Refixia

European Union - English - EMA (European Medicines Agency)

Active ingredient:
Nonacog beta pegol
Available from:
Novo Nordisk A/S
ATC code:
B02BD04
INN (International Name):
nonacog beta pegol
Therapeutic group:
Antihemorrhagics,
Therapeutic area:
Hemophilia B
Therapeutic indications:
Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia B (congenital factor IX deficiency).
Product summary:
Revision: 1
Authorization status:
Authorised
Authorization number:
EMEA/H/C/004178
Authorization date:
2017-06-02
EMEA code:
EMEA/H/C/004178

Documents in other languages

Patient Information leaflet Patient Information leaflet - Bulgarian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Bulgarian

02-08-2017

Public Assessment Report Public Assessment Report - Bulgarian

02-08-2017

Patient Information leaflet Patient Information leaflet - Spanish

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Spanish

02-08-2017

Public Assessment Report Public Assessment Report - Spanish

02-08-2017

Patient Information leaflet Patient Information leaflet - Czech

02-08-2017

Public Assessment Report Public Assessment Report - Czech

02-08-2017

Patient Information leaflet Patient Information leaflet - Danish

02-08-2017

Public Assessment Report Public Assessment Report - Danish

02-08-2017

Patient Information leaflet Patient Information leaflet - German

02-08-2017

Public Assessment Report Public Assessment Report - German

02-08-2017

Patient Information leaflet Patient Information leaflet - Estonian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Estonian

02-08-2017

Public Assessment Report Public Assessment Report - Estonian

02-08-2017

Patient Information leaflet Patient Information leaflet - Greek

02-08-2017

Public Assessment Report Public Assessment Report - Greek

02-08-2017

Patient Information leaflet Patient Information leaflet - French

02-08-2017

Public Assessment Report Public Assessment Report - French

02-08-2017

Patient Information leaflet Patient Information leaflet - Italian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Italian

02-08-2017

Public Assessment Report Public Assessment Report - Italian

02-08-2017

Patient Information leaflet Patient Information leaflet - Latvian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Latvian

02-08-2017

Public Assessment Report Public Assessment Report - Latvian

02-08-2017

Patient Information leaflet Patient Information leaflet - Lithuanian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Lithuanian

02-08-2017

Public Assessment Report Public Assessment Report - Lithuanian

02-08-2017

Patient Information leaflet Patient Information leaflet - Hungarian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Hungarian

02-08-2017

Public Assessment Report Public Assessment Report - Hungarian

02-08-2017

Patient Information leaflet Patient Information leaflet - Maltese

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Maltese

02-08-2017

Public Assessment Report Public Assessment Report - Maltese

02-08-2017

Patient Information leaflet Patient Information leaflet - Dutch

02-08-2017

Public Assessment Report Public Assessment Report - Dutch

02-08-2017

Patient Information leaflet Patient Information leaflet - Polish

02-08-2017

Public Assessment Report Public Assessment Report - Polish

02-08-2017

Patient Information leaflet Patient Information leaflet - Portuguese

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Portuguese

02-08-2017

Public Assessment Report Public Assessment Report - Portuguese

02-08-2017

Patient Information leaflet Patient Information leaflet - Romanian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Romanian

02-08-2017

Public Assessment Report Public Assessment Report - Romanian

02-08-2017

Patient Information leaflet Patient Information leaflet - Slovak

02-08-2017

Public Assessment Report Public Assessment Report - Slovak

02-08-2017

Patient Information leaflet Patient Information leaflet - Slovenian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Slovenian

02-08-2017

Public Assessment Report Public Assessment Report - Slovenian

02-08-2017

Patient Information leaflet Patient Information leaflet - Finnish

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Finnish

02-08-2017

Public Assessment Report Public Assessment Report - Finnish

02-08-2017

Patient Information leaflet Patient Information leaflet - Swedish

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Swedish

02-08-2017

Public Assessment Report Public Assessment Report - Swedish

02-08-2017

Patient Information leaflet Patient Information leaflet - Norwegian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Norwegian

02-08-2017

Patient Information leaflet Patient Information leaflet - Icelandic

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Icelandic

02-08-2017

Patient Information leaflet Patient Information leaflet - Croatian

02-08-2017

Summary of Product characteristics Summary of Product characteristics - Croatian

02-08-2017

Public Assessment Report Public Assessment Report - Croatian

02-08-2017

Read the complete document

B. PACKAGE LEAFLET

Package leaflet: Information for the user

Refixia 500 IU powder and solvent for solution for injection

Refixia 1000 IU powder and solvent for solution for injection

Refixia 2000 IU powder and solvent for solution for injection

nonacog beta pegol

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor. This includes any possible side effects not listed

in this leaflet. See section 4.

What is in this leaflet

What Refixia is and what it is used for

What you need to know before you use Refixia

How to use Refixia

Possible side effects

How to store Refixia

Contents of the pack and other information

1.

What Refixia is and what it is used for

What Refixia is

Refixia contains the active substance nonacog beta pegol and is a long-acting recombinant coagulation

factor IX product. Factor IX is a protein naturally found in the blood that helps to stop bleeding.

What Refixia

is used for

Refixia is used to treat and prevent bleeding in patients 12 years and above with haemophilia B

(inborn factor IX deficiency).

In patients with haemophilia B, factor IX is missing or does not work properly. Refixia replaces this

faulty or missing factor IX and helps blood to form clots at the site of bleeding. When you bleed,

Refixia is activated in the blood to form factor IX.

2.

What you need to know before you use Refixia

Do not use Refixia:

if you are allergic to the active substance or any of the other ingredients of this medicine (listed

in section 6).

if you are allergic to hamster proteins.

If you are not sure if either of the above applies to you, talk to your doctor before using this medicine.

