Helixate NexGen - patient leaflet, side effects, dosage

/O

Reporting of suspected adve rse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V'.

• 4.9 Overdose

No case of overdose with recombinant coagulation factor VIII has been reported.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1 Pharmacody­namic properties

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.

Mechanism of action

The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to vWF in the patient’s cir­culation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Pharmacodynamic effects

Determination of activated partial thromboplastin time (aPTT) is a conventional in vi for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. duration of aPTT normalisation observed after administration of Helixate Nex achieved with plasma-derived factor VIII.

Continuous Infusion

It has been shown in a clinical study performed with adult haemophilia A patients who undergo a major surgery that Helixate NexGen can be used for continuous infusion in surgeries (pre-, during and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions.

Hypersensitivity

Immune Tolerance Induction (I ction have been collected in patients with haemophilia A who had retrospective review has been done on 40 patients, and 39 patients tive investigator-initiated clinical study. Data show that Helixate NexGen immune tolerance. In patients where immune tolerance was achieved the bleedings could evented or controlled with Helixate NexGen again, and the patients could continue with prophylactic treatment as maintenance therapy.

>tion

The analysis of all recorded in vivo recoveries in previously treated patients demonstrated a mean rise of 2 % per IU/kg body weight for Helixate NexGen. This result is similar to the reported values for factor VIII derived from human plasma.

Distribution and elimination

After administration of Helixate NexGen, peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional pharmacokinetic parameters for Helixate NexGen for bolus injectionare: mean residence time [MRT (0–48)] of about 22 hours and clearance of about 160 mL/h.Mean baseline clearance for 14 adult patients undergoing major surgeries with continuous infusion are 188 mL/h corresponding to 3.0 mL/h/kg (range 1.6–4.6 mL/h/kg).

• 5.3 Preclinical safety data

  
  

Even doses several fold higher than the recommended clinical dose (related to body weight) fa demonstrate any acute or subacute toxic effects for Helixate NexGen in laboratory animals rat, rabbit, and dog).

Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with octocog alfa due to the immune response to heterologous proteins in all non-human mammalian species.

No studies were performed on the mutagenic potential of Helixate NexGen, since no mutagenic potential could be detected in vitro or in vivo for the predecessor

Glycine

Sodium chloride Calcium chloride Histidine Polysorbate 80 Sucrose inal product must not be mixed with other medicinal products except those mentioned in

Only the provided administration sets can be used because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf-life 30 months.

After reconstitution, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

However, during in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 30°C in PVC bags for continuous infusion". After reconstitution, the chemical and physical in-use stability has been demonstrated for 3 hours in in vitro studies.

Do not refrigerate after reconstitution.

• 6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vials in the outer carton in order to protect from light.

Within its overall shelf life of 30 months the product when kept in its outer carton, may be stored ambient room temperature (up to 25°C) for a limited period of 12 months. In this case, the produc expires at the end of this 12-month period or the expiration date on the product vial, whichever is earlier. The new expiry date must be noted on the top of the outer carton.

For storage conditions after reconstitution of the medicinal product, see sec

• 6.5 Nature and contents of container and special equipment for use, ad implantation

Each package of Helixate NexGen contains:

• one vial with powder (10 mL clear glass type 1 vial wi blend stopper and aluminium seal)
• one vial with solvent (6 mL clear glass type 1 vial wit stopper and aluminium seal)
• an additional package with:

• – 1 filter transfer device 20/20 [Mix2Vial]

• – 1 venipuncture set

• – 1 disposable 5 mL syringe

• – 2 alcohol swabs for single use

• 6.6 Special precautions for disp

  Detailed instructions for prepa with Helixate NexGen

  
  

ministration are contained in the package leaflet provided

duct is a clear and colourless solution.

ould only be reconstituted with the supplied solvent (2.5 mL (for 250 IU, L (for 2000 IU and 3000 IU) water for injections) using the supplied

transfer device. For infusion, the product must be prepared under aseptic component of the package is opened or damaged, do not use this component. e vial until all powder is dissolved. After reconstitution the solution is clear. Parenteral cts should be inspected visually for particulate matter and discoloration prior to istration. Do not use Helixate NexGen if you notice visible particulate matter or turbidity.

After reconstitution, the solution is drawn through the Mix2Vial filter transfer device into the sterile disposable syringe (both supplied). Helixate NexGen should be reconstituted and administered with the components provided with each package.

The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the Mix2Vial adapter.

