Advate

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 250 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 50 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



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On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for 3 – 4 days or more until 
pain and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the 
age of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the 
age of 6) until adequate wound healing, 
then continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



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Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from 
adult patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 
3 to 4 times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
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. 
 
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 of a 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. 
 



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Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. 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 summary of adverse reactions 
 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 



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Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 



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b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 
continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 

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increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to 
a specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval 
of 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 
438.6 

1538.5 ± 519.1 

Adjusted Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 



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The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



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6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 5 ml solvent are of type I glass closed with chlorobutyl 

rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 5 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with the 
system for reconstitution). 
 

6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 

Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 



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Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 



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3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 

administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/001 
EU/1/03/271/011 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


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1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 500 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 100 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



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On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for 3 – 4 days or more until 
pain and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the 
age of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the 
age of 6) until adequate wound healing, 
then continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



15 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
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. 
 
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 of a 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. 



16 

 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. 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 summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 



17 

Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 



18 

b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 
continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


19 

increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within 
a sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to 
a specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval 
of 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC (IU*·h/dl) 1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 
438.6 

1538.5 ± 519.1 

Adjusted Incremental 
Recovery at Cmax (IU/dL 
per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence Time (h) 11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 
Volume of Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 
The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 



20 

children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



21 

6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 5 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 5 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 

Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
-  
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 



22 

Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 



23 

4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 
administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/002 
EU/1/03/271/012 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


24 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 1000 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 200 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



25 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



26 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
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. 
 
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 of a 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. 



27 

 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. 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 summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 



28 

Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 



29 

b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 
continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


30 

increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to 
a specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval 
of 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 



31 

The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



32 

6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 5 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 5 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with the 
system for reconstitution). 
 

6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 



33 

Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 

Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 



34 

4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 
administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/003 
EU/1/03/271/013 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


35 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 1500 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 300 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clea and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



36 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for 3 – 4 days or more until 
pain and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the 
age of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the 
age of 6) until adequate wound healing, 
then continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



37 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
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. 
 
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 of a 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. 



38 

 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. 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 summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 



39 

Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 



40 

b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 
continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


41 

increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to 
a specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval 
of 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants 
(1 month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 



42 

The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



43 

6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 5 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 5 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with the 
system for reconstitution). 
 

6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
- 5. Open the package of BaxJect II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 



44 

Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 



45 

4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 
administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/004 
EU/1/03/271/014 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 
 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


46 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 2000 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 2000 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 400 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



47 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the 
age of 6) for 3 – 4 days or more until 
pain and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the 
age of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the 
age of 6) until adequate wound healing, 
then continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



48 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
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. 
 
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 of a 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. 



49 

 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. 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 summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 



50 

Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 



51 

b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 
continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


52 

increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within 
a sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to a 
specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 
72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 



53 

The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



54 

6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 5 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 5 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
- Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 



55 

Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 



56 

4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 
administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/005 
EU/1/03/271/015 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


57 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 3000 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 3000 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 600 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



58 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



59 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
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. 
 
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 of a 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. 



60 

 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. 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 summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 



61 

Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 



62 

b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 
continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 

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63 

increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to a 
specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 
72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 



64 

The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 



65 

6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 5 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 5 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 



66 

Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 



67 

4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 
administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/006 
EU/1/03/271/016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

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68 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 250 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 125 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



69 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life-threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



70 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. 
 
In case of shock, standard medical treatment for shock should be implemented. 
 
Due to the decrease in injection volume for ADVATE reconstituted in 2 ml sterilised water for 
injections, if hypersensitivity reactions occur there is less time to react by stopping the injection. 
Therefore, caution is advised during injection of ADVATE reconstituted in 2 ml sterilised water for 
injections, especially in children. 
 
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. 
 
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 of a 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 



71 

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. 
 
Misapplication of ADVATE 
For ADVATE reconstituted with 2 ml sterilised water for injections, misapplication (intra-arterially or 
paravenously) may lead to mild, short term injection site reactions, such as bruising and erythema. 
 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. If such inhibitors occur, the condition will manifest itself 



72 

as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia 
centre be contacted. 
 
Tabulated summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 
Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 



73 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 
b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 

continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 

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74 

Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 
increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved.  
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to a 
specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 
72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 311.8 1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 
438.6 

1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 



75 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 30.2 90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 
The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
A local tolerance study in rabbits showed that ADVATE reconstituted with 2 ml of sterilised water for 
injections is well tolerated after intravenous administration. Slight transient reddening at the 
administration site was observed after intraarterial application and after paravenous administration. 
However, no correlating adverse histopathological changes could be observed indicating a transient 
nature of this finding. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 



76 

6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 2 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 2 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 2 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 



77 

3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 
Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 



78 

Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 

administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/007 
EU/1/03/271/017 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


79 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 500 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 250 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



80 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



81 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 
hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. 
 
In case of shock, standard medical treatment for shock should be implemented. 
 
Due to the decrease in injection volume for ADVATE reconstituted in 2 ml sterilised water for 
injections, if hypersensitivity reactions occur there is less time to react by stopping the injection. 
Therefore, caution is advised during injection of ADVATE reconstituted in 2 ml sterilised water for 
injections, especially in children. 
 
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. 
 
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 of a 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 



82 

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. 
 
Misapplication of ADVATE 
For ADVATE reconstituted with 2 ml sterilised water for injections, misapplication (intra-arterially or 
paravenously) may lead to mild, short term injection site reactions, such as bruising and erythema. 
 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. If such inhibitors occur, the condition will manifest itself 



83 

as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia 
centre be contacted. 
 
Tabulated summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 
Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 



84 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 
b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 

continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 

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85 

The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 
increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within 
a sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to a 
specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 
72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 



86 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

(IU/dL per IU/kg)a 
Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 
The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
A local tolerance study in rabbits showed that ADVATE reconstituted with 2 ml of sterilised water for 
injections is well tolerated after intravenous administration. Slight transient reddening at the 
administration site was observed after intraarterial application and after paravenous administration. 
However, no correlating adverse histopathological changes could be observed indicating a transient 
nature of this finding. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 



87 

 
6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 2 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 2 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 2 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 



88 

1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 
from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 
Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 



89 

Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 

administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/008 
EU/1/03/271/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 
 

http://www.ema.europa.eu/
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90 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 1000 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 500 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



91 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



92 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 

hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. 
 
In case of shock, standard medical treatment for shock should be implemented. 
 
Due to the decrease in injection volume for ADVATE reconstituted in 2 ml sterilised water for 
injections, if hypersensitivity reactions occur there is less time to react by stopping the injection. 
Therefore, caution is advised during injection of ADVATE reconstituted in 2 ml sterilised water for 
injections, especially in children. 
 
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. 
 
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 of a 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 



93 

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. 
 
Misapplication of ADVATE 
For ADVATE reconstituted with 2 ml sterilised water for injections, misapplication (intra-arterially or 
paravenously) may lead to mild, short term injection site reactions, such as bruising and erythema. 
 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. If such inhibitors occur, the condition will manifest itself 



94 

as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia 
centre be contacted. 
 
Tabulated summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 
Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 



95 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 
b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 

continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 

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96 

The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 
Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 
increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to a 
specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 
72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 



97 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 
Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at Steady 
State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal 

post-infusion Factor VIII measurement. 
 
The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
A local tolerance study in rabbits showed that ADVATE reconstituted with 2 ml of sterilised water for 
injections is well tolerated after intravenous administration. Slight transient reddening at the 
administration site was observed after intraarterial application and after paravenous administration. 
However, no correlating adverse histopathological changes could be observed indicating a transient 
nature of this finding. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 



98 

6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 2 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 2 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 2 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 



99 

1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 
from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 
Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 



100 

Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 

administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/009 
EU/1/03/271/019 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


101 

1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains nominally 1500 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATE 
contains approximately 750 IU per ml of human coagulation factor VIII (rDNA), octocog alfa after 
reconstitution. 
 
The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ADVATE is approximately 4,000-10,000 IU/mg protein. 
Octocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 2332 amino acids. 
It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Prepared 
without the addition of any (exogenous) human- or animal-derived protein in the cell culture process, 
purification or final formulation. 
 
Excipients with known effect: 
0.45 mmol sodium (10 mg) per vial. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
Powder: White to off-white friable powder. 
Solvent: Clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). ADVATE is indicated in all age groups. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia and with resuscitation support immediately available in case of anaphylaxis. 
 
Posology 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of the bleeding and on the patient’s clinical condition. 
 
The number of units of factor VIII is expressed in International Units (IU), which are related to the 
WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a 
percentage (relative to normal human plasma) or in IUs (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. 
 



102 

On demand treatment 
The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor 
VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5 
 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 can 
be used to guide dosing in bleeding episodes and surgery: 
 

Table 1 Guide for dosing in bleeding episodes and surgery 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
During the course of treatment, appropriate determination of plasma factor VIII levels is advised to 
guide the dose to be administered and the frequency of repeated injections. In the case of major 
surgical interventions in particular, precise monitoring of the substitution therapy by means of plasma 
factor VIII activity assay is indispensable. Individual patients may vary in their response to factor 
VIII, achieving different levels of in vivo recovery and demonstrating different half-lives. 
 
Prophylaxis 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses 
are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. 
 



103 

Paediatric population 
For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adult 
patients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4 
times weekly are recommended for prophylactic therapy. 
 
