ADVATE 500UI 500UI / 5ml powder + solvent for injection medication leaflet

ADVATE 500 IU powder and solvent for solution for injection.

Each vial contains nominally 500 IU human coagulation factor VIII (rDNA), octocog alfa. ADVATEcontains approximately 100 IU per ml of human coagulation factor VIII (rDNA), octocog alfa afterreconstitution.

The potency (International Units) is determined using the European Pharmacopoeia chromogenicassay. 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. Preparedwithout the addition of any (exogenous) human- or animal-derived protein in the cell culture process,purification or final formulation.

This medicinal product contains 0.45 mmol sodium (10 mg) per vial.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: White to off-white friable powder.

Solvent: Clear and colourless solution.

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

Treatment should be initiated under the supervision of a physician experienced in the treatment ofhaemophilia and with resuscitation support immediately available in case of anaphylaxis.

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 apercentage (relative to normal human plasma) or in IUs (relative to the international standard forfactor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one mlof normal human plasma.

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 isdetermined 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 givenplasma activity level (in % of normal or IU/dl) in the corresponding period. The following table 1 canbe used to guide dosing in bleeding episodes and surgery:

Table 1 Guide for dosing in bleeding episodes and surgery

Degree of haemorrhage/type Factor VIII level Frequency of doses (hours)/durationof surgical procedure required (% or IU/dl) of therapy (days)

Early haemarthrosis, muscle 20 - 40 Repeat injections every 12 to 24 hoursbleeding or oral bleeding. (8 to 24 hours for patients under theage of 6) for at least 1 day, until thebleeding episode, as indicated by pain,is resolved or healing is achieved.

More extensive haemarthrosis, 30 - 60 Repeat injections every 12 to 24 hoursmuscle bleeding or haematoma. (8 to 24 hours for patients under theage of 6) for 3 - 4 days or more untilpain and acute disability are resolved.

Life threatening haemorrhages. 60 - 100 Repeat injections every 8 to 24 hours(6 to 12 hours for patients under theage of 6) until threat is resolved.

Minor 30 - 60 Every 24 hours (12 to 24 hours for

Including tooth extraction. patients under the age of 6), atleast 1 day, until healing is achieved.

Major 80 - 100 Repeat injections every 8 to 24 hours(pre- and postoperative) (6 to 24 hours for patients under theage of 6) until adequate wound healing,then continue therapy for at leastanother 7 days to maintain a factor VIIIactivity of 30% to 60% (IU/dl).

The dose and frequency of administration should be adapted to the clinical response in the individualcase. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than thosecalculated using the formula may be necessary.

During the course of treatment, appropriate determination of plasma factor VIII levels is advised toguide the dose to be administered and the frequency of repeated injections. In the case of majorsurgical interventions in particular, precise monitoring of the substitution therapy by means of plasmafactor 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.

For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual dosesare 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days.

For on demand treatment dosing in paediatric patients (0 to 18 years of age) does not differ from adultpatients. In patients under the age of 6, doses of 20 to 50 IU of factor VIII per kg body weight 3 to 4times weekly are recommended for prophylactic therapy.

ADVATE should be administered via the intravenous route. In case of administration by a non healthcare professional appropriate training is needed.

The rate of administration should be determined to ensure the comfort of the patient up to a maximumof 10 ml/min.

After reconstitution, the solution is clear, colourless, free from foreign particles and has a pHof 6.7 to 7.3.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse orhamster proteins.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in themanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulinsdirected against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) perml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity ofthe disease as well as the exposure to factor VIII, this risk being highest within the first 20 exposuredays. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIIIproduct to another in previously treated patients with more than 100 exposure days who have aprevious history of inhibitor development. Therefore, it is recommended to monitor all patientscarefully for inhibitor occurrence following any product switch.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titreinhibitors which are transiently present or remain consistently low titre posing less of a risk ofinsufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored forthe development of inhibitors by appropriate clinical observations and laboratory tests. If the expectedfactor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriatedose, testing for factor VIII inhibitor presence should be performed. In patients with high levels ofinhibitor, 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 ofhaemophilia and factor VIII inhibitors.