Warnings and precautions

Allergic reactions and development of inhibitors

There is a rare risk that you may experience a sudden and severe allergic reaction (e.g. anaphylactic

reaction) to Refixia. Stop the injection and contact your doctor or an emergency unit immediately if

you have signs of an allergic reaction such as rash, hives, weals, itching on large areas of skin, redness

and/or swelling of lips, tongue, face or hands, difficulty in swallowing or breathing, shortness of

breath, wheezing, tightness of the chest, pale and cold skin, fast heartbeat, and/or dizziness.

Your doctor may need to treat you promptly for these reactions. Your doctor may also do a blood test

to check if you have developed factor IX inhibitors (neutralising antibodies) against your medicine, as

inhibitors may develop together with allergic reactions. If you have such antibodies, you may be at an

increased risk of sudden and severe allergic reactions (e.g. anaphylactic reaction) during future

treatment with factor IX.

Because of the risk of allergic reactions with factor IX, your initial treatment with Refixia should be

given in a medical clinic or in the presence of health care professionals where proper medical care for

allergic reactions can be provided if needed.

Talk to your doctor immediately if your bleeding does not stop as expected or if you have to

significantly increase your usage of Refixia in order to stop a bleed. Your doctor will do a blood test to

check if you have developed inhibitors (neutralising antibodies) against Refixia. The risk for

developing inhibitors is highest if you have not been treated with factor IX medicines before i.e. for

small children.

Blood clots

Tell your doctor, if any of the following apply to you as there is an increased risk of blood clots during

treatment with Refixia:

you have recently had surgery

you suffer from other serious illness e.g. liver disease, heart disease, or cancer

you have risk factors for heart disease e.g high blood pressure, obesity, or smoking.

Kidney disorder (nephrotic syndrome)

There is a rare risk of developing a specific kidney disorder called “nephrotic syndrome” following

high doses of factor IX in haemophilia B patients with factor IX inhibitors and a history of allergic

reactions.

Catheter-related problems

If you have a central venous access device (CVAD), you may develop infections or blood clots at the

site of the catheter.

Other medicines and Refixia

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor for advice before using Refixia.

Driving and using machines

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

Refixia contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially “sodium-free”.

3.

How to use Refixia

Treatment with Refixia will be started by a doctor who is experienced in the care of patients with

haemophilia B. Always use this medicine exactly as your doctor has told you. Check with your doctor

if you are not sure about how to use Refixia.

Your doctor will calculate your dose for you. The dose will depend on your weight and what the

medicine is being used for.

Prevention of bleeding

The dose of Refixia is 40 international units (IU) per kg of body weight. This is given as one injection

every week. Your doctor may choose another dose or how often the injections should be given, based

on your need.

Treatment of bleeding

The dose of Refixia is 40 international units (IU) per kg of body weight. Depending on the location

and the severity of bleeding you may need a higher dose (80 IU per kg) or extra injections. Discuss

with your doctor the dose and number of injections you need.

Use in children and adolescents

Refixia can be used only in adolescents (12 years and above). The dose in adolescents is also

calculated according to body weight and is the same dose as for adults.

How Refixia is given

Refixia is given as an injection into a vein. See “Instructions on how to use Refixia” for more

information.

If you use more Refixia than you should

If you use more Refixia than you should, contact your doctor.

If you have to significantly increase your usage of Refixia to stop a bleed, talk to your doctor

immediately. For further information, see section 2 “Allergic reactions and development of inhibitors”.

If you forget to use Refixia

If you forget a dose, inject the missed dose as soon as you remember. Do not inject a double dose to

make up for a forgotten dose. If you are in doubt contact your doctor.

If you stop using Refixia

If you stop using Refixia you may no longer be protected against bleeding or a current bleed may not

stop. Do not stop using Refixia without talking to your doctor.

If you have any further questions on the use of this medicine, ask your doctor.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions are possible with this medicine.

If sudden and severe allergic reactions (e.g. anaphylactic reactions) occur, the injection must be

stopped immediately. You must contact your doctor or an emergency unit immediately if you have

early signs of an allergic reaction such as:

difficulty in swallowing or breathing

shortness of breath or wheezing

chest tightness

redness and/or swelling of the lips, tongue, face or hands

rash, hives, weals or itching

pale and cold skin, fast heartbeat, and/or dizziness (low blood pressure).

The following side effects have been observed with Refixia:

Common side effects

(may affect up to 1 in 10 people)

itching (pruritus)

skin reactions at the site of injection

feeling sick (nausea)

feeling very tired.

Uncommon side effects

(may affect up to 1 in 100 people)

allergic reactions (hypersensitivity). This may become severe and could be life-threatening

(anaphylactic reactions)

heart palpitations

hot flush.

Side effects with unknown frequency

(frequency cannot be estimated from the available data)

neutralising antibodies (inhibitors).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. 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 Refixia

Keep this medicine out of the sight and reach of children.

Do not use Refixia after the expiry date which is stated after “EXP” on the carton and on the vial and

the pre-filled syringe labels. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect

from light.

Refixia may be taken out of the refrigerator for a maximum period of 6 months and stored at room

temperature (up to 30°C). Please record on the carton the date Refixia is removed from the refrigerator

and placed at room temperature. This new expiry date should never exceed the one initially mentioned

on the outer carton. If the medicine has not been used before the new expiry date, it should be disposed

of. After storage at room temperature the medicine must not be put back in the refrigerator.

Use the injection immediately after reconstitution. If it cannot be used immediately, use within

24 hours if stored in a refrigerator at 2°C – 8°C or within 4 hours if stored out of the refrigerator at a

maximum temperature of 30°C.

The powder in the vial appears as a white to off-white powder. Do not use the powder if the colour has

changed.