Method of administration 
ADVATE should be administered via the intravenous route. In case of administration by a non health 
care professional appropriate training is needed. 
 
The rate of administration should be determined to ensure the comfort of the patient up to a maximum 
of 10 ml/min. 
 
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH 
of 6.7 to 7.3. 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse or 

hamster proteins. 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity 
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. 
The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, 
patients should be advised to discontinue use of the product immediately and contact their physician. 
Patients should be informed of the early signs of hypersensitivity reactions including hives, 
generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. 
 
In case of shock, standard medical treatment for shock should be implemented. 
 
Due to the decrease in injection volume for ADVATE reconstituted in 2 ml sterilised water for 
injections, if hypersensitivity reactions occur there is less time to react by stopping the injection. 
Therefore, caution is advised during injection of ADVATE reconstituted in 2 ml sterilised water for 
injections, especially in children. 
 
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. 
 
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 of a 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 



104 

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. 
 
Misapplication of ADVATE 
For ADVATE reconstituted with 2 ml sterilised water for injections, misapplication (intra-arterially or 
paravenously) may lead to mild, short term injection site reactions, such as bruising and erythema. 
 
Catheter-related complications in treatment 
If central venous access device (CVAD) is required, risk of CVAD-related complications including 
local infections, bacteremia and catheter site thrombosis should be considered. 
 
Excipient related considerations 
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken 
into consideration by patients on a controlled sodium diet. 
 
It is strongly recommended that every time ADVATE 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 to both adults and children. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with ADVATE. 
 
4.6 Fertility, pregnancy and lactation 
 
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence 
of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and 
breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-
feeding only if clearly indicated. 
 
4.7 Effects on ability to drive and use machines 
 
ADVATE has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE 
reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency 
were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. 
 
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 
rarely and may in some cases progress to severe anaphylaxis (including shock). 
 
Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions 
may be observed. 
 
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated 
with factor VIII, including with ADVATE. If such inhibitors occur, the condition will manifest itself 



105 

as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia 
centre be contacted. 
 
Tabulated summary of adverse reactions 
The following table 2 provides the frequency of adverse drug reactions in clinical trials and from 
spontaneous reporting. The table is according to the MedDRA system organ classification (SOC and 
Preferred Term Level). 
 
Frequency categories are defined 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). Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Infections and infestations Influenza Uncommon 
Laryngitis Uncommon 

Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)d 
Very common (PUPs)d 

 
Lymphangitis Uncommon 

Immune system disorders Anaphylactic reaction Not known 
Hypersensitivityc Not known 

Nervous system disorders Headache Common 
Dizziness Uncommon 
Memory impairment Uncommon 
Syncope Uncommon 
Tremor Uncommon 
Migraine Uncommon 
Dysgeusia Uncommon 

Eye disorders Eye inflammation Uncommon 
Cardiac disorders Palpitations Uncommon 
Vascular disorders Haematoma Uncommon 

Hot flush Uncommon 
Pallor Uncommon 

Respiratory, thoracic and mediastinal disorders Dyspnoea Uncommon 
Gastrointestinal disorders Diarrhoea Uncommon 

Abdominal pain upper Uncommon 
Nausea Uncommon 
Vomiting Uncommon 

Skin and subcutaneous tissue disorders Pruritus Uncommon 
Rash Uncommon 
Hyperhidrosis Uncommon 
Urticaria Uncommon 

General disorders and administration site 
conditions 

Pyrexia Common 
Peripheral oedema Uncommon 
Chest pain Uncommon 
Chest discomfort Uncommon 
Chills Uncommon 
Feeling abnormal Uncommon 
Vessel puncture site haematoma Uncommon 
Fatigue Not known 
Injection site reaction Not known 
Malaise Not known 

Investigations Monocyte Count increased Uncommon 
Coagulation factor VIII level 
decreasedb 

Uncommon 

Haematocrit decreased Uncommon 
Laboratory test abnormal Uncommon 



106 

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports 
MedDRA Standard System Organ Class Adverse reaction Frequencya 

Injury, poisoning and procedural complications Post procedural complication Uncommon 
Post procedural haemorrhage Uncommon 
Procedural site reaction Uncommon 

 
a) Calculated based on total number of patients who received ADVATE (418). 
b) The unexpected decrease in coagulation factor VIII levels occurred in one patient during 

continuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasis 
was maintained at all times during this period and both plasma factor VIII levels and clearance 
rates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assays 
performed after completion of continuous infusion and at study termination were negative. 

c) ADR explained in the section below. 
d) Frequency is based on studies with all FVIII products which included patients with severe 

haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients 
 
Description of selected adverse reactions 
ADRs specific to residues from the manufacturing process 
Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cell 
protein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks or 
transient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients who 
were assessed for antibodies to murine IgG, 10 showed a statistically significant upward 
trend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patients 
reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongst 
repeated exposures to the study product. 
 
Hypersensitivity 
Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash, 
flushing, face swelling, urticaria, and pruritus. 
 
Paediatric population 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in ADRs were noted in the clinical studies. 
 
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 symptoms of overdose with recombinant coagulation factor VIII have been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII. ATC code: B02BD02. 
 
The factor VIII/von Willebrand Factor complex consists of two molecules (factor VIII and von 
Willebrand Factor) with different physiological functions. ADVATE contains recombinant 
coagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIII 
glycoprotein found in human plasma. 
 

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107 

Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular mass 
of 280 kD. When infused into a haemophilia patient, octocog alfa binds to endogenous von Willebrand 
Factor 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 to 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 activity and results in profuse bleeding into joints, muscles or internal organs, either 
spontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII are 
increased by replacement therapy, thereby enabling a temporary correction of the factor VIII 
deficiency and correction of the bleeding tendency. 
 
Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Within a 
sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chart 
review was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospective 
registry (PASS-INT-004) documented ITI in 44 paediatric and adult subjects of whom 36 completed 
ITI therapy. Data show that immune tolerance may be achieved. 
 
In study 060201 two long-term prophylaxis treatment schemes have been compared in 53 PTPs: an 
individualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIII 
per kg body weight at intervals of 72 ± 6 hours, n=23) with a standard prophylactic dosing regimen 
(20 to 40 IU/kg every 48 ±6 hours, n=30). The pharmacokinetic guided dosing regimen (according to a 
specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing interval of 
72 hours. The data from this study demonstrate that the two prophylactic dosing regimens are 
comparable in terms of reduction of bleeding rate. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ADVATE in all subsets of the paediatric population in haemophilia A (congenital factor VIII 
deficiency) in "Immune Tolerance Induction (ITI) in patients with haemophilia A (congenital factor 
VIII deficiency) who have developed inhibitors to factor VIII" and "treatment and prophylaxis of 
bleeding in patients with haemophilia A (congenital factor VIII deficiency)". (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severe 
to moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples was 
conducted in a central laboratory using a one-stage clotting assay. 
 
A total of 195 subjects with severe haemophilia A (baseline factor VIII < 1%) provided PK parameters 
that were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1 
month to <2 years of age), children (2 to <5 years of age), older children (5 to <12 years of age), 
adolescents (12 to <18 years of age), and adults (18 years of age and older) were used to summarize 
PK parameters, where age was defined as age at time of PK infusion. 
 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Total AUC 
(IU*·h/dl) 

1362.1 ± 
311.8 

1180.0 ± 
432.7 

1506.6 ± 530.0 1317.1 ± 438.6 1538.5 ± 519.1 

Adjusted 
Incremental 
Recovery at Cmax 
(IU/dL per IU/kg)a 

2.2 ± 0.6 1.8 ± 0.4 2.0 ± 0.5 2.1 ± 0.6 2.2 ± 0.6 

Half-life (h) 9.0 ± 1.5 9.6 ± 1.7 11.8 ± 3.8 12.1 ± 3.2 12.9 ± 4.3 



108 

Table 3 Summary of Pharmacokinetic Parameters of ADVATE per Age Group with severe haemophilia A 
(baseline factor VIII < 1%) 

Parameter (mean ± 
standard deviation) 

Infants 
(n=5) 

Children 
(n=30) 

Older Children 
(n=18) 

Adolescents 
(n=33) 

Adults 
(n=109) 

Maximum Plasma 
Concentration Post 
Infusion (IU/dl) 

110.5 ± 
30.2 

90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1 

Mean Residence 
Time (h) 

11.0 ± 2.8 12.0 ± 2.7 15.1 ± 4.7 15.0 ± 5.0 16.2 ± 6.1 

Volume of 
Distribution at 
Steady State (dl/kg) 

0.4 ± 0.1 0.5 ± 0.1 0.5 ± 0.2 0.6 ± 0.2 0.5 ± 0.2 

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2 
a Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-
infusion Factor VIII measurement. 
 
The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of 
adult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in young 
children (less than 6 years of age) than in adults, which may be due in part to the known higher plasma 
volume per kilogram body weight in younger patients. 
 
Pharmacokinetic data with ADVATE on previously untreated patients are currently not available. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute 
toxicology, repeated dose toxicity, local toxicity and genotoxicity. 
 
A local tolerance study in rabbits showed that ADVATE reconstituted with 2 ml of sterilised water for 
injections is well tolerated after intravenous administration. Slight transient reddening at the 
administration site was observed after intraarterial application and after paravenous administration. 
However, no correlating adverse histopathological changes could be observed indicating a transient 
nature of this finding. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Mannitol 
Sodium chloride 
Histidine 
Trehalose 
Calcium chloride 
Trometamol 
Polysorbate 80 
Glutathione (reduced) 
 
Solvent 
Sterilised water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products or solvents. 
 