Catheter-related complications in treatment

If central venous access device (CVAD) is required, risk of CVAD-related complications includinglocal infections, bacteremia and catheter site thrombosis should be considered.

Excipient related considerations

This medicinal product contains 10 mg sodium per vial, equivalent to 0.5 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

It is strongly recommended that every time ADVATE is administered to a patient, the name and batchnumber of the product are recorded in order to maintain a link between the patient and the batch of themedicinal product.

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 occurrenceof haemophilia A in women, experience regarding the use of factor VIII during pregnancy andbreast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-feeding only if clearly indicated.

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

Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATEreporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequencywere development of neutralising antibodies to factor VIII (inhibitors), headache and fever.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observedrarely and may in some cases progress to severe anaphylaxis (including shock).

Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactionsmay be observed.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treatedwith factor VIII, including with ADVATE. If such inhibitors occur, the condition will manifest itselfas an insufficient clinical response. In such cases, it is recommended that a specialised haemophiliacentre be contacted.

The following table 2 provides the frequency of adverse drug reactions in clinical trials and fromspontaneous 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), veryrare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequencygrouping, 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 Pyrexia Commonconditions Peripheral oedema Uncommon

Chest pain Uncommon

Chest discomfort Uncommon

Table 2 Frequency of adverse drug reactions (ADRs) in clinical trials and from spontaneous reports

MedDRA Standard System Organ Class Adverse reaction Frequencya

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 Uncommondecreasedb

Haematocrit decreased Uncommon

Laboratory test abnormal Uncommon

Injury, poisoning and procedural complications Post procedural complication Uncommon

Post procedural haemorrhage Uncommon

Procedural site reaction Uncommona) Calculated based on total number of patients who received ADVATE (418).b) The unexpected decrease in coagulation factor VIII levels occurred in one patient duringcontinuous infusion of ADVATE following surgery (postoperative days 10-14). Haemostasiswas maintained at all times during this period and both plasma factor VIII levels and clearancerates returned to appropriate levels by postoperative day 15. Factor VIII inhibitor assaysperformed 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 severehaemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients

ADRs specific to residues from the manufacturing process

Of the 229 treated patients who were assessed for antibodies to Chinese hamster ovary (CHO) cellprotein, 3 showed a statistically significant upward trend in titres, 4 displayed sustained peaks ortransient spikes and one patient had both but no clinical symptoms. Of the 229 treated patients whowere assessed for antibodies to murine IgG, 10 showed a statistically significant upwardtrend, 2 displayed a sustained peak or transient spike and one patient had both. Four of these patientsreported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts amongstrepeated exposures to the study product.

Allergic type reactions include anaphylaxis and have been manifested by dizziness, paresthesias, rash,flushing, face swelling, urticaria, and pruritus.

Other than the development of inhibitors in previously untreated paediatric patients (PUPs), andcatheter-related complications, no age-specific differences in ADRs were noted in the clinical studies.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 recombinantcoagulation factor VIII (octocog alfa), a glycoprotein that is biologically equivalent to the factor VIIIglycoprotein found in human plasma.

Octocog alfa is a glycoprotein consisting of 2332 amino acids with an approximate molecular massof 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 convertsprothrombin 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 offactor VIII activity and results in profuse bleeding into joints, muscles or internal organs, eitherspontaneously or as a result of accidental or surgical trauma. The plasma levels of factor VIII areincreased by replacement therapy, thereby enabling a temporary correction of the factor VIIIdeficiency and correction of the bleeding tendency.

Data on Immune Tolerance Induction (ITI) in patients with inhibitors have been collected. Withina sub-study of PUP-study 060103, ITI-treatments in 11 PUPs were documented. Retrospective chartreview was done for 30 paediatric subjects on ITI (in study 060703). A non-interventional prospectiveregistry (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: anindividualized pharmacokinetic guided dosing regimen (within a range of 20 to 80 IU of factor VIIIper 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 toa specific formula) was targeted to maintain factor VIII trough levels ≥ 1% at the inter-dosing intervalof 72 hours. The data from this study demonstrate that the two prophylactic dosing regimens arecomparable 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 VIIIdeficiency) 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 ofbleeding in patients with haemophilia A (congenital factor VIII deficiency)'. (see section 4.2 forinformation on paediatric use).