The reconstituted solution will be clear and colourless. Do not use the reconstituted solution if you

notice any particles or discolouration.

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 information

What Refixia contains

The active substance is nonacog beta pegol (pegylated human coagulation factor IX (rDNA)).

Each vial of Refixia contains nominally 500 IU, 1000 IU or 2000 IU nonacog beta pegol

corresponding to approximately 125 IU/ml, 250 IU/ml or 500 IU/ml respectively after

reconstitution with histidine solvent.

The other ingredients in the powder are sodium chloride, histidine, sucrose, polysorbate 80,

mannitol, sodium hydroxide and hydrochloric acid.

The ingredients in the sterilised solvent are histidine, water for injections, sodium hydroxide and

hydrochloric acid.

What Refixia looks like and contents of the pack

Refixia is provided as a powder and solvent for solution for injection (500 IU, 1000 IU or

2000 IU powder in a vial and 4 ml solvent in a pre-filled syringe, a plunger rod with a vial

adapter – pack size of 1).

The powder is white to off-white and the solvent is clear and colourless.

Marketing Authorisation Holder and Manufacturer

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd, Denmark

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu

Instructions on how to use Refixia

Read these instructions carefully before using Refixia.

Refixia is supplied as a powder. Before injection it must be reconstituted with the solvent supplied in

the syringe. The solvent is a histidine solution. The reconstituted product must be injected into your

vein (intravenous (IV) injection). The equipment in this package is designed to reconstitute and inject

Refixia.

You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and

plasters. These items are not included in the Refixia package.

Do not use the equipment without proper training from your doctor or nurse.

Always wash your hands and ensure that the area around you is clean.

When you prepare and inject medicine directly into the veins, it is important to

use a clean and germ

free (aseptic) technique.

Incorrect technique can introduce germs that can infect the blood.

Do not open the equipment until you are ready to use it.

Do not use the equipment if it has been dropped, or if it is damaged.

Use a new package instead.

Do not use the equipment if it has expired.

Use a new package instead. The expiry date is printed on

the outer carton, on the vial, on the vial adapter, and on the pre-filled syringe.

Do not use the equipment if you suspect it is contaminated.

Use a new package instead.

Do not dispose of any of the items until after you have injected the reconstituted solution.

The equipment is for single use only.

Contents

The package contains:

1 vial with Refixia powder

1 vial adapter

1 pre-filled syringe with solvent

1 plunger rod (placed under the syringe)

Vial with Refixia powder

Plastic cap

Rubber stopper

(under plastic cap)

Overview

Vial adapter

Protective cap

Spike

(under protective paper)

Protective

paper

Pre-filled syringe with solvent

Syringe tip

(under syringe cap)

Scale

Plunger

Syringe cap

Plunger

rod

Thread

Wide top

1. Prepare the vial and the syringe

Take out the number of Refixia

packages

you need.

Check the expiry date.

Check the name, strength and colour

the package, to make sure it contains the

correct product.

Wash your hands

and dry them properly

using a clean towel or air dry.

Take the vial, the vial adapter and the pre-

filled syringe out of the carton.

Leave the

plunger rod untouched in the carton.

Bring the vial and the pre-filled syringe

to room temperature.

You can do this by

holding them in your hands until they feel

as warm as your hands.

Do not use any other way to

warm

vial and pre-filled syringe.

A

Remove the plastic cap

from the vial

. If

the plastic cap is loose or missing, do not

use the vial.

Wipe the rubber stopper with a sterile

alcohol swab

and allow it to air dry for a

few seconds before use to ensure that it is

as germ free as possible.

Do not touch the rubber stopper with

your fingers as this can transfer germs.

B

2. Attach the vial adapter

Remove the protective paper from the

vial adapter.

If the protective paper is not fully sealed

or if it is broken, do not use the vial

adapter.

Do not take the vial adapter out of the

protective cap with your fingers.

If you touch the spike on the vial adapter,

germs from your fingers can be transferred.

C

Place the vial on a flat and solid surface.

Turn over the protective cap,

and snap

the vial adapter onto the vial.

Once attached, do not remove the vial

adapter from the vial.

D

Lightly

squeeze the protective cap

with

your thumb and index finger as shown.

Remove the protective cap

from the vial

adapter.

Do not lift the vial adapter from the vial

when removing the protective cap.

E

3. Attach the plunger rod and the syringe

Grasp the plunger rod by the wide top end

and take it out of the carton.

Do not touch

the sides or the thread of the plunger

rod.

If you touch the sides or the thread,

germs from your fingers can be transferred.

Immediately

connect the plunger rod to

the syringe by turning it clockwise into the

plunger inside the pre-filled syringe until

resistance is felt.

F

Remove the syringe cap

from the

pre-filled syringe by bending it down until

the perforation breaks.

Do not touch the syringe tip under the

syringe cap.

If you touch the syringe tip,

germs from your fingers can be transferred.

If the syringe cap is loose or missing, do

G

not use the pre-filled syringe.

Screw the pre-filled syringe securely

onto

the vial adapter until resistance is felt.

H

4. Reconstitute the powder with the solvent

Hold the pre-filled syringe slightly tilted

with the vial pointing downwards.

Push the plunger rod

to inject all the

solvent into the vial.

I

Keep the plunger rod pressed down and

swirl

the vial gently until all the powder is

dissolved.

Do not shake the vial as this will cause

foaming.

Check the reconstituted solution.

It must

be clear and colourless and no particles

should be visible.

If you notice particles

or discolouration, do not use it.

Use a

new package instead.

J

Refixia is recommended to be used immediately after it has been reconstituted.

This is because if

left, the medicine may no longer be sterile and could cause infections.