109 

6.3 Shelf life 
 
2 years. 
 
After reconstitution, from a microbiological point of view, the product should be used immediately. 
However, chemical and physical in-use stability has been demonstrated for 3 hours at 25 °C. 
 
During the shelf life, the product may be kept at room temperature (up to 25 °C) for a single period not 
exceeding 6 months. The end of the 6 months storage at room temperature should be recorded on the 
product carton. The product may not be returned to refrigerated storage again. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
ADVATE with BAXJECT II device: Keep the product vial in the outer carton in order to protect from 
light. 
ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from 
light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Both the powder vial and the vial containing 2 ml solvent are of type I glass closed with chlorobutyl 
rubber stoppers. The product is provided in one of the following configurations: 
 
- ADVATE with BAXJECT II device: Each pack contains a powder vial, a vial containing 2 ml 

solvent and a device for reconstitution (BAXJECT II). 
- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system in 

a sealed blister (the powder vial and the vial containing 2 ml solvent are preassembled with the 
system for reconstitution). 

 
6.6 Special precautions for disposal and other handling 
 
ADVATE is to be administered intravenously after reconstitution of the product. 
The reconstituted solution should be inspected visually for any foreign particulate matter and/or 
discoloration. 
After reconstitution the solution should be clear, colourless and free from foreign particles. 
Do not use solutions that are cloudy or have deposits. 
 
- For administration the use of a luer-lock syringe is required. 
- Use within three hours after reconstitution. 
- Do not refrigerate the preparation after reconstitution. 
- Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 
 
Reconstitution with the BAXJECT II device 
- For reconstitution use only the sterilised water for injections and the reconstitution device 

provided in the pack. 
- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration. 
- Aseptic Technique should be used 
 



110 

1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 
from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 
Fig. a        Fig. b          Fig. c 
 

 
 
Reconstitution with the BAXJECT III system 
- Do not use if the lid is not completely sealed on the blister 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 



111 

Fig. 1 Fig. 2 Fig. 3 

   
 
Administration 
Use Aseptic Technique 
 
Parenteral medicinal products should be inspected for particulate matter prior to administration, 
whenever solution and container permit. Only a clear and colourless solution should be used. 
 
1. Remove the blue cap from BAXJECT II / BAXJECT III. Do not draw air into the syringe. 

Connect the syringe to BAXJECT II / BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be 

administered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 ml 
per minute. The pulse rate should be determined before and during administration of ADVATE. 
Should a significant increase occur, reducing the rate of administration or temporarily 
interrupting the injection usually allows the symptoms to disappear promptly (see 
sections 4.4 and 4.8). 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/010 
EU/1/03/271/020 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 March 2004 
Date of latest renewal: 20 December 2013 
 
 
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. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


112 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

ANNEX II 
 

A. MANUFACTURERS 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 
 
 



113 

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

 
Name and address of the manufacturers of the biological active substance 
 
Baxalta Manufacturing Sàrl 
Route de Pierre-à-Bot 111 
CH-2000 Neuchâtel 
Switzerland 
 
Baxalta Manufacturing SARL 
Singapore Branch 
2A Woodlands Industrial Park D Street 2 
Singapore 737779 
Singapore 
 
Name and address of the manufacturers responsible for batch release 
 
Baxalta Belgium Manufacturing SA 
Boulevard René Branquart 80 
B-7860 Lessines 
Belgium 
 
 

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 



114 

• 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. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 



115 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



116 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



117 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 250 IU octocog alfa, approx. 50 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 250 IU octocog alfa, 1 vial with 5 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



118 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/001 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 250 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



119 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 250 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
250 IU octocog alfa 
 
 
6. OTHER 
 
 



120 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 



121 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 250 IU octocog alfa, approx. 50 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 250 IU octocog alfa and 1 vial with 5 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



122 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/011 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 250 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



123 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 5 ml solvent preassembled in BAXJECT III system. 
 



124 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



125 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 250 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



126 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



127 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 500 IU octocog alfa, approx. 100 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 500 IU octocog alfa, 1 vial with 5 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



128 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/002 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



129 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 500 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 IU octocog alfa 
 
 
6. OTHER 
 
 



130 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 



131 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 500 IU octocog alfa, approx. 100 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 500 IU octocog alfa and 1 vial with 5 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



132 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/012 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



133 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 5 ml solvent preassembled in BAXJECT III system. 
 



134 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



135 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 500 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



136 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



137 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1000 IU octocog alfa, approx. 200 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1000 IU octocog alfa, 1 vial with 5 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



138 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/003 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



139 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1000 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1000 IU octocog alfa 
 
 
6. OTHER 
 
 



140 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 



141 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1000 IU octocog alfa, approx. 200 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1000 IU octocog alfa and 1 vial with 5 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



142 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/013 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



143 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 5 ml solvent preassembled in BAXJECT III system. 
 



144 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



145 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1000 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



146 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



147 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1500 IU octocog alfa, approx. 300 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1500 IU octocog alfa, 1 vial with 5 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



148 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/004 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



149 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1500 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1500 IU octocog alfa 
 
 
6. OTHER 
 
 



150 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 
 



151 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1500 IU octocog alfa, approx. 300 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1500 IU octocog alfa and 1 vial with 5 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



152 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/014 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



153 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 5 ml solvent preassembled in BAXJECT III system. 
 



154 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



155 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1500 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



156 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



157 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 2000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 2000 IU octocog alfa, approx. 400 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 2000 IU octocog alfa, 1 vial with 5 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



158 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/005 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 2000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



159 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 2000 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2000 IU octocog alfa 
 
 
6. OTHER 
 
 



160 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 



161 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 2000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 2000 IU octocog alfa, approx. 400 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 2000 IU octocog alfa and 1 vial with 5 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



162 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/015 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 2000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



163 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 2000 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 5 ml solvent preassembled in BAXJECT III system. 
 



164 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 2000 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



165 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 2000 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



166 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



167 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 3000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 3000 IU octocog alfa, approx. 600 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 3000 IU octocog alfa, 1 vial with 5 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



168 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/006 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 3000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



169 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 3000 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3000 IU octocog alfa 
 
 
6. OTHER 
 
 



170 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 
 



171 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 3000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 3000 IU octocog alfa, approx. 600 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 3000 IU octocog alfa and 1 vial with 5 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



172 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/016 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 3000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



173 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 3000 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 5 ml solvent preassembled in BAXJECT III system. 
 



174 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 3000 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



175 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 3000 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



176 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



177 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 250 IU octocog alfa, approx. 125 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 250 IU octocog alfa, 1 vial with 2 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



178 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/007 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 250 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



179 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 250 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
250 IU octocog alfa 
 
 
6. OTHER 
 
 



180 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 



181 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 250 IU octocog alfa, approx. 125 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 250 IU octocog alfa and 1 vial with 2 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



182 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/017 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 250 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



183 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 2 ml solvent preassembled in BAXJECT III system. 
 



184 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 250 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



185 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 250 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



186 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



187 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 500 IU octocog alfa, approx. 250 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 500 IU octocog alfa, 1 vial with 2 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



188 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/008 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



189 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 500 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 IU octocog alfa 
 
 
6. OTHER 
 
 



190 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 



191 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 500 IU octocog alfa, approx. 250 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 500 IU octocog alfa and 1 vial with 2 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



192 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/018 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



193 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 2 ml solvent preassembled in BAXJECT III system. 
 



194 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 500 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



195 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 500 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



196 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



197 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1000 IU octocog alfa, approx. 500 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1000 IU octocog alfa, 1 vial with 2 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



198 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/009 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



199 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1000 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1000 IU octocog alfa 
 
 
6. OTHER 
 
 



200 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 



201 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1000 IU octocog alfa, approx. 500 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1000 IU octocog alfa and 1 vial with 2 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



202 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/019 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



203 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 2 ml solvent preassembled in BAXJECT III system. 
 



204 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1000 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



205 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1000 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



206 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



207 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1500 IU octocog alfa, approx. 750 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1500 IU octocog alfa, 1 vial with 2 ml sterilised water for 
injections, 1 BAXJECT II device. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



208 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/010 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



209 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1500 IU powder for solution for injection 
Octocog alfa 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
Single use only. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1500 IU octocog alfa 
 
 
6. OTHER 
 
 



210 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT II DEVICE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2 ml 
 
 
6. OTHER 
 



211 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection 
Octocog alfa (recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 1500 IU octocog alfa, approx. 750 IU/ml after reconstitution. 
Specific activity: approx. 4,000 – 10,000 IU/mg protein 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, 
polysorbate 80, glutathione (reduced). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
Contents: 1 vial with 1500 IU octocog alfa and 1 vial with 2 ml sterilised water for 
injections preassembled in BAXJECT III system. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use, after reconstitution. 
Single use 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 
 
 
8. EXPIRY DATE 
 
EXP: 
End of 6 month period, if stored at room temperature: 
Do not use after the expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 



212 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Can be stored at room temperature (up to 25 °C) for a single period up to 6 months. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
A-1221 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/271/020 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ADVATE 1500 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



213 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 IU powder and solvent for solution for injection 
Octocog alfa 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
Intravenous use, after reconstitution. 
Use immediately or within 3 hours of reconstitution. 
Do not use if packaging is opened or damaged. 
Powder vial and 2 ml solvent preassembled in BAXJECT III system. 
 



