (octocog alfa) produced by recombinant DNA 
technology. Each vial of Helixate NexGen contains nominally 250, 500, 1000, 2000 or 3000 IU 
octocog alfa. 
The other ingredients are glycine, sodium chloride, calcium chloride, histidine, polysorbate 80, and 
sucrose (see end of section 2). 
 
Solvent 
Water for injections 
 
What Helixate NexGen looks like and content of the pack 
 
Helixate NexGen 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 this medicine. 
 
Marketing Authorisation Holder 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
Bayer HealthCare Manufacturing S.r.l. 
Via delle Groane 126 
20024 Garbagnate Milanese (MI) 
Italy 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



30 

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)15 28 89 20 

Lietuva 
CSL Behring GmbH 
Tel: +49-(0)69-30584437 

България 
Novimed Ltd. 
Teл. + 359 2 850 86 17 

Luxembourg/Luxemburg 
CSL Behring N.V. 
Tél/Tel: +32-(0)15 28 89 20 

Česká republika 
CSL Behring s.r.o. 
Tel: + 420 702 137 233 

Magyarország 
CSL Behring KFT 
Tel: +36-1-213 4290 

Danmark 
CSL Behring AB 
Tlf: +46-(0)8-54496670 

Malta 
AM Mangion Ltd. 
Tel: +356 2397 6333 

Deutschland 
CSL Behring GmbH 
Tel: +49-(0)69-30584437 

Nederland 
CSL Behring BV 
Tel: +31-(0) 85 111 96 00 

Eesti 
CSL Behring GmbH 
Tel: +49-(0)69-30584437 

Norge 
CSL Behring AB 
Tlf: +46-(0)8-54496670 

Ελλάδα 
CSL Behring ΕΠΕ, 
Τηλ:  +30-210 7255 660 

Österreich 
CSL Behring GmbH  
Tel: +43-(0)1-80101-2463 

España 
CSL Behring, S. A. 
Tel: +34 93 367 1870 

Polska 
CSL Behring sp. z o.o. 
Tel. +48 22 213 22 65 

France 
CSL Behring S.A. 
Tél: +33-(0)1-53585400 

Portugal 
CSL Behring, Lda. 
Tel. +351-21-7826230 

Hrvatska 
PharmaSwiss d.o.o. 
Tel: +385 (1) 631-1833 

România  
Prisum International Trading srl 
Tel. +40 21 322 01 71 

Ireland 
CSL Behring UK Limited 
Tel: +44-(0)1444 447405 

Slovenija 
MediSanus d.o.o. 
Tel: +386 1 25 71 496 

Ísland 
CSL Behring AB 
Simi: +46-(0)8-54496670 

Slovenská republika 
CSL Behring s.r.o. 
Tel: +421 911 653 862 

Italia 
CSL Behring S.p.A. 
Tel: +39-02-34964200 

Suomi/Finland 
CSL Behring AB 
Puh/Tel: +46-(0)8-54496670 

Κύπρος 
CSL Behring ΕΠΕ, 
Τηλ:  +30-210 7255 660 

Sverige 
CSL Behring AB 
Tel: +46-(0)8-54496670 

Latvija 
CSL Behring GmbH 
Tel: +49-(0)69-30584437 

United Kingdom 
CSL Behring UK Limited 
Tel: +44-(0)1444 447405 

 
This leaflet was last revised in {MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
-------------------------------------------------------------------------------------------------------------- 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



31 

Detailed instructions for reconstitution and administration of Helixate NexGen using the 
Mix2Vial  adapter: 
 
1. Wash your hands thoroughly using soap and warm water. 
 
2. Warm both unopened vials in your hands to a comfortable temperature (do not exceed 37 °C). 
 
3. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an 

antiseptic solution and allowed to dry prior to opening the Mix2Vial package. 
 
4. Open the Mix2Vial package by peeling away the lid. Do not remove the 

Mix2Vial from the blister package! 
 

4 
5. Place the solvent vial on an even, clean surface and hold the vial tight. Take 

the Mix2Vial together with the blister package and push the spike of the 
blue adapter end straight down through the solvent vial stopper. 