If you cannot use the reconstituted Refixia solution immediately,

it should be used within 4 hours

when stored at room temperature (up to 30°C) and within 24 hours when stored in a refrigerator

(2°C – 8°C). Store the reconstituted product in the vial.

Do not freeze reconstituted Refixia solution or store it in syringes.

Keep reconstituted Refixia solution out of direct light.

If your dose requires more than one vial, repeat steps

A

J

with additional vials, vial adapters and

pre-filled syringes until you have reached your required dose.

Keep the plunger rod pushed completely

in

Turn the syringe

with the vial upside

down.

Stop pushing the plunger rod and let it

move back

on its own while the

reconstituted solution fills the syringe.

Pull the plunger rod slightly downwards

to draw the reconstituted solution into the

syringe.

In case you only need part of the entire

vial, use the scale on the syringe to see

how much reconstituted solution you

withdraw, as instructed by your doctor

or nurse.

If, at any point, there is air in the syringe,

inject the air back into the vial.

While holding the vial upside down,

tap

the syringe gently

to let any air bubbles

rise to the top.

Push the plunger rod

slowly until all air

bubbles are gone.

K

Unscrew the vial adapter

with the vial.

Do not touch the syringe tip.

If you touch

the syringe tip, germs from your fingers

can be transferred.

L

5. Inject the reconstituted solution

Refixia is now ready to inject into your vein.

Inject the reconstituted solution as instructed by your doctor or nurse.

Inject slowly over 1 to 3 minutes.

Do not mix Refixia with any other intravenous infusions or medications.

Injecting Refixia via needleless connectors for intravenous (IV) catheters

Caution:

The pre-filled syringe is made of glass and is designed to be compatible with standard luer-

lock connections. Some needleless connectors with an internal spike are incompatible with the

pre-filled syringe. This incompatibility may prevent administration of the drug and/or result in damage

to the needleless connector.

Injecting the solution via a central venous access device (CVAD) such as a central venous catheter or

a subcutaneous port:

Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your

connector and CVAD in consultation with your doctor or nurse.

Injecting into a CVAD may require using a sterile 10 ml plastic syringe for withdrawal of the

reconstituted solution. This should be done right after step J.

If the CVAD line needs to be flushed before or after Refixia injection, use sodium chloride

9 mg/ml solution for injection.

Disposal

After injection, safely dispose

of all

unused Refixia solution, the syringe with

the infusion set, the vial with the vial

adapter and other waste materials as

instructed by your pharmacist.

Do not throw it out with the ordinary

household waste.

M

Do not disassemble the equipment before disposal.

Do not reuse the equipment.

Read the complete document

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

This medicinal product is subject to additional monitoring. This will allow quick identification of

new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

See section 4.8 for how to report adverse reactions.

1.

NAME OF THE MEDICINAL PRODUCT

Refixia 500 IU powder and solvent for solution for injection

Refixia 1000 IU powder and solvent for solution for injection

Refixia 2000 IU powder and solvent for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Refixia 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU nonacog beta pegol*.

After reconstitution, 1 ml of Refixia contains approximately 125 IU nonacog beta pegol.

Refixia 1000 IU powder and solvent for solution for injection

Each vial contains nominally 1000 IU nonacog beta pegol*.

After reconstitution, 1 ml of Refixia contains approximately 250 IU nonacog beta pegol.

Refixia 2000 IU powder and solvent for solution for injection

Each vial contains nominally 2000 IU nonacog beta pegol*.

After reconstitution, 1 ml of Refixia contains approximately 500 IU nonacog beta pegol.

*recombinant human factor IX, produced in Chinese Hamster Ovary (CHO) cells by recombinant

DNA technology, covalently conjugated to a 40 kDa polyethylene-glycol (PEG).

The potency (International Units) is determined using the European Pharmacopeia one-stage clotting

test. The specific activity of Refixia is approximately 152 IU/mg protein.

Refixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG)

selectively attached to specific N-linked glycans in the rFIX activation peptide. Upon activation of

Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving

the native activated factor IX molecule. The primary amino acid sequence of the rFIX in Refixia is

identical to the Ala148 allelic form of human plasma-derived factor IX. No additives of human or

animal origin are used in the cell culture, purification, conjugation, or formulation of Refixia.

Excipient with known effect

Less than 1 mmol sodium (23 mg) per vial.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

The powder is white to off-white.

The solvent is clear and colourless.

pH: 6.4.

Osmolality: 272 mOsmol/kg.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia B (congenital

factor IX deficiency).

4.2

Posology and method of administration

Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.

Previously untreated patients

The safety and efficacy of Refixia in previously untreated patients have not yet been established.

Treatment monitoring

Routine monitoring of factor IX activity levels for the purpose of dose adjustment is not necessary. In

the clinical trial programme, dose adjustment was not performed. Mean steady state factor IX trough

levels above 15% were observed for all age groups, see section 5.2 for details.

Due to the interference of polyethylene glycol (PEG) in the one-stage clotting assay with various aPTT

reagents, it is recommended to use a chromogenic assay (e.g. Rox Factor IX or Biophen) when

monitoring is needed. If a chromogenic assay is not available, it is recommended to use a one-stage

clotting assay with an aPTT reagent (e.g. Cephascreen) qualified for use with Refixia. For modified

long-acting factor products it is known that the one-stage clotting assay results are highly dependent

on the aPTT reagent and reference standard used. For Refixia some reagents will cause

underestimation (30–50%), while most silica containing reagents will cause severe overestimation of

the factor IX activity (more than 400%). Therefore, silica based reagents should be avoided. Use of a

reference laboratory is recommended when a chromogenic assay or a qualified one-stage clotting

assay is not available locally.

Posology

The number of units of factor IX administered is expressed in International Units (IU), which are

related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed

either as a percentage (relative to normal human plasma) or in International Units (relative to an

International Standard for factor IX in plasma).

