ADVATE 1000 IU

Advate SPC_License holder change_060120

This leaflet format has been determined by the Ministry of Health and the content thereof has been

checked and approved.

Date of approval : October 2013

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

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.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

ADVATE 250 IU powder and solvent for solution for injection.

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.

ADVATE 500 IU powder and solvent for solution for injection.

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.

ADVATE 1000 IU powder and solvent for solution for injection.

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.

ADVATE 1500 IU powder and solvent for solution for injection.

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.

ADVATE 2000 IU powder and solvent for solution for injection.

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.

ADVATE 3000 IU powder and solvent for solution for injection.

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.

Advate SPC_License holder change_060120

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 a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection

White to off-white friable powder.

After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH of 6.7 to

7.3.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII

deficiency).

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 posology 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.

Advate SPC_License holder change_060120

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).

Advate SPC_License holder change_060120

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.

Paediatric population

The safety and efficacy of ADVATE in all paediatric age groups has been established. For on demand

treatment dosing in paediatric patients 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.

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 signs of the early signs of hypersensitivity reactions including

hives, generalised urticaria, tightness in 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.

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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.

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 lactation

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

a. 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).

Advate SPC_License holder change_060120

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.

b. 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 calculated from the available data). Within each frequency

grouping, undesirable effects are presented in order of decreasing seriousness.

The following table 2 provides the frequency of adverse drug reactions in clinical trials:

Table 2

Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports

MedDRA Standard System

Organ Class

Adverse reaction

Frequency

a

Infections and infestations

Influenza

Uncommon

Laryngitis

Uncommon

Blood and lymphatic system

disorders

Factor VIII inhibition

Common

Lymphangitis

Uncommon

Immune system disorders

Anaphylactic reaction

Not known

Hypersensitivity

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

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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 decreased

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

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

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.

ADR explained in section c.

c. 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

antibodies

murine

IgG, 10 showed

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.

d. 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.

Advate SPC_License holder change_060120

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions.

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

conversion

Factor

activated

Factor

Activated

Factor

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

replacement

therapy,

thereby

enabling

temporary

correction

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.

Advate SPC_License holder change_060120

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)

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

Calculated as (Cmax - baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-

infusion Factor VIII measurement.

Advate SPC_License holder change_060120

The safety and haemostatic efficacy of ADVATE in the paediatric population are similar to that of

adult patients. Adjusted recovery and terminal half-life (t

) 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

Tris (hydroxymethyl) aminoethane

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

Unopened powder vial

2 years

After reconstitution

Chemical

physical

in-use

stability

been

demonstrated

hours

25°C.

From

microbiological point of view, the product should be used immediately after reconstitution.

6.4

Special precautions for storage

Store in a refrigerator (2

C – 8

C). Do not freeze.

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 beginning of storage at room temperature should be recorded on the product

carton. The product may not be returned to refrigerated storage again.

Keep the vial in the outer carton in order to protect from light.

Keep out of the reach and sight of children.

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

Advate SPC_License holder change_060120

6.5

Nature and contents of container

Each pack contains a powder vial, a vial containing 5 ml solvent (both type I glass closed with

chlorobutyl rubber stoppers) and a device for reconstitution (BAXJECT II)

.

6.6

Special precautions for disposal and other handling

ADVATE is to be administered intravenously after reconstitution of the lyophilized product with the

provided sterilised water for injections. After reconstitution the solution should be clear, colourless

and free from foreign particles.

For reconstitution use only the sterilised water for injections and the reconstitution device

provided in the pack. For administration the use of a luer-lock syringe is required.

Use within three hours after reconstitution.

Do not refrigerate the preparation after reconstitution.

Dispose any unused product or waste material in accordance with local requirements.

Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or

shows any sign of deterioration.

Reconstitution

Aseptic Technique should be used

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).

Wash your hands thoroughly using soap and warm water.

Remove caps from powder and solvent vials.

Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface.

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.

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.

For reconstitution only the 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

stopper. The vacuum will draw the solvent into the ADVATE vial (Fig. c).

Swirl gently until all material is dissolved. Be sure that ADVATE is completely dissolved,

otherwise

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

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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.

Remove the blue cap from BAXJECT II. DO NOT DRAW AIR INTO THE SYRINGE.

Connect the syringe to BAXJECT II (Fig. d).

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).

Disconnect the syringe.

Attach

butterfly

needle

syringe.

Inject

intravenously.

solution

should

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

significant

increase

occur,

reducing

rate

administration

temporarily

interrupting the injection usually allows the symptoms to disappear promptly (see sections 4.4

and 4.8).

Fig. d

Fig. e

7.

REGISTRATION NUMBERS:

ADVATE 250 IU powder and solvent for solution for injection.:

150 77 33649 00

ADVATE 500 IU powder and solvent for solution for injection.:

150 78 33665 00

ADVATE 1000 IU powder and solvent for solution for injection.:

150 79 33664 00

ADVATE 1500 IU powder and solvent for solution for injection.:

150 80 33663 00

ADVATE 2000 IU powder and solvent for solution for injection.:

150 81 33662 00

ADVATE 3000 IU powder and solvent for solution for injection.:

150 82 33661 00

8.

MANUFACTURER

Baxter AG,

Vienna, Austria.

9.

LICENCE HOLDER

Takeda Israel Ltd.

25 Efal st., Petach Tikva 4951125