 

5 
6. Carefully remove the blister package from the Mix2Vial set by holding at 

the rim, and pulling vertically upwards. Make sure that you only pull away 
the blister package and not the Mix2Vial set. 

 

6 
7. Place the product vial on an even and firm surface. Invert the solvent vial 

with the Mix2Vial set attached and push the spike of the transparent 
adapter end straight down through the product vial stopper. The solvent 
will automatically flow into the product vial. 

 

7 
8. With one hand grasp the product-side of the Mix2Vial set and with the other 

hand grasp the solvent-side and unscrew counter clockwise the set carefully 
into two pieces. Discard the solvent vial with the blue Mix2Vial adapter 
attached. 

 

8 
9. Gently swirl the product vial with the transparent adapter attached until the 

substance is fully dissolved. Do not shake. Carefully check for particles and 
discoloration before administration. Do not use solutions containing visible 
particles or that are cloudy. 

 9 
10.  Draw air into an empty, sterile syringe. While the product vial is upright, 

connect the syringe to the Mix2Vial´s Luer Lock fitting by screwing 
clockwise. Inject air into the product vial. 

 

10

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



32 

11. While keeping the syringe plunger pressed, turn the system upside down and 
draw the solution into the syringe by pulling the plunger back slowly. 

 

11 
12. Now that the solution has been transferred into the syringe, firmly hold on to 

the barrel of the syringe (keeping the syringe plunger facing down) and 
disconnect the transparent Mix2Vial adapter from the syringe by unscrewing 
counter clockwise. Hold the syringe upright and push the plunger until no air 
is left in the syringe. 

12 
13. Apply a tourniquet to your arm. 
 
14. Determine the point of injection and clean the skin with an alcohol swab.  
 
15. Puncture the vein and secure the venipuncture set with a plaster. 
 
16. Let blood flow back to the open end of the venipuncture set and then attach the syringe with the 

solution. Make sure that no blood enters the syringe. 
 
17. Remove tourniquet. 
 
18. Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of the needle. 

The speed of injection should be based on your comfort, but should not be faster than 2.0 mL 
per minute. 

 
19. If a further dose needs to be administered, use a new syringe with product reconstituted as 

described above. 
 
20. If no further dose is required, remove the venipuncture set and syringe. Hold a pad firmly over 

the injection site on your outstretched arm for about  2 minutes. Finally, apply a small pressure 
dressing to the injection site  and consider if a plaster is necessary. 

 
 
 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



33 

 

 

 

 

 

 

 

 

Annex IV 

Scientific conclusions  

 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



34 

Scientific conclusions  

Treatment of congenital haemophilia is currently based on prophylactic or on-demand replacement 
therapy with coagulation factor VIII (FVIII). FVIII replacement therapy can be generally 
categorised into two broad classes of products; plasma derived (pdFVIII) and recombinant (rFVIII) 
FVIII. A wide range of individual pdFVIII and rFVIII products are authorised for use in the 
European Union.  

A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that 
neutralise FVIII activity, causing loss of bleeding control. Treatment of patients who have 
developed inhibitors requires careful individual management and can be resistant to therapy.  

Treatment with both pdFVIII and rFVIII can lead to development of inhibitors (tested with the 
Nijmegen method of the Bethesda assay and defined as ≥ 0.6 Bethesda units (BU) for “a low titre” 
inhibitor and >5 BU for a “high-titre” inhibitor). 

The occurrence of inhibitor development in haemophilia A patients receiving FVIII products mostly 
occurs in previously-untreated patients (PUPs) or minimally treated patients (MTPs) who are still 
within the first 50 days of exposure (EDs) to the treatment. Inhibitors are less likely to occur in 
previously-treated patients (PTPs).  

The known risk factors for inhibitor development can be grouped into patient and treatment-related 
factors:  

 Patient-related risk factors include type of F8 gene mutation, severity of haemophilia, 
ethnicity, family history of inhibitor development and possibly HLA-DR (Human Leukocyte 
Antigen - antigen D Related) constitution.  

 Treatment-related factors include intensity of exposure, number of exposure days (EDs), on 
demand treatment posing a greater risk than prophylaxis, particularly in the context of 
danger signals such as trauma or surgery, and young age at first treatment poses a higher 
risk.  