Prophylaxis

40 IU/kg body weight once weekly.

Adjustments of doses and administration intervals may be considered based on achieved FIX levels

and individual bleeding tendency. The trough levels achieved with the weekly 40 IU/kg dosing

regimen are summarised in section 5.2.

Patients on prophylaxis who forget a dose are advised to take their dose upon discovery and thereafter

continue with the usual once weekly dosing schedule. A double dose should be avoided.

On-demand treatment

Dose and duration of the substitution therapy depend on the location and severity of the bleeding, see

Table 1 for dosing guidance in bleeding episodes.

Table 1

Treatment of bleeding episodes with Refixia

Degree of

haemorrhage

Recommended

dose IU/kg of

Refixia

Dosing recommendations

Early

haemarthrosis,

muscle bleeding or

oral bleeding.

More extensive

haemarthrosis,

muscle bleeding or

haematoma.

A single dose is recommended.

Severe or life

threatening

haemorrhages.

Additional doses of 40 IU/kg can be

given.

Surgery

The dose level and dosing intervals for surgery depend on the procedure and local practice. General

recommendations are provided in Table 2.

Table 2

Treatment in surgery with Refixia

Type of surgical

procedure

Recommended

dose IU/kg body

weight

Dosing recommendations

Minor surgery

including tooth

extraction.

Additional doses can be given if needed.

Major surgery.

Pre-operative dose.

Consider two repeated doses of 40 IU/kg

(in 1–3 day intervals) within the first

week after surgery.

Due to the long half-life of Refixia, the

frequency of dosing in the post-surgical

period may be extended to once weekly

after the first week until bleeding stops

and healing is achieved.

Paediatric population

The dose recommendations in adolescents (12–18 years) are the same as for adults: 40 IU/kg body

weight. The long-term safety of Refixia in children below 12 years has not yet been established.

Method of administration

Intravenous use.

Refixia is administered by intravenous bolus injection over several minutes after reconstitution of the

powder for injection with the histidine solvent. The rate of administration should be determined by the

patient’s comfort level up to a maximum injection rate of 4 ml/min.

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

In case of self-administration or administration by caregiver appropriate training is needed.

4.3

Contraindications

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

Known allergic reaction to hamster protein.

4.4

Special warnings and precautions for use

Hypersensitivity

Allergic type hypersensitivity reactions are possible with Refixia. The product contains traces of

hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use

of the medicinal product immediately and contact their physician. Patients should be informed of the

early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest,

wheezing, hypotension, and anaphylaxis.

In case of shock, standard medical treatment for shock should be implemented.

Inhibitors

After repeated treatment with human coagulation factor IX (rDNA) products, patients should be

monitored for the development of neutralising antibodies (inhibitors) that should be quantified in

Bethesda Units (BU) using appropriate biological testing.

There have been reports in the literature showing a correlation between the occurrence of a factor IX

inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated

for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an

increased risk of anaphylaxis with subsequent challenge with factor IX.

Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IX

should, according to the treating physician’s judgement, be performed under medical observation

where proper medical care for allergic reactions could be provided.

In case of residual FIX activity levels, there is a risk of interference when performing the Nijmegen

modified Bethesda assay for inhibitor testing. Therefore a pre-heating step or a wash-out is

recommended in order to ensure detection of low-titre inhibitors.

Thromboembolism

Because of the potential risk of thrombotic complications, clinical surveillance for early signs of

thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when

administering this product to patients with liver disease, to patients post-operatively, to new-born

infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit

of treatment with Refixia should be weighed against the risk of these complications.

Cardiovascular event

In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the

cardiovascular risk.

Catheter-related complications

If a central venous access device (CVAD) is required, risk of CVAD-related complications including

local infections, bacteraemia and catheter site thrombosis should be considered.

Paediatric population

Refixia is not indicated for use in children (below 12 years). The listed warnings and precautions apply

both to adults and adolescents (12–18 years).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially

“sodium-free”.

Record of use

It is strongly recommended that every time that Refixia 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.

4.5

Interaction with other medicinal products and other forms of interaction

No interactions of human coagulation factor IX (rDNA) products with other medicinal products have

been reported.

4.6

Fertility, pregnancy and lactation

Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of

haemophilia B in women, experience regarding the use of factor IX during pregnancy and

breastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only

if clearly indicated.

4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

Summary of the safety profile

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 with recombinant factor IX products and may in some cases progress to severe anaphylaxis

(including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have

occurred in close temporal association with development of factor IX inhibitors (see also section 4.4).

Nephrotic syndrome has been reported following attempted immune tolerance induction in

haemophilia B patients with factor IX inhibitors and a history of allergic reaction.

Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has

been observed.

Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. 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 is contacted.

There is a potential risk of thromboembolic episodes following the administration of factor IX

products, with a higher risk for low purity preparations. The use of low purity factor IX products has

been associated with instances of myocardial infarction, disseminated intravascular coagulation,

venous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia is

rarely associated with such adverse reactions.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and

Preferred Term Level).

Frequencies have been evaluated according to the following convention: very common (≥ 1/10);

common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very

rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

A total of 115 previously treated male patients with moderate or severe haemophilia B have been

exposed to Refixia for a total of 170 patient years in the completed clinical trials.

Table 3

Frequency of adverse reactions in clinical trials

System Organ Class

Adverse reaction

Frequency

Immune system disorders

Hypersensitivity

Anaphylaxis

Inhibitors

Uncommon

Unknown

Unknown

Cardiac disorders

Palpitations

Uncommon

Gastrointestinal disorders

Nausea

Common

Skin and subcutaneous tissue

disorders

Pruritus*

Common

General disorders and

administration site conditions

Fatigue

Hot flush

Injection site reactions**

Common

Uncommon

Common

*Pruritus includes the terms pruritus and ear pruritus

**Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and

injection site rash.