For single use only.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

• 7. MARKETING AUTHORISATION HOLDER

Bayer AG

51368 Leverkusen

Germany

• 8. MARKETING AUTHORISATION NUMBER(S)

EU/1/00/144/001 – Helixate NexGen 250 IU

EU/1/00/144/002 – Helixate NexGen 500 IU

EU/1/00/144/003 – Helixate NexGen 1000 IU

EU/1/00/144/004 – Helixate NexGen 2000 IU

EU/1/00/144/005 – Helixate NexGen 3000 IU

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTH

  TION

  
  

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

• 10. DATE OF REVISION OF THE TEXT

  
  
  
  

ble on the website of the European Medicines

OR RESTRICTIONS WITH REGARD TO THE SAFE AND SE OF THE MEDICINAL PRODUCT

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

Name and address of the manufacturer(s) of the biological active substance

Bayer Corporation (license holder)

Bayer HealthCare LLC

800 Dwight Way

Berkeley, CA 94710

USA

Name and address of the manufacturer(s) responsible for batch release

Bayer HealthCare Manufacturing S.r.l.

Via delle Groane 126

20024 Garbagnate Milanese (MI)

Italy

B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

Periodic Safety Update Reports

rform the required pharmacovigilance activities and interventions detailed in the nted in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent P.

dated RMP should be submitted:

At the request of the European Medicines Agency;

Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON

• 1. NAME OF THE MEDICINAL PRODUCT

Helixate NexGen 250 IU powder and solvent for solution for injection

Helixate NexGen 500 IU powder and solvent for solution for injection

Helixate NexGen 1000 IU powder and solvent for solution for injection

Helixate NexGen 2000 IU powder and solvent for solution for injection

Helixate NexGen 3000 IU powder and solvent for solution for injection

Recombinant coagulation factor VIII (octocog alfa)

• 2. STATEMENT OF ACTIVE SUBSTANCE(S)

  after

  
  

Helixate NexGen 250 IU contains (250 IU / 2.5 mL) = 100 IU octocog alfa pe reconstitution.

Helixate NexGen 500 IU contains (500 IU / 2.5 mL) = 200 IU octocog alfa, pel reconstitution.

Helixate NexGen 1000 IU contains (1000 IU / 2.5 mL) = 400 IU octocog alfa p reconstitution.

Helixate NexGen 2000 IU contains (2000 IU / 5 mL) = 400 IU ccto.og alfa per mL after reconstitution.

Helixate NexGen 3000 IU contains (3000 IU / 5 mL) = reconstitution.

1 vial with powder for on for injection.

1 vial with 2.5 mL watinjections.

1 vial with 5 mL water for injections.

AND ROUTE(S) OF ADMINISTRATION

For intravenous use, single dose administration only. Read the package leaflet before use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

• 8. EXPIRY DATE,

EXP

EXP (End of the 12 month period, if stored at room temperature):­...........

Do not use after this date.

May be stored at temperatures up to 25°C for up to 12 months within the expiry date indicated on the label. Note the new expiry date on the top of the carton. After reconstitution, the product must be used within 3 hours. Do not refrigerate after reconstitution.

• 9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2°C – 8°C). Do not freeze.

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

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MED OR WASTE MATERIALS DERIVED FROM SUCH MEDICI APPROPRIATE

Any unused solution must be discarded.

• 11. NAME AND ADDRESS OF THE MARKET

  HORISATION HOLDER

  
  

Bayer AG

51368 Leverkusen

Germany

EU/1/00/144/001 – Helixate NexGen 250 IU

EU/1/00/144/002 – Helixate NexGen 500 IU

EU/1/00/144/003 – Helixate NexGen 1000 IU

EU/1/00/144/004 – Heli

EU/1/00/144/005

• 14. GENERAL CLASSIFICATION FOR SUPPLY

• 15. INSTRUCTIONS ON USE

• 16. INFORMATION IN BRAILLE

Helixate NexGen 250

Helixate NexGen 500

Helixate NexGen 1000

Helixate NexGen 2000

Helixate NexGen 3000

• 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included.

• 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

VIAL WITH POWDER FOR SOLUTION FOR INJECTION

• 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Helixate NexGen 250 IU powder for solution for injection Helixate NexGen 500 IU powder for solution for injection Helixate NexGen 1000 IU powder for solution for injection Helixate NexGen 2000 IU powder for solution for injection Helixate NexGen 3000 IU powder for solution for injection

Recombinant coagulation factor VIII (octocog alfa)

• 2. METHOD OF ADMINISTRATION

Read the package leaflet before use.