Whether there are significant differences in the risk of inhibitor development between different 
types of FVIII replacement product remains an area of uncertainty. Differences between products 
in each FVIII class  and consequently differential risks between individual products, are biologically 
plausible. The pdFVIII class consists of products with or without Von Willebrand Factor (VWF), and 
those with VWF contain a range of VWF levels. Some experimental studies have suggested a role 
for VWF in protecting FVIII epitopes from recognition by the antigen-presenting cells, thereby 
reducing immunogenicity, although this remains theoretical. VWF is not present in rFVIII, but there 
is significant heterogeneity within the rFVIII class for instance due to the different manufacturing 
processes used, with a wide range of products from different manufacturers produced over the past 
20 years. These different manufacturing processes (including the different cell lines used to 
engineer the rFVIII products) can in theory lead to differential immunogenicity. 

In May 2016, an open-label, randomised controlled trial aimed at addressing the incidence of 
inhibitors between the two classes (pdFVIII vs. rFVIII products) was published in the New England 
Journal of Medicine1. This trial, known as the SIPPET study (“Survey of Inhibitors in Plasma-Product 
Exposed Toddlers”) was conducted to evaluate the relative risk of inhibitors in patients treated with 
pdFVIII compared to rFVIII. It found that patients treated with rFVIII products had an 87% higher 
incidence of all inhibitors than those treated with pdFVIII (which contained VWF) (hazard ratio, 
1.87; 95% CI, 1.17 to 2.96).  

                                                      
1 F. Peyvandi et al. “A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A” 
N Engl J Med. 2016 May 26;374(21):2054-64)   

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



35 

On 6 July 2016 Paul-Ehrlich-Institut Germany initiated a referral under Article 31 of Directive 
2001/83/EC resulting from pharmacovigilance data, and requested the PRAC to assess the 
potential impact of the results of the SIPPET study on the marketing authorisations of relevant 
FVIII products and to issue a recommendation on whether these should be maintained, varied, 
suspended or revoked and whether any risk minimisation measures should be implemented. The 
referral focuses on the risk of inhibitor development in PUPs.  

Further to the recent publication on the SIPPET study, the MAHs were requested to assess the 
potential impact of the results of this study and other relevant safety data on inhibitor development 
in PUPs on the MA of their FVIII product including consideration on risk minimisation measures.  

The lead authors of the SIPPET study were also invited to respond to a list of questions regarding 
the study methods and findings and to present their conclusions at the February 2017 PRAC 
plenary meeting. Information submitted by the lead authors of the SIPPET study during the course 
of the referral was also taken into consideration by PRAC in reaching its conclusion.  

Clinical discussion  

Published observational studies 

The responses of MAHs referred to a range of published observational studies (the CANAL, RODIN, 
FranceCoag, UKHCDO, amongst others) which have sought to evaluate any differential risks of 
inhibitor development between the classes of pdFVIII and rFVIII, as well as any differential risk of 
inhibitor development between products within the rFVIII class.  

These studies have yielded different results and suffer from the limitations of observational studies, 
and in particular from possible selection bias. The risk of inhibitor development is multifactorial 
(aside from any putative product-specific risk), and such studies have not always been able to 
collect information on relevant covariates and to adjust the analyses accordingly; residual 
confounding is inevitably a significant uncertainty. Furthermore, over time there have been 
changes in manufacturing process of individual products and changes in treatment regimens 
between centres, hence “like for like” comparisons between products is not always possible. These 
factors make control of such studies and interpretation of the results challenging. 

The CANAL study2 found no evidence of a class difference, including pdFVIII products with 
considerable quantities of von Willebrand factor; for ‘clinically relevant’ inhibitors the adjusted 
hazard ratio was 0.7 (95% CI 0.4-1.1), and for high titre inhibitors (≥5 BU) was 0.8 (95% CI 0.4-
1.3).  

The RODIN/Pednet study3 also found no evidence of a class difference in inhibitor risk between all 
pdFVIII vs all rFVIII; for ‘clinically relevant’ inhibitors the adjusted hazard ratio was 0.96 (95% CI 
0.62-1.49), and for high titre inhibitors (≥5 BU/ml) was 0.95 (95% CI 0.56-1.61). However, the 
study found evidence of an increased risk of inhibitors (all and high titre) for 2nd generation rFVIII 
octocog alfa (Kogenate FS/Helixate NexGen) compared with 3rd generation rFVIII octocog alfa 
(which was driven solely by data for Advate). 