Description of selected adverse reactions

In an ongoing trial in previously untreated patients, anaphylaxis has occurred in close temporal

association with development of factor IX inhibitors following treatment with Refixia. There are

insufficient data to provide information on inhibitor incidence in previously untreated patients.

Paediatric population

Refixia is indicated for patients 12 years and above.

No difference in the safety profile of Refixia was

observed between previously treated adolescent (12–18 years) and adult patients.

Reporting of suspected adverse reactions

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

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9

Overdose

Overdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated with

overdoses have been reported.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04.

Mechanism of action

Refixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG)

conjugated to the protein. The average molecular weight of Refixia is approximately 98 kDa and the

molecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activation

peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated

factor IX molecule.

Factor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it is

synthesised in the liver. Factor IX is activated by factor XIa and by factor VII/tissue factor complex.

Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X

converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is

formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased

levels of factor IX 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 IX are increased, thereby enabling a temporary correction of the factor deficiency and

correction of the bleeding tendencies.

Clinical efficacy

The completed clinical trial programme included one phase 1 trial and four phase 3 multicentre, non-

controlled trials.

Prophylaxis

Fifty-four of the patients across all age-groups were treated with a weekly prophylactic dose of

40 IU/kg where 23 (43%) of these patients had no bleeding episodes.

Pivotal trial

The pivotal trial included 74 adolescent (13–17 years) and adult (18–65 years) previously treated

patients. The trial included one open-label on-demand arm with treatment for approximately 28 weeks

and two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or 40 IU/kg

once-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kg treatments, the

annualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lower than the bleeding

rate (95% CI: 5%;73%) for patients in the 10 IU/kg arm (p<0.05).

The median (IQR) overall annual bleeding rate (ABR) in patients (13–65 years) treated with a

prophylactic dose of 40 IU/kg once weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00

(0.00; 2.05), joint ABR was 0.97 (0.00; 2.07) and spontaneous ABR was 0.00 (0.00; 0.99).

Of note, ABR is not comparable between different factor concentrates and between different clinical

studies.

In this pivotal trial in adolescent and adult patients, there were 70 breakthrough bleeding episodes for

16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment of

breakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70

bleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at

40 IU/kg for mild or moderate bleeds.

In 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one year

with a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longer

considered target joints at the end of the trial.

On-demand treatment

In the pivotal trial there was a non-randomised arm where 15 patients were treated in an on-demand

regimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overall

success rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleeds

treated with one or two injections.

Paediatric population

The use of Refixia in children below 12 years is not indicated (see section 4.2 for information on

paediatric use).

A trial including 25 paediatric previously treated patients (ages 0–12 years) who received a

prophylactic dose 40 IU/kg once weekly was performed.

In children aged 0–12 years, the median (IQR) annualised bleeding rate was 1.0 (0.00; 2.06) and the

spontaneous bleeding rate was 0.00 (0.00; 0.00).

For treatment of bleeds in paediatrics, the overall success rate (defined as excellent or good) was 93%

(39 out of 42 bleeds), where 36 (86 %) of the bleeds were resolved with 1 injection, and 5 (12%) of the

bleeds were resolved with 2 injections of Refixia.

The European Medicines Agency has deferred the completion of the study with Refixia in previously

untreated patients (see section 4.2 for information on paediatric use).

Overall haemostatic efficacy

Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg for

severe bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacy

was performed by the patient or caretaker (for home treatment) or study site investigator (for treatment

under health care professional supervision) using a 4-point scale of excellent, good, moderate, or poor.

The overall success rate (defined as excellent or good) for treatment of bleeds was 93% (551 out of

591). Of the 597 treated bleeds observed in 79 (75%) of the 105 patients, 521 (87%) of the bleeds were

resolved with 1 injection and 60 (10%) of the bleeds were resolved with 2 injections of Refixia.

The success rate and dose needed for treatment of the bleeding episodes were independent of the

localisation of the bleed. The success rate for treatment of bleeding episodes was also independent of

whether the bleed was traumatic or spontaneous of nature.

Surgery

Three trials of which one trial was a dedicated surgery trial included in total 15 major and 26 minor

surgery procedures (patients aged 13 to 56 years). Haemostatic effect of Refixia during surgery was

confirmed with a success rate of 100% in the 15 major surgeries in the trials. All evaluated minor

surgeries were performed successfully.

In a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in

13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1

gastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of

80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of

80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In the

post-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg doses

administered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and after

surgery was 241 IU/kg (range: 81–460 IU/kg).

5.2

Pharmacokinetic properties

Refixia has a prolonged half-life compared to unmodified factor IX. All pharmacokinetic studies with

Refixia were conducted in previously treated patients with haemophilia B (factor IX ≤2%). The

analysis of plasma samples was conducted using the one-stage clotting assay.

Steady state pharmacokinetic parameters for adolescents and adults are shown in Table 4

Table 4

Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescents and

adults (geometric mean (CV%))

PK Parameter

13–17 years

N=3

≥18 years

N=6

Half-life (t

) (hours)

103 (14)

115 (10)

Incremental Recovery (IR) (IU/ml per

IU/kg)

0.018 (28)

0.019 (20)

Area under the curve (AUC)

0-168h

(IU*hours/ml)

91 (22)

93 (15)

Clearance (CL) (ml/hour/kg)

0.4 (17)

0.4 (11)

Mean residence time (MRT) (hours)

144 (15)

158 (10)

Volume of distribution (Vss) (ml/kg)

61 (31)

66 (12)

Factor IX activity 168 h post dosing

(IU/ml)

0.29 (19)

0.32 (17)

Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of

distribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation.