IU-mL after reconstitution).

IU/mL after reconstitution).

0 IU/mL after reconstitution).

(400 IU/mL after reconstitution).

VIAL WITH 2.5 mL or 5 mL WATER FOR INJECTIONS

• 1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF ADMINISTRATION

Water for injections

• 2. METHOD OF ADMINISTRATION

  
  

For reconstitution of Helixate NexGen, see package leaflet. Use entire content.

EXP

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

• 2.5 mL [for reconstitution of strengths 250/500/1000 IU]

5 mL [for reconstitution of strengths 2000/3000 IU]

u need to know before you use Helixate NexGen

use Helixate NexGen

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

if you are allergic to mouse or hamster protein.

Warnings and precautions

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

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

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

you have previously developed a factor VIII inhibitor and you switch factor VIII products,

you may be at risk of your inhibitor coming back.

you have been told you have heart disease or are at risk for heart disease.

you require a central venous access device (CVAD) for the administration of NexGen. You may be at risk of CVAD-related complications including bacteria in the blood (bacteremia) and the formation of a blood clot in t (thrombosis) where the catheter is inserted.

Your doctor may carry out tests to ensure that your current dose of this medicine provides adequate factor VIII levels.

Other medicines and Helixate NexGen

Interactions with other medicines are not known. However, pleayour doctor or pharmacist if you are taking, have recently taken or might take any medicines.

Children and adolescents

The listed warnings and precautions apply to pati

f Helixate NexGen during pregnancy and breast-feeding is ant or breast-feeding, think you may be pregnant or are for advice before using this medicine.

t the fertility in male or female patients, as the active substance

es

ve or use machines have been observed.

Helixate NexGen contains sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per vial and is therefore considered essentially “sodium-free”.

Documentation

It is recommended that every time that you use Helixate NexGen, the name and batch number of the product are documented.

3. How to use Helixate NexGen

Always use this medicine exactly as described in this leaflet or as your doctor or pharmacist has told you. Check with your doctor, pharmacist or nurse if you are not sure.

Treatment of bleeding

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

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

Prevention of bleeding

If you are using Helixate NexGen to prevent bleeding (prophylaxis), your doctor will calculate dose for you. This will usually be in the range of 20 to 40 IU of octocog alfa per kg of body we given every 2 to 3 days. However, in some cases, especially for younger patients, shorte intervals or higher doses may be necessary.

How Helixate NexGen is given

This medicine is intended for injection into a vein over 2 to 5 minutes depending on the total volume and your comfort level and should be used within 3 hours after preparing the solution.

How Helixate NexGen is prepared for administration

Use only the items that are provided with each package of this medicine. If these components cannot be used, please contact your doctor. If any component of the package is opened or damaged, do not use it.

You must filter the reconstituted product before administration to remove any possible particles in the solution. You are filtering by using the Mix2Vial adapter.

This medicine must not be mixed with other infusion solutions. Do not use solutions containing visible particles or that are cloudy. Follow the directions given by your doctor closely and use the detailed instructions for reconstitution and administration provided at the end of this leaflet.

If you use more Helixate NexGen than you should

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

If you have used more Helixate NexGen than you should, please inform your doctor.

If you forget to use Helixate NexGen

• Proceed with your next dose immediately and continue at regular intervals as advised by your doctor.
• Do not take a double dose to make up for a forgotten dose.

If you want to stop using Helixate NexGen

Do not stop using Helixate NexGen without consulting your

If you have any further questions on the use of this medicin

4. Possible side effects

Like all medicines, this medicine can cause

The most serious side effects are hypersensitivity reactions or anaphylactic shock (rare side effect).

If allergic or anaphylactic reactions the injection/infusion should be stopped immediately.

Please consult your doctor imm

For children not previously treatwith Factor VIII medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients); however patients who have received previous treatment with Factor VIII (more than 150 days of treatment) the risk is uncommon (less than

1 in 100 patients). If this happens your or your child’s medicines may stop working properly and you or your child may experience persistent bleeding. If this happens, you should contact your doctor immediately.