Similar to RODIN/Pednet, the UKHCDO study found a significant increased risk of inhibitors (all and 
high titre) for Kogenate FS/Helixate NexGen (2nd generation rFVIII) compared to Advate (3rd 
generation rFVIII). Although this became non-significant when UK patients (also included in the 
RODIN/Pednet study were excluded. There was also evidence for an increased risk with Refacto AF 
(another 3rd generation rFVIII) vs Advate, but only for all inhibitor development. Like the UKHCDO 

                                                      
2 http://www.bloodjournal.org/content/109/11/4648.full.pdf 
3 Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development 
in severe hemophilia A. N Engl J Med 2013; 368: 231-9. - 
http://www.bloodjournal.org/content/121/20/4046.full.pdf 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



36 

study, the FranceCoag study also found no statistically significant increased risk for any rFVIII 
products vs Advate when French patients (also in the RODIN/Pednet study) were excluded.  

Prior to the current referral, it was noted that PRAC had already considered the implications of the 
RODIN/Pednet, the UKHCDO and the FranceCoag studies for the EU marketing authorisations for 
FVIII products. In 2013, PRAC had concluded that the RODIN/Pednet findings were not sufficiently 
robust to support a conclusion that Kogenate FS/Helixate NexGen was associated with an increased 
risk of developing factor VIII inhibitors compared with other products. In 2016, PRAC had 
considered the findings of meta-analysis of all three studies (RODIN/Pednet, UKHCDO and 
FranceCoag studies), and again concluded that the currently available evidence does not confirm 
that Kogenate Bayer/Helixate NexGen is associated with an increased risk of factor VIII inhibitors, 
compared with other recombinant factor VIII products in PUPs. 

  MAH-sponsored studies 

The MAHs provided an analysis of low and high titre inhibitor development in PUPs with severe 
haemophilia A (FVIII < 1%) from all clinical trials and observational studies conducted with their 
products, along with critical discussion on the limitations of these studies.   

The data came from a very wide range of heterogenous studies across products and over time. 
Many of these studies were small and not specifically designed to evaluate the inhibitor risk in PUPs 
with severe haemophilia A. The studies were mostly single arm and do not provide data to perform 
comparative analysis (either between pdFVIII and rFVIII as a class comparison, or within the rFVIII 
class). However, the general estimates of inhibitor rates from these studies for individual products 
are broadly in line with the findings from large observational studies. 

Of the larger and more relevant studies for pdFVIII products, inhibitor rates observed (often not 
stated if high or low titre) ranged from 3.5 to 33%, with most around 10-25%. However, in many 
cases little information was provided on the methods, patient populations and nature of the 
inhibitors to assess the information in the context of more recent published data. For most rFVIII 
products, newer and more relevant information from clinical trials in PUPs is available. Inhibitor 
rates in these studies range from 15 to 38% for all inhibitors and 9 to 22.6% for high titre 
inhibitors; i.e. within the range of ‘very common’.  

The PRAC also considered interim results submitted by the MAHs from ongoing studies from CSL 
(CRD019_5001) and Bayer (Leopold KIDS, 13400, part B.). 

Furthermore, the PRAC examined clinical trials and the scientific literature for de novo inhibitors in 
PTPs. The analysis demonstrated that the frequency of inhibitor development is much lower in PTPs 
compared to PUPs. The available data showed that in many studies including the EUHASS registry 
(Iorio A, 20174; Fischer K, 20155) the frequency could be classified as “uncommon”.  