All patients assessed in the steady state pharmacokinetic session had factor IX activity levels above

0.24 IU/ml at 168 hours post dosing with a weekly dose of 40 IU/kg.

Single-dose pharmacokinetic parameters of Refixia are listed by age in Table 5

The use of Refixia in

children below 12 years is not indicated.

Table 5

Single-dose pharmacokinetic parameters of Refixia (40 IU/kg) by age (geometric

mean (CV%))

PK Parameter

0–6 years

N=12

7–12 years

N=13

13–17 years

N=3

≥18 years

N=6

Half-life (t

(hours)

70 (16)

76 (26)

89 (24)

83 (23)

Incremental

Recovery (IR)

(IU/ml per IU/kg)

0.015 (7)

0.016 (16)

0.020 (15)

0.023 (11)

Area under the

curve (AUC)

(IU*hours/ml)

46 (14)

56 (19)

80 (35)

91 (16)

Clearance CL

(ml/hour/kg)

0.8 (13)

0.6 (22)

0.5 (30)

0.4 (15)

Mean residence

time (MRT)

(hours)

95 (15)

105 (24)

124 (24)

116 (22)

Volume of

distribution (Vss)

(ml/kg)

72 (15)

68 (22)

59 (8)

47 (16)

Factor IX activity

168 h post dosing

(IU/ml)

0.08 (16)

0.11 (19)

0.15 (60)

0.17 (31)

Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of

distribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation.

As expected, body weight adjusted clearance in paediatric and adolescent patients was higher

compared to adults. No dose adjustment was required for paediatric or adolescent patients in clinical

trials.

The mean trough levels at steady state are presented in Table 6; based on all pre-dose measurements

taken every 8 weeks at steady state for all patients on once weekly dosing of 40 IU/kg. The use of

Refixia in children below 12 years is not indicated.

Table 6

Mean of trough levels* of Refixia (40 IU/kg) at steady state

0–6 years

7–12 years

13–17 years

18–65 years

N=12

N=13

N=9

N=20

Estimated mean

factor IX trough

levels IU/ml

(95% CI)

0.15

(0.13;0.18)

0.19

(0.16;0.22)

0.24

(0.20;0.28)

0.29

(0.26;0.33)

* Factor IX trough levels = factor IX activity measured prior to next weekly dose (5 to 10 days post dosing) at steady state.

Pharmacokinetics were investigated in 16 adult and adolescent patients of which 6 were normal weight

(BMI 18.5–24.9 kg/m

) and 10 were overweight (BMI 25–29.9 kg/m

). There were no apparent

differences in the pharmacokinetic profiles between normal weight and overweight patients.

5.3

Preclinical safety data

In a repeat dose toxicity study in monkeys, mild and transient body tremors were seen 3 hours post

dosing and abated within 1 hour. These body tremors were seen at doses of Refixia (3,750 IU/kg),

which were more than 90 times higher than the recommended dose for humans (40 IU/kg). No

mechanism behind the tremors was identified. Tremors have not been reported in the clinical trials.

Non-clinical data reveal no concern for humans based on conventional safety pharmacology and

repeated dose toxicity studies in rats and monkeys.

In repeat dose toxicity studies in rats and monkeys, 40 kDa polyethylene-glycol (PEG) was detected

by immunohistochemical staining in epithelial cells of choroid plexus in the brain. This finding was

not associated with tissue damage or abnormal clinical signs.

In distribution and excretion studies in mice and rats, the 40 kDa polyethylene-glycol (PEG) moiety of

Refixia was shown to be widely distributed to and eliminated from organs, and excreted via plasma in

urine (44–56%) and faeces (28–50%). Based on modelled data using observed terminal half-lives (15–

49 days) in rat tissue distribution studies, the 40 kDa polyethylene-glycol (PEG) moiety will reach

steady state levels in all human tissues within 1–2 years of treatment.

Long-term studies in animals to evaluate the carcinogenic potential of Refixia, or studies to determine

the effects of Refixia on genotoxicity, fertility, development, or reproduction have not been performed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Powder

Sodium chloride

Histidine

Sucrose

Polysorbate 80

Mannitol

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Solvent

Histidine

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

6.2

Incompatibilities

In the absence of compatibility studies, this medicine must not be mixed with other medicinal products

or reconstituted with infusion solutions other than the provided histidine solvent.

6.3

Shelf life

Unopened

2 years. During the shelf life Refixia may be stored up to 30°C for a single period not exceeding

6 months. Once the product has been taken out of the refrigerator the product must not be returned to

the refrigerator. Please record the beginning of storage at room temperature on the product carton.

After reconstitution

Chemical and physical in-use stability have been demonstrated for 24 hours stored in a refrigerator

(2°C – 8°C) and 4 hours stored at room temperature (≤ 30°C).

From a microbiological point of view, the reconstituted product should be used immediately. If not

used immediately, in-use storage times and conditions prior to use are the responsibility of the users

and would normally not be recommended for longer than 4 hours stored at room temperature (≤ 30°C)

or 24 hours in a refrigerator (2°C – 8°C), unless reconstitution has taken place under controlled and

validated aseptic conditions.

6.4

Special precautions for storage

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

Store in the original package in order to protect from light.

For storage at room temperature and storage conditions after reconstitution of the medicinal product,

see section 6.3.

6.5

Nature and contents of container

Each pack contains:

1 glass vial (type I) with powder and chlorobutyl rubber stopper

1 sterile vial adapter for reconstitution

1 pre-filled syringe of 4 ml histidine solvent with backstop (polypropylene), a rubber plunger

(bromobutyl) and a tip cap with a stopper (bromobutyl)

1 plunger rod (polypropylene).

Pack size of 1.