Other possible side effects:

on may affect up to 1 in 10 users):

rash/itchy rash

local reactions where you injected the medication (e.g. burning sensation, temporary redness)

Rare (may affect up to 1 in 1,000 users):

• hypersensitivity reactions including severe sudden allergic reaction (which may include hives, nausea, urticaria, angioedema, chills, flushing, headache, lethargy, wheezing or difficulty breathing, restlessness, tachycardia, tingling or anaphylactic shock, e.g. tightness of the chest/general feeling of being unwell, dizziness and nausea and mildly reduced blood pressure, which may make you feel faint upon standing)
• fever
• Not known (frequency cannot be estimated from the available data): dysgeusia (strange taste)

If you notice any of the following symptoms during injection/infU­sion :

• chest tightness/general feeling of being unwell
• dizziness
• mild hypotension (mildly reduced blood pressure, which may make you feel faint upon standing)
• nausea

this can constitute an early warning for hypersensitivity and anaphylactic reactions.

If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately.

Please consult your doctor immediately.

Hypersensitivity reactions

During clinical studies, no patient developed clinically relevant antibody titres against t amounts of mouse protein and hamster protein present in the preparation. The possibi reactions to substances contained in this medication, e.g. trace amounts of mouse and exists in certain predisposed patients.

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the- safety of this medicine.

5. How to store Helixate NexGen

Keep this medicine out of the sight and reach of chi

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vials in the outer carton in order to protect from light.

Do not refrigerate the solution after reconstitution. The reconstituted solution must be used within 3 hours. This product is for single use only. Any unused solution must be discarded.

Do not use this medicine after the expiry date which is stated on labels and cartons. The expiry date refers tost day of that month.

s medicine if you notice any particles or the solution is cloudy.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other informationWhat Helixate NexGen containsPowder

The active substance is human coagulation factor VIII (octocog alfa) produced by recombinant DNA technology. Each vial of Helixate NexGen contains nominally 250, 500, 1000, 2000 or 3000 IU octocog alfa.

The other ingredients are glycine, sodium chloride, calcium chloride, histidine, polysorbate 80, and sucrose (see end of section 2).

Solvent

Water for injections

What Helixate NexGen looks like and content of the pack

Helixate NexGen is provided as a powder and solvent for solution for injection and is a dry white to slightly yellow powder or cake. After reconstitution the solution is clear. Medical devices for reconstitution and administration are provided with each package of this medicine.

Manufacturer

Bayer HealthCare Manufacturing S.r.l.

Via delle Groane 126

20024 Garbagnate Milanese (MI)

Italy

Detailed instructions for reconstitution and administration of Helixate NexGen using the

Mix2Vial adapter:

1.	Wash your hands thoroughly using soap and warm water.
2.	Warm both unopened vials in your hands to a comfortable temperature (do not	exceed 37 °C).
3.	Ensure product and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
4.	Open the Mix2Vial package by peeling away the lid. Do not remove the Mix2Vial from the blister package!
5.	Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.
		u5
6.	Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.
		Li 6
7.	Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.
		fl.
8.	With one hand grasp the product side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew counter clockwise the set carefully into two pieces. Discard the solvent vial with the blue Mix2Vial adapter attached. <
		UJs
9.	Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake. Carefully check for particles and discoloration before administration. Do not use solutions containing visible kparticles or that are cloudy.	9
10.	^ Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the product vial.	L
		io

• 14. Determine the point of injection and clean the skin with an alcohol swab.

• 15. Puncture the vein and secure the venipuncture set with a plaster.

• 16. Let blood flow back to the open end of the venipuncture set and then attach the syringe with the solution. Make sure that no blood enters the syringe.

• 17. Remove tourniquet.

  
  

• 18. Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of the needle. The speed of injection should be based on your comfort, but should not be faster than 2.0 mL per minute.

  19. If a further dose needs to be administe described above.

  
  

  a new syringe with product reconstituted as

  
  

  20. If no further dose is required, re

  
  

  the injection site on your ou dressing to the injection site

  
  

  ove the venipuncture set and syringe. Hold a pad firmly over ched arm for about 2 minutes. Finally, apply a small pressure

  
  

  d consider if a plaster is necessary.

  
  
  
  

Scientific conclusions

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

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

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

The occurrence of inhibitor development in haemophilia A patients receiving FVIII

occurs in previously-untreated patients (PUPs) or minimally treated patients within the first 50 days of exposure (EDs) to the treatment. Inhibitors are le previously-treated patients (PTPs).