The SIPPET study 

The SIPPET study was an open-label, randomized, multi-centre, multi-national trial investigating 
the incidence of neutralising allo-antibodies in patients with severe congenital haemophilia A 
(plasma FVIII concentration<1%) with either the use of pdFVIII or rFVIII concentrates. Eligible 

                                                      
4 Iorio A, Barbara AM, Makris M, Fischer K, Castaman G, Catarino C, Gilman E, Kavakli K, Lambert 
T, Lassila R, Lissitchkov T, Mauser-Bunschoten E, Mingot-Castellano ME0, Ozdemir N1, Pabinger I, 
Parra R1, Pasi J, Peerlinck K, Rauch A6, Roussel-Robert V, Serban M, Tagliaferri A, Windyga J, 
Zanon E: Natural history and clinical characteristics of inhibitors in previously treated haemophilia 
A patients: a case series. Haemophilia. 2017 Mar;23(2):255-263. doi: 10.1111/hae.13167. Epub 
2017 Feb 15. 
5 Fischer K, Lassila R, Peyvandi F, Calizzani G, Gatt A, Lambert T, Windyga J, Iorio A, Gilman E, 
Makris M; EUHASS participants Inhibitor development in haemophilia according to concentrate. 
Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb 
Haemost. 2015 May;113(5):968-75. doi: 10.1160/TH14-10-0826. Epub 2015 Jan 8. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



37 

patients (<6 years, male, severe haemophilia A, no previous treatment with any FVIII concentrate 
or only minimal treatment with blood components) were included from 42 sites. The primary and 
secondary outcomes assessed in the study were the incidence of all inhibitors (≥0.4 BU/ml) and 
the incidence of high-titre inhibitors (≥5 BU/ml), respectively. 

Inhibitors developed in 76 patients, 50 of whom had high-titre inhibitors (≥5 BU). Inhibitors 
developed in 29 of the 125 patients treated with pdFVIII (20 patients had high-titre inhibitors) and 
in 47 of the 126 patients treated with rFVIII (30 patients had high-titre inhibitors). The cumulative 
incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with pdFVIII and 
44.5% (95% CI, 34.7 to 54.3) with rFVIII; the cumulative incidence of high-titre inhibitors was 
18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression 
models for the primary end point of all inhibitors, rFVIII was associated with an 87% higher 
incidence than pdFVIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association was 
consistently observed in multivariable analysis. For high-titre inhibitors, the hazard ratio was 1.69 
(95% CI, 0.96 to 2.98).  

 Ad hoc expert group meeting 

The PRAC considered the views expressed by experts during an ad-hoc meeting. The expert group 
was of the view that the relevant available data sources have been considered. The expert group 
suggested that further data are needed to establish if there are clinically relevant differences in 
frequency of inhibitor development between different factor VIII products and that, in principle, 
such data should be collected separately for individual products, as degree of immunogenicity will 
be difficult to generalise across the classes of products (i.e. recombinant vs. plasma-derived). 

The experts also agreed that the degree of immunogenicity of different products was adequately 
described overall with the amendments to the SmPC proposed by the PRAC highlighting the clinical 
relevance of inhibitor development (in particular low compared to high titre inhibitors), as well as 
the  frequency of ‘very common’ in PUPs and ‘uncommon’ in PTPs. The experts also suggested 
studies which could further characterise the immunogenic properties of the factor VIII medicinal 
products (e.g. mechanistic, observational studies).   

Discussion  

The PRAC considered that as a prospective randomised trial, the SIPPET study avoided many of the 
design limitations of the observational and registry-based studies undertaken so far to evaluate the 
risk of inhibitor development in PUPs. However the PRAC is of the view that there are uncertainties 
with regards to the findings of the SIPPET study which preclude the conclusion that there is a 
higher risk of inhibitor development in PUPs treated with rFVIII products than pdFVIII products 
studied in this clinical trial, as detailed below:   

 The SIPPET analysis does not allow for product-specific conclusions to be made as it relates 
only to a small number of certain FVIII products. The study was not designed and powered 
to generate sufficient product-specific data and, therefore, to draw any conclusions on the 
risk of inhibitor development for individual products. In particular, only 13 patients (10% of 
the FVIII arm) received a third generation rFVIII product. However, despite the lack of 
robust evidence to support differential risks between rFVIII products, differential risks 
cannot be excluded, as this is a heterogeneous product class with differences in 
composition and formulations. Therefore, there is a high degree of uncertainty around 
extrapolating the SIPPET findings to the entire rFVIII class, particularly for more recently-
authorised rFVIII products which were not included in the SIPPET trial.  

 The SIPPET study has methodological limitations, with particular uncertainty around whether 
the randomisation process (block size of 2) may have introduced a selection bias in the 
study.   