214 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
ASSEMBLY LABEL (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ADVATE 1500 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Manufacturing Austria AG 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 

   
 



215 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE POWDER (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ADVATE 1500 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



216 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR THE SOLVENT (BAXJECT III SYSTEM) 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Sterilised water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 



217 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



218 

Package leaflet: Information for the user 
 

ADVATE 250 IU powder and solvent for solution for injection 
ADVATE 500 IU powder and solvent for solution for injection 
ADVATE 1000 IU powder and solvent for solution for injection 
ADVATE 1500 IU powder and solvent for solution for injection 
ADVATE 2000 IU powder and solvent for solution for injection 
ADVATE 3000 IU powder and solvent for solution for injection 

 
Octocog alfa (recombinant human coagulation factor VIII) 

 
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. 
- 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. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What ADVATE is and what it is used for 
2. What you need to know before you use ADVATE 
3. How to use ADVATE 
4. Possible side effects 
5. How to store ADVATE 
6. Contents of the pack and other information 
 
 
1. What ADVATE is and what it is used for 
 
ADVATE contains the active substance octocog alfa, human coagulation factor VIII produced by 
recombinant DNA technology. Factor VIII is necessary for the blood to form clots and stop bleedings. 
In patients with haemophilia A (inborn lack of factor VIII), it is missing or not working properly. 
 
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with 
haemophilia A (an inherited bleeding disorder caused by lack of factor VIII). 
 
ADVATE is prepared without the addition of any human- or animal-derived protein in the entire 
manufacturing process. 
 
 
2. What you need to know before you use ADVATE 
 
Do not use ADVATE 
- if you are allergic to octocog alfa or any of the other ingredients of this medicine (listed in 

section 6) 
- if you are allergic to mouse or hamster proteins 
 
If you are unsure about this, ask your doctor. 
 
Warnings and precautions 
Talk to your doctor before using ADVATE. You should tell your doctor if you have been previously 
treated with Factor VIII products, especially if you developed inhibitors, since there might be a higher 
risk that it happens again. Inhibitors are blocking antibodies against factor VIII that reduce the efficacy 



219 

of ADVATE to prevent or control bleeding. Development of inhibitors is a known complication in the 
treatment of haemophilia A. If your bleeding is not controlled with ADVATE, tell your doctor 
immediately. 
 
There is a rare risk that you may experience an anaphylactic reaction (a severe, sudden allergic 
reaction) to ADVATE. You should be aware of the early signs of allergic reactions such as rash, hives, 
wheals, generalised itching, swelling of lips and tongue, difficulty in breathing, wheezing, tightness in 
the chest, general feeling of being unwell, and dizziness. These symptoms can constitute an early 
symptom of an anaphylactic shock, manifestations of which may additionally include extreme 
dizziness, loss of consciousness, and extreme difficulty in breathing. 
If any of these symptoms occur, stop the injection immediately and contact your doctor. Severe 
symptoms, including difficulty in breathing and (near) fainting, require prompt emergency treatment. 
 
Patients developing Factor VIII inhibitors 
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 
you or your child’s bleeding is not being controlled with ADVATE, tell your doctor immediately. 
 
Children and adolescents 
The listed warnings and precautions apply to both adults and children (from 0 to 18 years of age). 
 
Other medicines and ADVATE 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding 
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. 
 
Driving and using machines 
ADVATE has no influence on your ability to drive or to use machines. 
 
ADVATE contains sodium 
This medicine contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients 
on a controlled sodium diet. 
 
 
3. How to use ADVATE 
 
Treatment with ADVATE will be started by a doctor who is experienced in the care of patients with 
haemophilia A. 
 
Your doctor will calculate your dose of ADVATE (in international units or IU) depending on your 
condition and body weight, and on whether it is used for prevention or treatment of bleeding. The 
frequency of administration will depend on how well ADVATE is working for you. Usually, the 
replacement therapy with ADVATE is a life-long treatment. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Prevention of bleeding 
The usual dose of octocog alfa is 20 to 40 IU per kg body weight, administered every 2 to 3 days. 
However, in some cases, especially in younger patients, more frequent injections or higher doses may 
be necessary. 
 



220 

Treatment of bleeding 
The dose of octocog alfa is calculated depending on your body weight and the factor VIII levels to be 
achieved. The target factor VIII levels will depend on the severity and location of the bleeding. 
 
Dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal) x 0.5 
 
If you have the impression that the effect of ADVATE is insufficient, talk to your doctor. 
Your doctor will perform appropriate laboratory tests to make sure that you have adequate Factor VIII 
levels. This is particularly important if you are having major surgery. 
 
Use in children and adolescents (from 0 to 18 years of age) 
For the treatment of bleeding the dosing in children does not differ from adult patients. For the 
prevention of bleeding in children under the age of 6, doses of 20 to 50 IU per kg body weight 3 to 
4 times weekly are recommended. The administration of ADVATE in children (intravenously) does 
not differ from the administration in adults. A central venous access device (CVAD) may become 
necessary to allow frequent infusions of factor VIII products. 
 
How ADVATE is given 
ADVATE is usually injected into a vein (intravenously) by your doctor or nurse. You or someone else 
might also administer ADVATE as an injection, but only after receiving adequate training. Detailed 
instructions for self-administration are given at the end of this package leaflet. 
 
If you use more ADVATE than you should 
Always take ADVATE exactly as your doctor has told you. You should check with your doctor if you 
are not sure. If you inject more ADVATE than recommended, tell your doctor as soon as possible. 
 
If you forget to use ADVATE 
Do not inject a double dose to make up for a forgotten dose. Proceed with the next injection as 
scheduled and continue as advised by your doctor. 
 
If you stop using ADVATE 
Do not stop using ADVATE without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If severe, sudden allergic reactions (anaphylactic) occur, the injection must be stopped 
immediately. You must contact your doctor immediately if you have any of the following early 
symptoms of allergic reactions: 
 
- rash, hives, wheals, generalised itching, 
- swelling of lips and tongue, 
- difficulty in breathing, wheezing, tightness in the chest, 
- general feeling of being unwell, 
- dizziness and loss of consciousness. 
 
Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency 
treatment. 
 
For children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) 
may form very commonly (more than 1 in 10 people); 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 



221 

people). 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. 
 
Very common side effects (may affect more than 1 in 10 people) 
Factor VIII inhibitors (for children not previously treated with Factor VIII medicines).  
 
Common side effects (may affect up to 1 in 10 people) 
headache and fever. 
 
Uncommon side effects (may affect up to 1 in 100 people) 
Factor VIII inhibitors (for patients who have received previous treatment with Factor VIII (more than 
150 days of treatment)), dizziness, flu, fainting, abnormal heartbeat, red itchy bumps on the skin, chest 
discomfort, injection site bruise, injection site reaction, itching, increased sweating, unusual taste in 
the mouth, hot flushes, migraines, memory impairment, chills, diarrhoea, nausea, vomiting, shortness 
of breath, sore throat, infection of the lymphatic vessels, whitening of skin, eye inflammation, rashes, 
excessive sweating, foot and leg swelling, reduced percentage of red blood cells, increase in a type of 
white blood cells (monocytes), and pain in the upper abdomen or lower chest. 
 
Related to surgery 
catheter-related infection, decreased red cell blood count, swelling of limbs and joints, prolonged 
bleeding after drain removal, decreased Factor VIII level and post-operative bruise. 
 
Related to central venous access devices (CVAD) 
catheter-related infection, systemic infection and local blood clot at the catheter site. 
 
Side effects with unknown frequency (frequency cannot be estimated from the available data) 
potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), 
general disorders (tiredness, lack of energy). 
 
Additional side effects in children 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in side effects were noted in the clinical 
studies. 
 
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 ADVATE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the label after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
 
During the shelf life the powder vial may be kept at room temperature (up to 25 °C) for a single period 
not exceeding 6 months. In this case, this medicine expires at the end of this 6 month period or the 
expiration date printed on the product vial, whichever is earlier. Please record the end of the 6 months 
storage at room temperature on the product carton. The product may not be returned to refrigerated 
storage after storage at room temperature. 
 
Keep the vial in the outer carton in order to protect from light. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
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222 

 
This product is for single use only. Discard any unused solution appropriately. 
 
Use the product immediately once the powder is completely dissolved. 
 
Do not refrigerate the solution after preparation. 
 
Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ADVATE contains 
- The active substance is octocog alfa (human coagulation Factor VIII produced by recombinant 

DNA technology). Each powder vial contains nominally 250, 500, 1000, 1500, 2000, or 
3000 IU octocog alfa. 

- The other ingredients are mannitol, sodium chloride, histidine, trehalose, calcium chloride, 
trometamol, polysorbate 80, and glutathione (reduced). 

 
Solvent vial: 5 ml sterilised water for injections 
 
What ADVATE looks like and contents of the pack 
ADVATE is a white to off-white friable powder. After reconstitution, the solution is clear, colourless 
and free from foreign particles. 
Each pack also contains a device for reconstitution (BAXJECT II). 
 
Marketing Authorisation Holder 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Tel: +800 66838470 
e-mail: medinfoEMEA@shire.com 
 
Manufacturer 
Baxalta Belgium Manufacturing SA 
Boulevard René Branquart 80 
B-7860 Lessines 
Belgium 
 
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 
 
Instructions for preparation and administration 
 
Aseptic technique is required during preparation of the solution and administration. 
 