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

• Patient-related risk factors include type of F8 gene mutation, severity of haemophilia, ethnicity, family history of inhibitor development and possibly HLA-DR (Human Leukocyte Antigen – antigen D Related) constitution.
• Treatment-related factors include intensity of exposure, number of exposure days (EDs), on demand treatment posing a greater risk than prophylaxis, particularly in the context of danger signals such as trauma or ry, and young age at first treatment poses a higher risk.

the risk of inhibitor development between different

s an area of uncertainty. Differences between products

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

rFVIII products) can in theory lead to differential immunogenicity.

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

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

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

The lead authors of the SIPPET study were also invited to respond to a list of questions regardi the study methods and findings and to present their conclusions at the February 2017 PRAC plenary meeting. Information submitted by the lead authors of the SIPPET study during the course of the referral was also taken into consideration by PRAC in reaching its conclusion. study, the FranceCoag study also found no statistically significant increased risk for any rFVIII products vs Advate when French patients (also in the RODIN/Pednet study) were excluded.

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

MAH-sponsored studies

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

The data came from a very wide range of heterogenous studies across prond over time.

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

Of the larger and more relevant studies for pdFVIII pr

Furthermore, the PRAC examined clinical trials and the scientific literature for de novo inhibitors in PTPs. The analysis demonstrated that the frequency of inhibitor development is much lower in PTPs compared to PUPs. The available data showed that in many studies including the EUHASS registry

er K, 2015) the frequency could be classified as “uncommon”.

study was an open-label, randomized, multi-centre, multi-national trial investigating incidence of neutralising allo-antibodies in patients with severe congenital haemophilia A (plasma FVIII concentration<1%) with either the use of pdFVIII or rFVIII concentrates. Eligible patients (<6 years, male, severe haemophilia A, no previous treatment with any FVIII concentrate or only minimal treatment with blood components) were included from 42 sites. The primary and secondary outcomes assessed in the study were the incidence of all inhibitors (>0.4 BU/ml) and the incidence of high-titre inhibitors (>5 BU/ml), respectively.

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

Ad hoc expert group meeting

The PRAC considered the views expressed by experts during an ad-hoc meeti

was of the view that the relevant available data sources have been con suggested that further data are needed to establish if there are clinicall

frequency of inhibitor development between different factor VIII products and that, in principle, such data should be collected separately for individual products, as degree of immunogenicity will be difficult to generalise across the classes of products (i.e. recombinant vs. plasma-derived).

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

The PRAC considered that as ective randomised trial, the SIPPET study avoided many of the

design limitations of the obse al and registry-based studies undertaken so far to evaluate the

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

• The SIPPET study has methodological limitations, with particular uncertainty around whether the randomisation process (block size of 2) may have introduced a selection bias in the study.
• There were also deviations from the final protocol and statistical analysis plan. The statistical concerns include the fact that no pre-specified primary analysis has been published and the fact that the study was stopped early following the publication of the RODIN study indicating that Kogenate FS might be associated with an increased risk of inhibitor formation. Although this could not have been prevented, an early termination of an open label trial raises the possibility of investigator bias and inflation of the probability of detecting an effect that is not present.
• Treatment regimens in EU are different from those in the SIPPET study. The relevance for clinical practice in the EU (and therefore for the products subject to this procedure) is therefore questioned. It is uncertain whether the findings of SIPPET can be extrapolated to the risk of inhibitors in PUPs in current clinical practice in the EU as treatment modality and intensity have been suggested as risk factors for inhibitor development in previous studies. Importantly, the EU SmPCs do not include modified prophylaxis (as defined in SIPPET

study) as an authorised posology, and the impact of the apparent imbal unspecified other combinations of treatment modality on the SIPPET fin Therefore, it remains uncertain whether the same differential risk of inh

observed in the SIPPET study would be apparent in patient popu care in other countries where the modality of treatment (i.e. pri different from that in the study. The additional points of clarifica SIPPET authors do not fully resolve this uncertainty.

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

Inhibitor development is an identified risk with both pdFVIII and rFVIII products. Although the clinical studies for some individual products have identified limited numbers of cases of inhibitor development, these tend small studies with methodological limitations, or

, and the plausibility of different rates of inhibitor oducts cannot be excluded.

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

was not designed to evaluate the risk of inhibitor development for

individual products, and included a limited number of FVIII products. Due to heterogeneity acr roducts, there is considerable uncertainty in extrapolating the findings of studies thae evaluated only class effects to individual products; and particularly to products more recently authorised products) which are not included in such studies.