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



38 

 There were also deviations from the final protocol and statistical analysis plan. The statistical 
concerns include the fact that no pre-specified primary analysis has been published and the 
fact that the study was stopped early following the publication of the RODIN study 
indicating that Kogenate FS might be associated with an increased risk of inhibitor 
formation. Although this could not have been prevented, an early termination of an open 
label trial raises the possibility of investigator bias and inflation of the probability of 
detecting an effect that is not present. 

 Treatment regimens in EU are different from those in the SIPPET study. The relevance for 
clinical practice in the EU (and therefore for the products subject to this procedure) is 
therefore questioned. It is uncertain whether the findings of SIPPET can be extrapolated to 
the risk of inhibitors in PUPs in current clinical practice in the EU as treatment modality and 
intensity have been suggested as risk factors for inhibitor development in previous studies. 
Importantly, the EU SmPCs do not include modified prophylaxis (as defined in the SIPPET 
study) as an authorised posology, and the impact of the apparent imbalance in the 
unspecified other combinations of treatment modality on the SIPPET findings is unclear. 
Therefore, it remains uncertain whether the same differential risk of inhibitor development 
observed in the SIPPET study would be apparent in patient populations treated in routine 
care in other countries where the modality of treatment (i.e. primary prophylaxis) is 
different from that in the study. The additional points of clarification provided by the 
SIPPET authors do not fully resolve this uncertainty. 

Having considered the abovementioned results from SIPPET, the published literature and all the 
information submitted by the MAHs, as well as the views expressed by experts expressed at the 
ad-hoc expert meeting, the PRAC concluded that: 

 Inhibitor development is an identified risk with both pdFVIII and rFVIII products. Although 
the clinical studies for some individual products have identified limited numbers of cases of 
inhibitor development, these tend to be small studies with methodological limitations, or 
studies not adequately designed to evaluate this risk. 

 The FVIII products are heterogenous, and the plausibility of different rates of inhibitor 
development between individual products cannot be excluded.  

 Individual studies have identified a wide range of inhibitor development across products, but 
the direct comparability of study results is questionable based on diversity of study 
methods and patient populations over time.  

 The SIPPET study was not designed to evaluate the risk of inhibitor development for 
individual products, and included a limited number of FVIII products. Due to heterogeneity 
across products, there is considerable uncertainty in extrapolating the findings of studies 
that have evaluated only class effects to individual products; and particularly to products 
(including more recently authorised products) which are not included in such studies. 

 Finally, the PRAC noted that to date most studies evaluating a differential risk of inhibitor 
development between classes of FVIII products suffer from a variety of potential 
methodological limitations and based on the available data considered there is no clear and 
consistent evidence to suggest differences in relative risk between classes of FVIII 
products. Specifically, the findings from the SIPPET study, as well as those from the 
individual clinical trials and observational studies included in the MAH responses, are not 
sufficient to confirm any consistent statistically and clinically meaningful differences in 
inhibitor risk between the rFVIII and pdFVIII product classes. 

In view of the above, the PRAC recommended the following updates of sections 4.4, 4.8 and 5.1 of 
the SmPC as well as sections 2 and 4 of the Package Leaflet for the FVIII products indicated for the 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



39 

treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency) as follows: 

 The section 4.4 of the SmPC should be amended to include a warning on the clinical 
importance of monitoring patients for FVIII inhibitor development (in particular warning on 
the clinical consequences of low compared to high titre inhibitors).  

 With regards to sections 4.8 and 5.1 of the SmPC, the PRAC noted that several FVIII 
products currently include reference to data from study results which do not allow for a 
definite conclusion on the inhibitor risk for individual products. As the evidence suggests 
that all human FVIII products carry a risk of inhibitor development such statements should 
be removed. The available data supports a frequency of FVIII inhibitor development within 
the frequency of ‘very common’ and ‘uncommon’, for PUPs and PTPs respectively, therefore 
the PRAC recommends that the SmPCs should be aligned with these frequencies unless 
justified by product specific data. For products for which section 4.2 contains the following 
statement for PUPs: “<Previously untreated patients. The safety and efficacy of 
{(Invented) name} in previously untreated patients have not yet been established. No data 
are available. >), the above frequency for PUPs should not be implemented. In relation to 
section 5.1, any reference to inhibitor development studies in PUPs and PTPs should be 
deleted unless the studies were conducted in compliance with a Paediatric Investigation 
Plan or the studies provide robust evidence of a frequency of inhibitors in PUP which is less 
than ‘very common’ or for PTPs which is different from ‘uncommon’ (as laid down in the 
attachments of the PRAC AR). 