Use only the sterilised water for injections and the reconstitution device for preparation of the solution 
that are provided with each package of ADVATE. ADVATE must not be mixed with other medicinal 
products or solvents. 
 
It is strongly recommended that every time ADVATE is administered, the name and batch number of 
the product are recorded. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


223 

 
Instructions for reconstitution 
• Do not use after the expiry date stated on the labels and carton. 
• Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration as indicated by the symbol: . 
• Do not refrigerate the solution after preparation. 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 
Fig. a        Fig. b          Fig. c 

 
 
Instructions for injection 
For administration the use of a luer-lock syringe is required. 
 
Important note: 
• Do not try to administer the injection unless you have received special training from your doctor 

or nurse. 
• Inspect the prepared solution for particulate matter and discoloration prior to administration (the 

solution should be clear, colourless and free from foreign particles). 
Do not use ADVATE if the solution is not fully clear or not completely dissolved. 

 
1. Remove the blue cap from BAXJECT II. Do not draw air into the syringe. Connect the 

syringe to BAXJECT II (Fig. d). 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly (Fig. e). 
3. Disconnect the syringe. 



224 

4. Attach a butterfly needle to the syringe and inject the reconstituted solution into a vein. The 
solution should be administered slowly, at a rate as determined by the patient’s comfort level, 
not to exceed 10 ml per minute. (See Section 4 “Possible side effects”). 

5. Discard any unused solution appropriately. 
 
Fig. d       Fig. e 

 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
On demand treatment 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be 
used to guide dosing in bleeding episodes and surgery. 
 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
Degree of haemorrhage/type of 
surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life-threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 



225 

Degree of haemorrhage/type of 
surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, 
then continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 



226 

Package leaflet: Information for the user 
 

ADVATE 250 IU powder and solvent for solution for injection 
ADVATE 500 IU powder and solvent for solution for injection 
ADVATE 1000 IU powder and solvent for solution for injection 
ADVATE 1500 IU powder and solvent for solution for injection 
ADVATE 2000 IU powder and solvent for solution for injection 
ADVATE 3000 IU powder and solvent for solution for injection 

 
Octocog alfa (recombinant human coagulation factor VIII) 

 
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. 
- 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. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What ADVATE is and what it is used for 
2. What you need to know before you use ADVATE 
3. How to use ADVATE 
4. Possible side effects 
5. How to store ADVATE 
6. Contents of the pack and other information 
 
 
1. What ADVATE is and what it is used for 
 
ADVATE contains the active substance octocog alfa, human coagulation factor VIII produced by 
recombinant DNA technology. Factor VIII is necessary for the blood to form clots and stop bleedings. 
In patients with haemophilia A (inborn lack of factor VIII), it is missing or not working properly. 
 
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with 
haemophilia A (an inherited bleeding disorder caused by lack of factor VIII). 
 
ADVATE is prepared without the addition of any human- or animal-derived protein in the entire 
manufacturing process. 
 
 
2. What you need to know before you use ADVATE 
 
Do not use ADVATE 
- if you are allergic to octocog alfa or any of the other ingredients of this medicine (listed in 

section 6) 
- if you are allergic to mouse or hamster proteins 
 
If you are unsure about this, ask your doctor. 
 
Warnings and precautions 
Talk to your doctor before using ADVATE. You should tell your doctor if you have been previously 
treated with Factor VIII products, especially if you developed inhibitors, since there might be a higher 
risk that it happens again. Inhibitors are blocking antibodies against factor VIII that reduce the efficacy 



227 

of ADVATE to prevent or control bleeding. Development of inhibitors is a known complication in the 
treatment of haemophilia A. If your bleeding is not controlled with ADVATE, tell your doctor 
immediately. 
 
There is a rare risk that you may experience an anaphylactic reaction (a severe, sudden allergic 
reaction) to ADVATE. You should be aware of the early signs of allergic reactions such as rash, hives, 
wheals, generalised itching, swelling of lips and tongue, difficulty in breathing, wheezing, tightness in 
the chest, general feeling of being unwell, and dizziness. These symptoms can constitute an early 
symptom of an anaphylactic shock, manifestations of which may additionally include extreme 
dizziness, loss of consciousness, and extreme difficulty in breathing. 
If any of these symptoms occur, stop the injection immediately and contact your doctor. Severe 
symptoms, including difficulty in breathing and (near) fainting, require prompt emergency treatment. 
 
Patients developing Factor VIII inhibitors 
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 
you or your child’s bleeding is not being controlled with ADVATE, tell your doctor immediately. 
 
Children and adolescents 
The listed warnings and precautions apply to both adults and children (from 0 to 18 years of age). 
 
Other medicines and ADVATE 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding 
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. 
 
Driving and using machines 
ADVATE has no influence on your ability to drive or to use machines. 
 
ADVATE contains sodium 
This medicine contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients 
on a controlled sodium diet. 
 
 
3. How to use ADVATE 
 
Treatment with ADVATE will be started by a doctor who is experienced in the care of patients with 
haemophilia A. 
 
Your doctor will calculate your dose of ADVATE (in international units or IU) depending on your 
condition and body weight, and on whether it is used for prevention or treatment of bleeding. The 
frequency of administration will depend on how well ADVATE is working for you. Usually, the 
replacement therapy with ADVATE is a life-long treatment. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Prevention of bleeding 
The usual dose of octocog alfa is 20 to 40 IU per kg body weight, administered every 2 to 3 days. 
However, in some cases, especially in younger patients, more frequent injections or higher doses may 
be necessary. 
 



228 

Treatment of bleeding 
The dose of octocog alfa is calculated depending on your body weight and the factor VIII levels to be 
achieved. The target factor VIII levels will depend on the severity and location of the bleeding. 
 
Dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal) x 0.5 
 
If you have the impression that the effect of ADVATE is insufficient, talk to your doctor. 
Your doctor will perform appropriate laboratory tests to make sure that you have adequate Factor VIII 
levels. This is particularly important if you are having major surgery. 
 
Use in children and adolescents (from 0 to 18 years of age) 
For the treatment of bleeding the dosing in children does not differ from adult patients. For the 
prevention of bleeding in children under the age of 6, doses of 20 to 50 IU per kg body weight 3 to 
4 times weekly are recommended. The administration of ADVATE in children (intravenously) does 
not differ from the administration in adults. A central venous access device (CVAD) may become 
necessary to allow frequent infusions of factor VIII products. 
 
How ADVATE is given 
ADVATE is usually injected into a vein (intravenously) by your doctor or nurse. You or someone else 
might also administer ADVATE as an injection, but only after receiving adequate training. Detailed 
instructions for self-administration are given at the end of this package leaflet. 
 
If you use more ADVATE than you should 
Always take ADVATE exactly as your doctor has told you. You should check with your doctor if you 
are not sure. If you inject more ADVATE than recommended, tell your doctor as soon as possible. 
 
If you forget to use ADVATE 
Do not inject a double dose to make up for a forgotten dose. Proceed with the next injection as 
scheduled and continue as advised by your doctor. 
 
If you stop using ADVATE 
Do not stop using ADVATE without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If severe, sudden allergic reactions (anaphylactic) occur, the injection must be stopped 
immediately. You must contact your doctor immediately if you have any of the following early 
symptoms of allergic reactions: 
 
- rash, hives, wheals, generalised itching, 
- swelling of lips and tongue, 
- difficulty in breathing, wheezing, tightness in the chest, 
- general feeling of being unwell, 
- dizziness and loss of consciousness. 
 
Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency 
treatment.  
 
For children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) 
may form very commonly (more than 1 in 10 people); 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 



229 

people). 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. 
 
Very common side effects (may affect more than 1 in 10 people) 
Factor VIII inhibitors (for children not previously treated with Factor VIII medicines).  
 
Common side effects (may affect up to 1 in 10 people) 
headache and fever. 
 
Uncommon side effects (may affect up to 1 in 100 people) 
Factor VIII inhibitors (for patients who have received previous treatment with Factor VIII (more than 
150 days of treatment)), dizziness, flu, fainting, abnormal heartbeat, red itchy bumps on the skin, chest 
discomfort, injection site bruise, injection site reaction, itching, increased sweating, unusual taste in 
the mouth, hot flushes, migraines, memory impairment, chills, diarrhoea, nausea, vomiting, shortness 
of breath, sore throat, infection of the lymphatic vessels, whitening of skin, eye inflammation, rashes, 
excessive sweating, foot and leg swelling, reduced percentage of red blood cells, increase in a type of 
white blood cells (monocytes), and pain in the upper abdomen or lower chest. 
 
Related to surgery 
catheter-related infection, decreased red cell blood count, swelling of limbs and joints, prolonged 
bleeding after drain removal, decreased Factor VIII level and post-operative bruise. 
 
Related to central venous access devices (CVAD) 
catheter-related infection, systemic infection and local blood clot at the catheter site. 
 
Side effects with unknown frequency (frequency cannot be estimated from the available data) 
potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), 
general disorders (tiredness, lack of energy). 
 
Additional side effects in children 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in side effects were noted in the clinical 
studies. 
 
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 ADVATE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the label after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
 
During the shelf life the blister with the product may be kept at room temperature (up to 25 °C) for a 
single period not exceeding 6 months. In this case, this medicine expires at the end of this 6 month 
period or the expiration date printed on the blister, whichever is earlier. Please record the end of the 
6 months storage at room temperature on the product carton. The product may not be returned to 
refrigerated storage after storage at room temperature. 
 