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

In view of the above, the PRAC recommended the following updates of sections 4.4, 4.8 and 5.1 of the SmPC as well as sections 2 and 4 of the Package Leaflet for the FVIII products indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency) as follows:

• The section 4.4 of the SmPC should be amended to include a warning on the clinical importance of monitoring patients for FVIII inhibitor development (in particular warning on the clinical consequences of low compared to high titre inhibitors).
• With regards to sections 4.8 and 5.1 of the SmPC, the PRAC noted that several FVIII products currently include reference to data from study results which do not allow for a definite conclusion on the inhibitor risk for individual products. As the evidence suggests that all human FVIII products carry a risk of inhibitor development such statements should be removed. The available data supports a frequency of FVIII inhibitor development wi the frequency of ‘very common’ and ‘uncommon’, for PUPs and PTPs respectively, t the PRAC recommends that the SmPCs should be aligned with these frequencies justified by product specific data. For products for which section 4.2 contains the f statement for PUPs: “<Previously untreated patients. The safety and effica

The group also agreed that specific data about frequency of inhibitors for each product should not be includ he SmPC as the available studies are not adequately powered to draw precise conclusiothe absolute frequency for each product or on the relative frequency of inhibitors roducts.

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

PRAC conclusions

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

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

Overall summary of the scientific evaluation by the PRAC

Whereas,

• The PRAC considered the procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data, for human plasma derived and recombinant coagulation factor VIII containing medicinal products (see Annex I and Annex A).
• The PRAC considered the totality of the data submitted with regards to the risk of inhibitor development for the classes of recombinant and plasma derived FVIII products, in previously untreated patients (PUPs). This included published literature (SIPPET study), data generated in individual clinical trials and a range of observational studies submitted by the marketing authorisation holders, including the data generated in large multicentre cohort studies, data submitted by the national competent authorities of the EU Member States as well as responses provided by the Authors of the SIPPET study. PRAC also considered grounds submitted by LFB Biomedicaments as basis for their request for reexamination of the PRAC recommendation and the views of two experts meetings held on 22 February and 3 August 2017.
• The PRAC noted that the SIPPET study was not designed to evaluate the risk of inhibitor development for individual products, and included a limited number of FVIII products in total. Due to the heterogeneity across products, there is considerable uncertainty in extrapolating the findings of studies evaluating only class effects to individual products; and particularly to the products that are not included in such studies.

The PRAC also considered that studies conducted to date suffer from a variety of

methodological limitations and, on balance, there is no clear and consistent evidence to

suggest differences in relative risks between FVIII product classes based on available data. Specifically, the findings from the SIPPET study, as well as those from the individual clinical

ed in the MAH responses, are not sufficient to confirm meaningful differences in inhibitor risk between

rFVIII and pdFVIII product classes. Given these are heterogenous products, this does not

ing associated with an increased risk of inhibitor re PUP studies.

• The PRAC noted that the efficacy and safety of Factor VIII products as indicated in the treatment and prophylaxis of bleeding in patients with haemophilia A have been established.Based on the available data, the PRAC considered that SmPC updates for the

e warranted: section 4.4 should be amended to include a warning on the

clinical importance of monitoring patients for FVIII inhibitor development. With regards to sections 4.8 and 5.1, the PRAC noted that several FVIII products currently include reference to data from study results which do not allow a definite conclusion on the inhibitor risk for individual products. Results of clinical studies not sufficiently robust (e.g. suffering from methodolical limitations) should not be reflected in the product information on FVIIII products. The PRAC recommended changes to the product information accordingly. Besides, as the evidence suggests that all human FVIII products carry a risk of inhibitor development, within the frequency of ‘very common’ and ‘uncommon’, for PUPs and PTPs respectively, the PRAC recommended that the product information of these products should be aligned with these frequencies unless justified by product specific data.

Therefore, the PRAC concluded that the benefit-risk balance of the human plasma derived and recombinant coagulation Factor VIII containing medicinal products remains favourable and recommended the variations to the terms of the marketing authorisations.

CHMP opinion

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

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Fischer K , Lassila R , Peyvandi F , Calizzani G , Gatt A , Lambert T, Windyga J , Iorio A , Gilman E , Makris M; EUHASS participants Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost. 2015 May;113(5):968–75. doi: 10.1160/TH14–10–0826. Epub 2015 Jan 8.

Peyvandi F, Mannucci PM, Garagiola I, et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. The New England journal of medicine 2016 May 26;374(21):2054–64