Further to the assessment of the totality of the responses submitted by the MAH for susoctocog 
alfa (Obizur), the PRAC is of the opinion that the outcome of this article 31 referral procedure does 
not apply to this product in view of the indication of Obizur (acquired haemophilia A due to 
inhibitory antibodies to endogenous FVIII) and the different target population. 

Benefit –risk balance 

Based on the current evidence from the SIPPET study, as well as data from the individual clinical 
trials and observational studies included in the MAH responses, and the views expressed by the 
experts of the ad-hoc expert meeting, the PRAC agreed that the current evidence does not provide 
clear and consistent evidence of any statistically and clinically meaningful differences in inhibitor 
risk between rFVIII and pdFVIII products. No conclusions can be drawn on any role of VWF in 
protecting against inhibitor development. 

Given these are heterogenous products, this does not preclude individual products being associated 
with an increased risk of inhibitor development in ongoing or future PUP studies. 

Individual studies have identified a wide range of inhibitor frequency in PUPs across products, and 
the SIPPET study was not designed to differentiate between individual products in each class. Due 
to very different study methods and patient populations that have been studied over time, and 
inconsistent findings across studies, the PRAC found that the totality of evidence does not support 
a conclusion that recombinant factor VIII medicines, as a class, poses a greater risk of inhibitor 
development than the class derived from plasma. 

Besides, the PRAC noted that several FVIII products currently include in their product information 
reference to data from study results which do not allow a definite conclusion on the inhibitor risk 
for individual products. As the evidence suggests that all human FVIII products carry a risk of 
inhibitor development, within the frequency of ‘very common’ and ‘uncommon’ for PUPs and PTPs 
respectively, the PRAC recommends that the SmPCs should be aligned with these frequencies 
unless justified by product specific data. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



40 

In view of the above, the PRAC concluded that the benefit-risk balance of Factor VIII products 
indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital 
factor VIII deficiency), remains favourable subject to the changes to the product information 
agreed (section 4.4, 4.8 and 5.1 of the SmPC).  

Re-examination procedure 

Following the adoption of the PRAC recommendation during the May 2017 PRAC meeting, the MAH 
LFB Biomedicaments expressed their disagreement with the initial PRAC recommendation.  

Given the detailed grounds provided by the MAH, the PRAC carried out a new assessment of the 
available data in the context of the re-examination.  

PRAC discussion on grounds for re-examination 

The SIPPET study was not designed to evaluate the risk of inhibitor development for individual 
products, and included a limited number of FVIII products. Due to heterogeneity across products, 
there is considerable uncertainty in extrapolating the findings of studies that have evaluated only 
class effects to individual products; and particularly to products (including more recently authorised 
products) which are not included in such studies. The findings from the SIPPET study, as well as 
those from the individual clinical trials and observational studies, are not sufficient to confirm any 
consistent statistically and clinically meaningful differences in inhibitor risk between the rFVIII and 
pdFVIII product classes. 

Overall, the PRAC maintains its conclusions that standardised information on the frequency for 
FVIII products in PUP and PTP should be reflected in section 4.8 of the SmPC, unless another 
frequency range for a specific medicinal product is demonstrated by robust clinical studies for 
which the results would be summarised in section 5.1. 

Expert consultation 

The PRAC consulted an ad-hoc expert meeting on some of the aspects that formed part of the 
detailed grounds submitted by LFB Biomedicaments. 

Overall, the expert group supported the PRAC initial conclusions and agreed that the proposed 
product information provides an adequate level of information to appropriately communicate to 
prescribers and patients about the risk of inhibitor development. No additional communication, on 
risk factors for inhibitor development beyond the product information or any additional risk 
minimisation measures was recommended. 