Keep the blister with the product in the outer carton in order to protect from light. 

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230 

 
This product is for single use only. Discard any unused solution appropriately. 
 
Use the product immediately once the powder is completely dissolved. 
 
Do not refrigerate the solution after preparation. 
 
Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ADVATE contains 
- The active substance is octocog alfa (human coagulation Factor VIII produced by recombinant 

DNA technology). Each powder vial contains nominally 250, 500, 1000, 1500, 2000, or 
3000 IU octocog alfa. 

- The other ingredients are mannitol, sodium chloride, histidine, trehalose, calcium chloride, 
trometamol, polysorbate 80, and glutathione (reduced). 

 
Solvent vial: 5 ml sterilised water for injections 
 
What ADVATE looks like and contents of the pack 
ADVATE is a white to off-white friable powder. After reconstitution, the solution is clear, colourless 
and free from foreign particles. 
 
Marketing Authorisation Holder 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Tel: +800 66838470 
e-mail: medinfoEMEA@shire.com 
 
Manufacturer 
Baxalta Belgium Manufacturing SA 
Boulevard René Branquart 80 
B-7860 Lessines 
Belgium 
 
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 
 
Instructions for preparation and administration 
 
ADVATE must not be mixed with other medicinal products or solvents. 
 
It is strongly recommended that every time ADVATE is administered, the name and batch number of 
the product are recorded. 
 
Instructions for reconstitution 
• Do not use after the expiry date stated on the labels and carton. 
• Do not use if the lid is not completely sealed on the blister 
• Do not refrigerate the solution after preparation. 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


231 

 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Instructions for injection 
Aseptic technique is required during administration. 
For administration the use of a luer-lock syringe is required. 
 
Important note: 
• Do not try to administer the injection unless you have received special training from your doctor 

or nurse. 
• Inspect the prepared solution for particulate matter and discoloration prior to administration (the 

solution should be clear, colourless and free from foreign particles). 
Do not use ADVATE if the solution is not fully clear or not completely dissolved. 

 
1. Remove the blue cap from BAXJECT III. Do not draw air into the syringe. Connect the 

syringe to BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe and inject the reconstituted solution into a vein. The 

solution should be administered slowly, at a rate as determined by the patient’s comfort level, 
not to exceed 10 ml per minute. (See Section 4 “Possible side effects”). 

5. Discard any unused solution appropriately. 
 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
On demand treatment 



232 

In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be 
used to guide dosing in bleeding episodes and surgery. 
 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
Degree of haemorrhage/type of 
surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life-threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the 
bleeding episode, as indicated by pain, 
is resolved or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain 
and acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, 
then continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 



233 

Package leaflet: Information for the user 
 

ADVATE 250 IU powder and solvent for solution for injection 
ADVATE 500 IU powder and solvent for solution for injection 

ADVATE 1000 IU powder and solvent for solution for injection 
ADVATE 1500 IU powder and solvent for solution for injection 

 
Octocog alfa (recombinant human coagulation factor VIII) 

 
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. 
- 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. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What ADVATE is and what it is used for 
2. What you need to know before you use ADVATE 
3. How to use ADVATE 
4. Possible side effects 
5. How to store ADVATE 
6. Contents of the pack and other information 
 
 
1. What ADVATE is and what it is used for 
 
ADVATE contains the active substance octocog alfa, human coagulation factor VIII produced by 
recombinant DNA technology. Factor VIII is necessary for the blood to form clots and stop bleedings. 
In patients with haemophilia A (inborn lack of factor VIII), it is missing or not working properly. 
 
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with 
haemophilia A (an inherited bleeding disorder caused by lack of factor VIII). 
 
ADVATE is prepared without the addition of any human- or animal-derived protein in the entire 
manufacturing process. 
 
 
2. What you need to know before you use ADVATE 
 
Do not use ADVATE 
- if you are allergic to octocog alfa or any of the other ingredients of this medicine (listed in 

section 6) 
- if you are allergic to mouse or hamster proteins 
 
If you are unsure about this, ask your doctor. 
 
Warnings and precautions 
Talk to your doctor before using ADVATE. You should tell your doctor if you have been previously 
treated with Factor VIII products, especially if you developed inhibitors, since there might be a higher 
risk that it happens again. Inhibitors are blocking antibodies against factor VIII that reduce the efficacy 
of ADVATE to prevent or control bleeding. Development of inhibitors is a known complication in the 



234 

treatment of haemophilia A. If your bleeding is not controlled with ADVATE, tell your doctor 
immediately. 
 
There is a rare risk that you may experience an anaphylactic reaction (a severe, sudden allergic 
reaction) to ADVATE. You should be aware of the early signs of allergic reactions such as rash, hives, 
wheals, generalised itching, swelling of lips and tongue, difficulty in breathing, wheezing, tightness in 
the chest, general feeling of being unwell, and dizziness. These symptoms can constitute an early 
symptom of an anaphylactic shock, manifestations of which may additionally include extreme 
dizziness, loss of consciousness, and extreme difficulty in breathing. 
If any of these symptoms occur, stop the injection immediately and contact your doctor. Severe 
symptoms, including difficulty in breathing and (near) fainting, require prompt emergency treatment. 
 
Patients developing Factor VIII inhibitors 
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 
you or your child’s bleeding is not being controlled with ADVATE, tell your doctor immediately. 
 
Children and adolescents 
The listed warnings and precautions apply to both adults and children (from 0 to 18 years of age). 
 
Other medicines and ADVATE 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding 
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. 
 
Driving and using machines 
ADVATE has no influence on your ability to drive or to use machines. 
 
ADVATE contains sodium 
This medicine contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients 
on a controlled sodium diet. 
 
Misapplication of ADVATE 
Misapplication (injection into the artery or outside the vein) should be avoided as mild, short term 
injection site reactions, such as bruising and redness, may occur. 
 
 
3. How to use ADVATE 
 
Treatment with ADVATE will be started by a doctor who is experienced in the care of patients with 
haemophilia A. 
 
Your doctor will calculate your dose of ADVATE (in international units or IU) depending on your 
condition and body weight, and on whether it is used for prevention or treatment of bleeding. The 
frequency of administration will depend on how well ADVATE is working for you. Usually, the 
replacement therapy with ADVATE is a life-long treatment. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Prevention of bleeding 
The usual dose of octocog alfa is 20 to 40 IU per kg body weight, administered every 2 to 3 days. 
However, in some cases, especially in younger patients, more frequent injections or higher doses may 
be necessary. 



235 

 
Treatment of bleeding 
The dose of octocog alfa is calculated depending on your body weight and the factor VIII levels to be 
achieved. The target factor VIII levels will depend on the severity and location of the bleeding. 
 
Dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal) x 0.5 
 
If you have the impression that the effect of ADVATE is insufficient, talk to your doctor. 
Your doctor will perform appropriate laboratory tests to make sure that you have adequate Factor VIII 
levels. This is particularly important if you are having major surgery. 
 
Use in children and adolescents (from 0 to 18 years of age) 
For the treatment of bleeding the dosing in children does not differ from adult patients. For the 
prevention of bleeding in children under the age of 6, doses of 20 to 50 IU per kg body weight 3 to 
4 times weekly are recommended. The administration of ADVATE in children (intravenously) does 
not differ from the administration in adults. A central venous access device (CVAD) may become 
necessary to allow frequent infusions of factor VIII products.  
 
Due to the decrease in injection volume for ADVATE reconstituted in 2 ml, the time to react to 
hypersensitivity reactions during an injection is further reduced. Therefore, caution is advised during 
injection of ADVATE reconstituted in 2 ml, especially in children. 
 
How ADVATE is given 
ADVATE is usually injected into a vein (intravenously) by your doctor or nurse. You or someone else 
might also administer ADVATE as an injection, but only after receiving adequate training. Detailed 
instructions for self-administration are given at the end of this package leaflet. 
 
If you use more ADVATE than you should 
Always take ADVATE exactly as your doctor has told you. You should check with your doctor if you 
are not sure. If you inject more ADVATE than recommended, tell your doctor as soon as possible. 
 
If you forget to use ADVATE 
Do not inject a double dose to make up for a forgotten dose. Proceed with the next injection as 
scheduled and continue as advised by your doctor. 
 
If you stop using ADVATE 
Do not stop using ADVATE without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If severe, sudden allergic reactions (anaphylactic) occur, the injection must be stopped 
immediately. You must contact your doctor immediately if you have any of the following early 
symptoms of allergic reactions: 
- rash, hives, wheals, generalised itching, 
- swelling of lips and tongue, 
- difficulty in breathing, wheezing, tightness in the chest, 
- general feeling of being unwell, 
- dizziness and loss of consciousness. 
 
Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency 
treatment.  
 



236 

For children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) 
may form very commonly (more than 1 in 10 people); 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 
people). 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. 
 
Very common side effects (may affect more than 1 in 10 people) 
Factor VIII inhibitors (for children not previously treated with Factor VIII medicines).  
 
Common side effects (may affect up to 1 in 10 people) 
headache and fever. 
 