All pharmacokinetic studies with ADVATE were conducted in previously treated patients with severeto moderately severe haemophilia A (baseline factor VIII ≤ 2%). The analysis of plasma samples wasconducted 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 parametersthat were included in the Per-Protocol PK analysis set. Categories of these analyses for infants (1month 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 ± Infants Children Older Children Adolescents Adultsstandard deviation) (n=5) (n=30) (n=18) (n=33) (n=109)

Total AUC (IU*·h/dl) 1362.1 ± 1180.0 ± 1506.6 ± 530.0 1317.1 ± 1538.5 ± 519.1311.8 432.7 438.6

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

Recovery at Cmax (IU/dLper 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 110.5 ± 90.8 ± 19.1 100.5 ± 25.6 107.6 ± 27.6 111.3 ± 27.1

Concentration Post 30.2

Infusion (IU/dl)

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

Steady State (dl/kg)

Clearance (ml/kg*h) 3.9 ± 0.9 4.8 ± 1.5 3.8 ± 1.5 4.1 ± 1.0 3.6 ± 1.2a 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 ofadult patients. Adjusted recovery and terminal half-life (t½) was approximately 20% lower in youngchildren (less than 6 years of age) than in adults, which may be due in part to the known higher plasmavolume 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, acutetoxicology, repeated dose toxicity, local toxicity and genotoxicity.

Mannitol

Sodium chloride

Histidine

Trehalose

Calcium chloride

Trometamol

Polysorbate 80

Glutathione (reduced)

Sterilised water for injections

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

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 notexceeding 6 months. The end of the 6 months storage at room temperature should be recorded on theproduct carton. The product may not be returned to refrigerated storage again.

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 fromlight.

ADVATE in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect fromlight.

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 orbromobutyl 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 mlsolvent and a device for reconstitution (BAXJECT II).

- ADVATE in BAXJECT III system: Each pack contains a ready to use BAXJECT III system ina sealed blister (the powder vial and the vial containing 5 ml solvent are preassembled with thesystem for reconstitution).

ADVATE is to be administered intravenously after reconstitution of the product.

The reconstituted solution should be inspected visually for any foreign particulate matter and/ordiscoloration.

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 localrequirements.

Reconstitution with the BAXJECT II device

- For reconstitution use only the sterilised water for injections and the reconstitution deviceprovided in the pack.

- Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged orshows any sign of deterioration.

- Aseptic Technique should be used1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vialsfrom 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 theinside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT IIdevice, 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 thepackage at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue capfrom the BAXJECT II device.

7. For reconstitution only the sterilised water for injections and the reconstitution device providedin the pack should be used. With BAXJECT II attached to the solvent vial, invert the system sothat the solvent vial is on top of the device. Insert the white plastic spike through the ADVATEpowder 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 completelydissolved, otherwise not all reconstituted solution will pass through the device filter. Theproduct dissolves rapidly (usually in less than 1 minute). After reconstitution the solution shouldbe 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 blister1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and solventvials preassembled with the system for reconstitution) from the refrigerator and let it reach roomtemperature (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 fromthe blister.4. Place the ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has ablue 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 thesolvent vial with the other hand until the system is fully collapsed and the solvent flows downinto 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 surethat the ADVATE powder is completely dissolved, otherwise not all reconstituted solution willpass 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

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 thereconstituted 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 beadministered slowly, at a rate as determined by the patient’s comfort level, not to exceed 10 mlper minute. The pulse rate should be determined before and during administration of ADVATE.

Should a significant increase occur, reducing the rate of administration or temporarilyinterrupting the injection usually allows the symptoms to disappear promptly (seesections 4.4 and 4.8).

Takeda Manufacturing Austria AG

Industriestrasse 67

A-1221 Vienna

AustriamedinfoEMEA@takeda.com

EU/1/03/271/002

EU/1/03/271/012

Date of first authorisation: 02 March 2004

Date of latest renewal: 20 December 2013

Detailed information on this medicinal product is available on the website of the European Medicines

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