The group also agreed that specific data about frequency of inhibitors for each product should not 
be included in the SmPC as the available studies are not adequately powered to draw precise 
conclusions on the absolute frequency for each product or on the relative frequency of inhibitors 
between products.  

The experts emphasized that collaboration between academia, industry and regulators should be 
encouraged to collect harmonised data through registries.  

PRAC conclusions 

In conclusion, further to the initial assessment and the re-examination procedure, PRAC maintains 
its conclusion that the benefit-risk balance of the human plasma derived and recombinant 
coagulation Factor VIII containing medicinal products remains favourable subject to the agreed 
changes to the product information (section 4.4, 4.8 and 5.1 of the SmPC). 

The PRAC adopted a recommendation on 01 September 2017 which was then considered by the 
CHMP, in accordance with Article 107k of Directive 2001/83/EC. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



41 

Overall summary of the scientific evaluation by the PRAC 

Whereas,  

• The PRAC considered the procedure under Article 31 of Directive 2001/83/EC resulting from 
pharmacovigilance data, for human plasma derived and recombinant coagulation factor 
VIII containing medicinal products (see Annex I and Annex A).  

• The PRAC considered the totality of the data submitted with regards to the risk of inhibitor 
development for the classes of recombinant and plasma derived FVIII products, in 
previously untreated patients (PUPs). This included published literature (SIPPET study6), 
data generated in individual clinical trials and a range of observational studies submitted by 
the marketing authorisation holders, including the data generated in large multicentre 
cohort studies, data submitted by the national competent authorities of the EU Member 
States as well as responses provided by the Authors of the SIPPET study. PRAC also 
considered grounds submitted by LFB Biomedicaments as basis for their request for re-
examination of the PRAC recommendation and the views of two experts meetings held on 
22 February and 3 August 2017. 

• The PRAC noted that the SIPPET study was not designed to evaluate the risk of inhibitor 
development for individual products, and included a limited number of FVIII products in 
total. Due to the heterogeneity across products, there is considerable uncertainty in 
extrapolating the findings of studies evaluating only class effects to individual products; 
and particularly to the products that are not included in such studies. 

• The PRAC also considered that studies conducted to date suffer from a variety of 
methodological limitations and, on balance, there is no clear and consistent evidence to 
suggest differences in relative risks between FVIII product classes based on available data. 
Specifically, the findings from the SIPPET study, as well as those from the individual clinical 
trials and observational studies included in the MAH responses, are not sufficient to confirm 
any consistent statistically and clinically meaningful differences in inhibitor risk between 
rFVIII and pdFVIII product classes. Given these are heterogenous products, this does not 
preclude individual products being associated with an increased risk of inhibitor 
development in ongoing or future PUP studies. 

 The PRAC noted that the efficacy and safety of Factor VIII products as indicated in the 
treatment and prophylaxis of bleeding in patients with haemophilia A have been 
established.Based on the available data, the PRAC considered that SmPC updates for the 
FVIII products are warranted: section 4.4 should be amended to include a warning on the 
clinical importance of monitoring patients for FVIII inhibitor development. With regards to 
sections 4.8 and 5.1, the PRAC noted that several FVIII products currently include 
reference to data from study results which do not allow a definite conclusion on the 
inhibitor risk for individual products. Results of clinical studies not sufficiently robust (e.g. 
suffering from methodolical limitations) should not be reflected in the product information 
on FVIIII products. The PRAC recommended changes to the product information 
accordingly. Besides, as the evidence suggests that all human FVIII products carry a risk of 
inhibitor development, within the frequency of ‘very common’ and ‘uncommon’, for PUPs 
and PTPs respectively, the PRAC recommended that the product information of these 
products should be aligned with these frequencies unless justified by product specific data.  

Therefore, the PRAC concluded that the benefit-risk balance of the human plasma derived and 
recombinant coagulation Factor VIII containing medicinal products remains favourable and 
recommended the variations to the terms of the marketing authorisations. 
                                                      
6 Peyvandi F, Mannucci PM, Garagiola I, et al. A Randomized Trial of Factor VIII and Neutralizing 
Antibodies in Hemophilia A. The New England journal of medicine 2016 May 26;374(21):2054-64 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



42 

CHMP opinion 

Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall conclusions 
and grounds for recommendation. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Annex IV