Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII
deficiency). ADVATE is indicated in all age groups.

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.
3
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.
4
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.

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) against 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. In patients who develop inhibitors to factor VIII, the
condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that
a specialised haemophilia centre be contacted. The risk of developing inhibitors is correlated to the
extent of exposure to factor VIII, the risk being highest within the first 20 exposure days, and to other
genetic and environmental factors. 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.
In general, all patients treated with coagulation factor VIII 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 substitution therapy may not be effective and other therapeutic options should be
considered. The management of such patients should be directed by physicians with experience in the
care of patients with haemophilia and factor VIII inhibitors.
5
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.

No interaction studies have been performed with ADVATE.

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 breastfeeding
only if clearly indicated.

ADVATE has no influence on the ability to drive and use machines.

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.
Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. 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).
6
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 inhibitionc Common
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).
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.
7
Description of selected adverse reactions
Inhibitor Development
Inhibitor development in previously treated patients (PTPs) and in previously untreated patients
(PUPs) has been reported. For details refer to sections 5.1 (Pharmacological properties) and 4.4
(Special warnings and precautions for use).
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 below.
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc
• Other GCC States:
- Please contact the relevant competent authority.

No symptoms of overdose with recombinant coagulation factor VIII have been reported.

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
increased by replacement therapy, thereby enabling a temporary correction of the factor VIII
deficiency and correction of the bleeding tendency.
Inhibitor Development
The immunogenicity of ADVATE was evaluated in previously treated patients. During clinical trials
with ADVATE in 233 paediatric and adult patients [paediatric patients (age 0 –16 years) and adult
patients (age over 16 years)] diagnosed with severe haemophilia A (factor VIII < 1%), with previous
exposure to factor VIII concentrates ≥ 150 days for adults and older children and ≥ 50 days for
children < 6 years of age, one patient developed a low-titre inhibitor (2.4 BU in the modified Bethesda
assay) after 26 exposure days to ADVATE. Follow-up inhibitor tests in this patient after withdrawal
from the study were negative. Across all studies, median exposure to ADVATE was 97.0 exposure days
per subject (range 1 to 709) for previously treated patients. The overall incidence of any factor VIII
inhibitor development (low or high) was 0.4% (1 of 233).
In the completed uncontrolled study 060103, 16 out of 45 (35.6%) of previously untreated patients
with severe haemophilia A (FVIII < 1%) and at least 25 EDs to FVIII developed FVIII inhibitors: 7
(15.6%) subjects developed high-titre inhibitors and 9 (20%) subjects developed low-titre inhibitors, 1
of which was also classified as a transient inhibitor.
Risk factors related to inhibitor development in this study included non-Caucasian ethnicity, family
history of inhibitors and intensive treatment at high dose within the first 20 EDs. In the 20 subjects
who had none of these risk factors there was no inhibitor development.
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 subjects on ITI (study 060703) and collection of Registry data is on-going.
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
9
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).

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 postinfusion
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.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, acute
toxicology, repeated dose toxicity, local toxicity and genotoxicity.

Powder
Mannitol
Sodium chloride
Histidine
10
Trehalose
Calcium chloride
Trometamol
Polysorbate 80
Glutathione (reduced)
Solvent
Sterilised water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products or solvents.

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.
For storage conditions after reconstitution of the medicinal product, see section 6.3.

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 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.
11
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.
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).