Uncommon side effects (may affect up to 1 in 100 people) 
Factor VIII inhibitors (for patients who have received previous treatment with Factor VIII (more than 
150 days of treatment)), dizziness, flu, fainting, abnormal heartbeat, red itchy bumps on the skin, chest 
discomfort, injection site bruise, injection site reaction, itching, increased sweating, unusual taste in 
the mouth, hot flushes, migraines, memory impairment, chills, diarrhoea, nausea, vomiting, shortness 
of breath, sore throat, infection of the lymphatic vessels, whitening of skin, eye inflammation, rashes, 
excessive sweating, foot and leg swelling, reduced percentage of red blood cells, increase in a type of 
white blood cells (monocytes), and pain in the upper abdomen or lower chest. 
 
Related to surgery 
catheter-related infection, decreased red cell blood count, swelling of limbs and joints, prolonged 
bleeding after drain removal, decreased Factor VIII level and post-operative bruise. 
 
Related to central venous access devices (CVAD) 
catheter-related infection, systemic infection and local blood clot at the catheter site. 
 
Side effects with unknown frequency (frequency cannot be estimated from the available data) 
potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), 
general disorders (tiredness, lack of energy). 
 
Additional side effects in children 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in side effects were noted in the clinical 
studies. 
 
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 ADVATE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the label after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
 
During the shelf life the powder vial may be kept at room temperature (up to 25 °C) for a single period 
not exceeding 6 months. In this case, this medicine expires at the end of this 6 month period or the 
expiration date printed on the product vial, whichever is earlier. Please record the end of the 6 months 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
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237 

storage at room temperature on the product carton. The product may not be returned to refrigerated 
storage after storage at room temperature. 
 
Keep the vial in the outer carton in order to protect from light. 
 
This product is for single use only. Discard any unused solution appropriately. 
 
Use the product immediately once the powder is completely dissolved. 
 
Do not refrigerate the solution after preparation. 
 
Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ADVATE contains 
- The active substance is octocog alfa (human coagulation Factor VIII produced by recombinant 

DNA technology). Each powder vial contains nominally 250, 500, 1000, or 1500 IU octocog 
alfa. 

- The other ingredients are mannitol, sodium chloride, histidine, trehalose, calcium chloride, 
trometamol, polysorbate 80, and glutathione (reduced). 

 
Solvent vial: 2 ml sterilised water for injections 
 
What ADVATE looks like and contents of the pack 
ADVATE is a white to off-white friable powder. After reconstitution, the solution is clear, colourless 
and free from foreign particles. 
Each pack also contains a device for reconstitution (BAXJECT II). 
 
Marketing Authorisation Holder 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Tel: +800 66838470 
e-mail: medinfoEMEA@shire.com 
 
Manufacturer 
Baxalta Belgium Manufacturing SA 
Boulevard René Branquart 80 
B-7860 Lessines 
Belgium 
 
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 
------------------------------------------------------------------------------------------------------------------------- 
 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


238 

Instructions for preparation and administration 
 
Aseptic technique is required during preparation of the solution and administration. 
 
Use only the sterilised water for injections and the reconstitution device for preparation of the solution 
that are provided with each package of ADVATE. ADVATE must not be mixed with other medicinal 
products or solvents. 
 
It is strongly recommended that every time ADVATE is administered, the name and batch number of 
the product are recorded. 
 
Instructions for reconstitution 
• Do not use after the expiry date stated on the labels and carton. 
• Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or 

shows any sign of deterioration as indicated by the symbol: . 
• Do not refrigerate the solution after preparation. 
 
1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials 

from the refrigerator and let them reach room temperature (between 15 °C and 25 °C). 
2. Wash your hands thoroughly using soap and warm water. 
3. Remove caps from powder and solvent vials. 
4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface. 
5. Open the package of BAXJECT II device by peeling away the paper lid without touching the 

inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II 
device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration. 

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the 
package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap 
from the BAXJECT II device. 

7. For reconstitution only the sterilised water for injections and the reconstitution device provided 
in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so 
that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE 
powder stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c). 

8. Swirl gently until all material is dissolved. Be sure that the ADVATE powder is completely 
dissolved, otherwise not all reconstituted solution will pass through the device filter. The 
product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should 
be clear, colourless and free from foreign particles. 

 
Fig. a        Fig. b          Fig. c 

 
 
Instructions for injection 
For administration the use of a luer-lock syringe is required. 
 
Important note: 
• Do not try to administer the injection unless you have received special training from your doctor 

or nurse. 



239 

• Inspect the prepared solution for particulate matter and discoloration prior to administration (the 
solution should be clear, colourless and free from foreign particles). 
Do not use ADVATE if the solution is not fully clear or not completely dissolved. 

 
1. Remove the blue cap from BAXJECT II. Do not draw air into the syringe. Connect the 

syringe to BAXJECT II (Fig. d). 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly (Fig. e). 
3. Disconnect the syringe. 
4. Attach a butterfly needle to the syringe and inject the reconstituted solution into a vein. The 

solution should be administered slowly, at a rate as determined by the patient’s comfort level, 
not to exceed 10 ml per minute. (See Section 4 “Possible side effects”). 

5. Discard any unused solution appropriately. 
 
Fig. d       Fig. e 

 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
On demand treatment 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be 
used to guide dosing in bleeding episodes and surgery. 
 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 



240 

Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life-threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the bleeding 
episode, as indicated by pain, is resolved 
or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain and 
acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and 
postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 



241 

Package leaflet: Information for the user 
 

ADVATE 250 IU powder and solvent for solution for injection 
ADVATE 500 IU powder and solvent for solution for injection 

ADVATE 1000 IU powder and solvent for solution for injection 
ADVATE 1500 IU powder and solvent for solution for injection 

 
Octocog alfa (recombinant human coagulation factor VIII) 

 
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. 
- 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. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What ADVATE is and what it is used for 
2. What you need to know before you use ADVATE 
3. How to use ADVATE 
4. Possible side effects 
5. How to store ADVATE 
6. Contents of the pack and other information 
 
 
1. What ADVATE is and what it is used for 
 
ADVATE contains the active substance octocog alfa, human coagulation factor VIII produced by 
recombinant DNA technology. Factor VIII is necessary for the blood to form clots and stop bleedings. 
In patients with haemophilia A (inborn lack of factor VIII), it is missing or not working properly. 
 
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with 
haemophilia A (an inherited bleeding disorder caused by lack of factor VIII). 
 
ADVATE is prepared without the addition of any human- or animal-derived protein in the entire 
manufacturing process. 
 
 
2. What you need to know before you use ADVATE 
 
Do not use ADVATE 
- if you are allergic to octocog alfa or any of the other ingredients of this medicine (listed in 

section 6) 
- if you are allergic to mouse or hamster proteins 
 
If you are unsure about this, ask your doctor. 
 
Warnings and precautions 
Talk to your doctor before using ADVATE. You should tell your doctor if you have been previously 
treated with Factor VIII products, especially if you developed inhibitors, since there might be a higher 
risk that it happens again. Inhibitors are blocking antibodies against factor VIII that reduce the efficacy 
of ADVATE to prevent or control bleeding. Development of inhibitors is a known complication in the 



242 

treatment of haemophilia A. If your bleeding is not controlled with ADVATE, tell your doctor 
immediately. 
 
There is a rare risk that you may experience an anaphylactic reaction (a severe, sudden allergic 
reaction) to ADVATE. You should be aware of the early signs of allergic reactions such as rash, hives, 
wheals, generalised itching, swelling of lips and tongue, difficulty in breathing, wheezing, tightness in 
the chest, general feeling of being unwell, and dizziness. These symptoms can constitute an early 
symptom of an anaphylactic shock, manifestations of which may additionally include extreme 
dizziness, loss of consciousness, and extreme difficulty in breathing. 
 
If any of these symptoms occur, stop the injection immediately and contact your doctor. Severe 
symptoms, including difficulty in breathing and (near) fainting, require prompt emergency treatment. 
 
Patients developing Factor VIII inhibitors 
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 
you or your child’s bleeding is not being controlled with ADVATE, tell your doctor immediately. 
 
Children and adolescents 
The listed warnings and precautions apply to both adults and children (from 0 to 18 years of age). 
 
Other medicines and ADVATE 
Tell your doctor if you are using, have recently used or might use any other medicines. 
 
Pregnancy and breast-feeding 
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. 
 
Driving and using machines 
ADVATE has no influence on your ability to drive or to use machines. 
 
ADVATE contains sodium 
This medicine contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients 
on a controlled sodium diet. 
 
Misapplication of ADVATE 
Misapplication (injection into the artery or outside the vein) should be avoided as mild, short term 
injection site reactions, such as bruising and redness, may occur. 
 
 
3. How to use ADVATE 
 
Treatment with ADVATE will be started by a doctor who is experienced in the care of patients with 
haemophilia A. 
 
Your doctor will calculate your dose of ADVATE (in international units or IU) depending on your 
condition and body weight, and on whether it is used for prevention or treatment of bleeding. The 
frequency of administration will depend on how well ADVATE is working for you. Usually, the 
replacement therapy with ADVATE is a life-long treatment. 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 



243 

Prevention of bleeding 
The usual dose of octocog alfa is 20 to 40 IU per kg body weight, administered every 2 to 3 days. 
However, in some cases, especially in younger patients, more frequent injections or higher doses may 
be necessary. 
 
Treatment of bleeding 
The dose of octocog alfa is calculated depending on your body weight and the factor VIII levels to be 
achieved. The target factor VIII levels will depend on the severity and location of the bleeding. 
 
Dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal) x 0.5 
 
If you have the impression that the effect of ADVATE is insufficient, talk to your doctor. 
Your doctor will perform appropriate laboratory tests to make sure that you have adequate Factor VIII 
levels. This is particularly important if you are having major surgery. 
 
Use in children and adolescents (from 0 to 18 years of age) 
For the treatment of bleeding the dosing in children does not differ from adult patients. For the 
prevention of bleeding in children under the age of 6, doses of 20 to 50 IU per kg body weight 3 to 
4 times weekly are recommended. The administration of ADVATE in children (intravenously) does 
not differ from the administration in adults. A central venous access device (CVAD) may become 
necessary to allow frequent infusions of factor VIII products.  
 
Due to the decrease in injection volume for ADVATE reconstituted in 2 ml, the time to react to 
hypersensitivity reactions during an injection is further reduced. Therefore, caution is advised during 
injection of ADVATE reconstituted in 2 ml, especially in children. 
 
How ADVATE is given 
ADVATE is usually injected into a vein (intravenously) by your doctor or nurse. You or someone else 
might also administer ADVATE as an injection, but only after receiving adequate training. Detailed 
instructions for self-administration are given at the end of this package leaflet. 
 
If you use more ADVATE than you should 
Always take ADVATE exactly as your doctor has told you. You should check with your doctor if you 
are not sure. If you inject more ADVATE than recommended, tell your doctor as soon as possible. 
 
If you forget to use ADVATE 
Do not inject a double dose to make up for a forgotten dose. Proceed with the next injection as 
scheduled and continue as advised by your doctor. 
 
If you stop using ADVATE 
Do not stop using ADVATE without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If severe, sudden allergic reactions (anaphylactic) occur, the injection must be stopped 
immediately. You must contact your doctor immediately if you have any of the following early 
symptoms of allergic reactions: 
- rash, hives, wheals, generalised itching, 
- swelling of lips and tongue, 
- difficulty in breathing, wheezing, tightness in the chest, 
- general feeling of being unwell, 
- dizziness and loss of consciousness. 



244 

 
Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency 
treatment.  
 
For children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) 
may form very commonly (more than 1 in 10 people); 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 
people). 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. 
 
Very common side effects (may affect more than 1 in 10 people) 
Factor VIII inhibitors (for children not previously treated with Factor VIII medicines).  
 
Common side effects (may affect up to 1 in 10 people) 
headache and fever. 
 
Uncommon side effects (may affect up to 1 in 100 people) 
Factor VIII inhibitors (for patients who have received previous treatment with Factor VIII (more than 
150 days of treatment)), dizziness, flu, fainting, abnormal heartbeat, red itchy bumps on the skin, chest 
discomfort, injection site bruise, injection site reaction, itching, increased sweating, unusual taste in 
the mouth, hot flushes, migraines, memory impairment, chills, diarrhoea, nausea, vomiting, shortness 
of breath, sore throat, infection of the lymphatic vessels, whitening of skin, eye inflammation, rashes, 
excessive sweating, foot and leg swelling, reduced percentage of red blood cells, increase in a type of 
white blood cells (monocytes), and pain in the upper abdomen or lower chest. 
 
Related to surgery 
catheter-related infection, decreased red cell blood count, swelling of limbs and joints, prolonged 
bleeding after drain removal, decreased Factor VIII level and post-operative bruise. 
 
Related to central venous access devices (CVAD) 
catheter-related infection, systemic infection and local blood clot at the catheter site. 
 
Side effects with unknown frequency (frequency cannot be estimated from the available data) 
potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), 
general disorders (tiredness, lack of energy). 
 
Additional side effects in children 
Other than the development of inhibitors in previously untreated paediatric patients (PUPs), and 
catheter-related complications, no age-specific differences in side effects were noted in the clinical 
studies. 
 
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 ADVATE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the label after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2 °C – 8 °C). 
Do not freeze. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


245 

During the shelf life the blister with the product may be kept at room temperature (up to 25 °C) for a 
single period not exceeding 6 months. In this case, this medicine expires at the end of this 6 month 
period or the expiration date printed on the blister, whichever is earlier. Please record the end of the 
6 months storage at room temperature on the product carton. The product may not be returned to 
refrigerated storage after storage at room temperature. 
 
Keep the blister with the product in the outer carton in order to protect from light. 
 
This product is for single use only. Discard any unused solution appropriately. 
 
Use the product immediately once the powder is completely dissolved. 
 
Do not refrigerate the solution after preparation. 
 
Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ADVATE contains 
- The active substance is octocog alfa (human coagulation Factor VIII produced by recombinant 

DNA technology). Each powder vial contains nominally 250, 500, 1000, or 1500 IU octocog 
alfa. 

- The other ingredients are mannitol, sodium chloride, histidine, trehalose, calcium chloride, 
trometamol, polysorbate 80, and glutathione (reduced). 

 
Solvent vial: 2 ml sterilised water for injections 
 
What ADVATE looks like and contents of the pack 
ADVATE is a white to off-white friable powder. After reconstitution, the solution is clear, colourless 
and free from foreign particles. 
 
Marketing Authorisation Holder 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
A-1221 Vienna 
Tel: +800 66838470 
e-mail: medinfoEMEA@shire.com 
 
Manufacturer 
Baxalta Belgium Manufacturing SA 
Boulevard René Branquart 80 
B-7860 Lessines 
Belgium 
 
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 
------------------------------------------------------------------------------------------------------------------------- 
 

http://www.ema.europa.eu/
http://www.ema.europa.eu/


246 

Instructions for preparation and administration 
 
ADVATE must not be mixed with other medicinal products or solvents. 
 
It is strongly recommended that every time ADVATE is administered, the name and batch number of 
the product are recorded. 
 
Instructions for reconstitution 
• Do not use after the expiry date stated on the labels and carton. 
• Do not use if the lid is not completely sealed on the blister 
• Do not refrigerate the solution after preparation. 
 
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solvent 

vials preassembled with the system for reconstitution) from the refrigerator and let it reach room 
temperature (between 15 °C and 25 °C). 

2. Wash your hands thoroughly using soap and warm water. 
3. Open the ADVATE package by peeling away the lid. Remove the BAXJECT III system from 

the blister. 
4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a 

blue stripe. Do not remove the blue cap until instructed in a later step. 
5. With one hand holding the ADVATE in the BAXJECT III system, press down firmly on the 

solvent vial with the other hand until the system is fully collapsed and the solvent flows down 
into the ADVATE vial (Fig. 2). Do not tilt the system until the transfer is complete. 

6. Verify that the solvent transfer is complete. Swirl gently until all material is dissolved. Be sure 
that the ADVATE powder is completely dissolved, otherwise not all reconstituted solution will 
pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). 
After reconstitution the solution should be clear, colourless and free from foreign particles. 

 
Fig. 1 Fig. 2 Fig. 3 

   
 
Instructions for injection 
Aseptic technique is required during administration. 
For administration the use of a luer-lock syringe is required. 
 
Important note: 
• Do not try to administer the injection unless you have received special training from your doctor 

or nurse. 
• Inspect the prepared solution for particulate matter and discoloration prior to administration (the 

solution should be clear, colourless and free from foreign particles). 
Do not use ADVATE if the solution is not fully clear or not completely dissolved. 

 
1. Remove the blue cap from BAXJECT III. Do not draw air into the syringe. Connect the 

syringe to BAXJECT III. 
2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the 

reconstituted solution into the syringe by pulling the plunger back slowly. 
3. Disconnect the syringe. 



247 

4. Attach a butterfly needle to the syringe and inject the reconstituted solution into a vein. The 
solution should be administered slowly, at a rate as determined by the patient’s comfort level, 
not to exceed 10 ml per minute. (See Section 4 “Possible side effects”). 

5. Discard any unused solution appropriately. 
 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
On demand treatment 
In case of the following haemorrhagic events, the factor VIII activity should not fall below the given 
plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be 
used to guide dosing in bleeding episodes and surgery. 
 
The dose and frequency of administration should be adapted to the clinical response in the individual 
case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those 
calculated using the formula may be necessary. 
 
Degree of haemorrhage/type 
of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

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

Haemorrhage 
 
Early haemarthrosis, muscle 
bleeding or oral bleeding. 
 
 
 
 
More extensive haemarthrosis, 
muscle bleeding or haematoma. 
 
 
 
Life-threatening haemorrhages. 

 
 
20 – 40 
 
 
 
 
 
30 – 60 
 
 
 
 
60 – 100 

 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for at least 1 day, until the bleeding 
episode, as indicated by pain, is resolved 
or healing is achieved. 
 
Repeat injections every 12 to 24 hours 
(8 to 24 hours for patients under the age 
of 6) for 3 – 4 days or more until pain and 
acute disability are resolved. 
 
Repeat injections every 8 to 24 hours 
(6 to 12 hours for patients under the age 
of 6) until threat is resolved. 

Surgery 
 
Minor 
Including tooth extraction. 
 
 
Major 
 

 
 
30 – 60 
 
 
 
80 – 100 
(pre- and 
postoperative) 

 
 
Every 24 hours (12 to 24 hours for 
patients under the age of 6), at 
least 1 day, until healing is achieved. 
 
Repeat injections every 8 to 24 hours 
(6 to 24 hours for patients under the age 
of 6) until adequate wound healing, then 
continue therapy for at least 
another 7 days to maintain a factor VIII 
activity of 30% to 60% (IU/dl). 

 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURERS 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