6.6

Special precautions for disposal and other handling

Refixia is to be administered intravenously after reconstitution of the powder with the solvent supplied

in the syringe. After reconstitution the solution appears as a clear and colourless liquid free of visible

particles. Reconstituted medicinal product should be inspected visually for particulate matter and

discoloration prior to administration. Do not use solutions that are cloudy or have deposits.

For instructions on reconstitution of the medicinal product before administration, see the package

leaflet.

The rate of administration should be determined by the patient’s comfort level up to a maximum

injection rate of 4 ml/min.

An infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters will also

be needed. These devices are not included in the Refixia package.

Always use an aseptic technique.

Disposal

After injection, safely dispose of the syringe with the infusion set and the vial with the vial adapter.

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

8.

MARKETING AUTHORISATION NUMBERS

EU/1/17/1193/001

EU/1/17/1193/002

EU/1/17/1193/003

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.

DATE OF REVISION OF THE TEXT

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

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

Read the complete document

30 Churchill Place

Canary Wharf

London E14 5EU

United Kingdom

An agency of the European Union

Telephone

+44 (0)20 3660 6000

Facsimile

+44 (0)20 3660 5555

Send a question via our website

www.ema.europa.eu/contact

© European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.

EMA/212538/2017

EMEA/H/C/004178

EPAR summary for the public

Refixia

nonacog beta pegol

This is a summary of the European public assessment report (EPAR) for Refixia. It explains how the

Agency assessed the medicine to recommend its authorisation in the EU and its conditions of use. It is

not intended to provide practical advice on how to use Refixia.

For practical information about using Refixia, patients should read the package leaflet or contact their

doctor or pharmacist.

What is Refixia and what is it used for?

Refixia is a medicine used to treat and prevent bleeding in patients with haemophilia B, an inherited

bleeding disorder caused by lack of a clotting protein called factor IX. It can be used in adults and

children from 12 years of age.

Refixia contains the active substance nonacog beta pegol.

How is Refixia used?

Refixia can only be obtained with a prescription and treatment should be under the supervision of a

doctor who has experience in the treatment of haemophilia.

Refixia is available as a powder and a liquid that are mixed together to make a solution for injection

into a vein. The dose and frequency of treatment depend on whether Refixia is used to treat or prevent

bleeding, or to reduce bleeding during surgery, the extent and location of the bleeding, and the

patient’s bodyweight. For further information on how to use this medicine, see the summary of product

characteristics (also part of the EPAR).

Patients or their carers may be able to inject Refixia themselves at home once they have been trained

appropriately. For full details, see the package leaflet.

Refixia

EMA/212538/2017

Page 2/3

How does Refixia work?

Patients with haemophilia B lack factor IX, a protein needed for normal clotting of the blood, and as a

result, they bleed readily. The active substance in Refixia, nonacog beta pegol, works in the body in

the same way as human factor IX. It replaces the missing factor IX, thereby helping the blood to clot

and giving temporary control of bleeding.

What benefits of Refixia have been shown in studies?

Refixia has been shown to be effective at both treating bleeding episodes and keeping the number of

episodes low.

In a study involving 74 adults and adolescents aged 13 or above, 29 patients given Refixia as a weekly

preventive treatment had around 1 bleeding episode a year, and 15 patients given Refixia for treating

bleedings ‘on demand’ had around 16 bleeding episodes a year. In addition, when bleeding did occur,

Refixia was rated excellent or good at treating around 92% of bleeding episodes. 87% of bleeding

episodes resolved with one injection of Refixia.

In the second study in 25 children aged below 13 years, all patients were given Refixia as a weekly

preventive treatment. Patients had around 1 bleeding episode per year and Refixia was rated excellent

or good at treating around 93% of bleeding episodes. Around 86% of bleeding episodes resolved with

one injection.

What are the risks associated with Refixia?

Hypersensitivity (allergic) reactions are uncommon with Refixia (may affect up to 1 in 100 patients)

and may include: swelling, burning and stinging at the injection site, chills, flushing, itchy rash,

headache, hives, low blood pressure, lethargy, nausea and vomiting, restlessness, a fast heartbeat,

tightness of the chest and wheezing. In some cases these reactions can become severe.

Some patients taking factor IX medicines may develop inhibitors (antibodies) against factor IX, causing

the medicine to stop working and resulting in a loss of bleeding control. Factor IX medicines can also

potentially cause problems due to the formation of blood clots in the blood vessels.

Refixia must not be used in patients allergic to hamster proteins. For the full list of side effects and

restrictions, see the package leaflet.

Why is Refixia approved?

The Agency’s Committee for Medicinal Products for Human Use (CHMP) decided that Refixia’s benefits

are greater than its risks and recommended that it be approved for use in the EU.

Studies show that Refixia is effective at preventing and treating bleeding episodes in patients with

haemophilia B and its safety is comparable to that of other factor IX products. However, part of the

active substance in Refixia (called PEG) may accumulate in the body, including in a structure in the

brain called choroid plexus, following long-term treatment. Since this could potentially cause problems

especially in children below 12 years of age, Refixia is only approved for use in in adults and children

from 12 years of age.

Refixia

EMA/212538/2017

Page 3/3

What measures are being taken to ensure the safe and effective use of

Refixia?

The company that markets Refixia will conduct a study to investigate the potential effects of PEG

accumulation in the choroid plexus of the brain and other organs.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Refixia have been included in the summary of product characteristics and the

package leaflet.

Other information about Refixia

The European Commission granted a marketing authorisation valid throughout the European Union for

Refixia on 02 June 2017.

The full EPAR for Refixia can be found on the Agency’s website: ema.europa.eu/Find medicine/Human

medicines/European public assessment reports. For more information about treatment with Refixia,

read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 06-2017.

Similar products

Search alerts related to this product

View documents history

Share this information