Consumer medicine information

NovoThirteen

Catridecacog

BRAND INFORMATION

Brand name

NovoThirteen

Active ingredient

Catridecacog

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using NovoThirteen.

What is in this leaflet

What NovoThirteen® is used for

Before you use NovoThirteen®

Using NovoThirteen®

While you are using NovoThirteen®

Side effects

Storage

Product Description

NovoThirteen® User Instructions

This leaflet answers some common questions about NovoThirteen®. It does not contain all the available information. It does not take the place of talking to your doctor or healthcare professional.

All medicines have risks and benefits. Your doctor has weighed the risks of you using NovoThirteen® against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or healthcare professional.

Keep this leaflet with the medicine. You may need to read it again.

What NovoThirteen® is used for

NovoThirteen® contains the active substance catridecacog, which is identical to human coagulation factor XIII, and is produced by recombinant technology. FXIII is an enzyme necessary for blood clotting.

NovoThirteen® is used to prevent bleeding in patients who are missing the factor XIII (A-subunit) protein. NovoThirteen® replaces the missing Factor XIII and helps to stabilise the initial blood clot by producing a mesh around the clot.

Ask your doctor or healthcare professional if you have any questions about why NovoThirteen® has been given to you. Your doctor may have prescribed it for another reason.

Before you use NovoThirteen®

When NovoThirteen® should not be used

You should not use or be treated with NovoThirteen® if you have an allergy to:

  • catridecacog or any of the ingredients listed at the end of this leaflet

(refer to the section “Side effects” to look for signs of an allergic reaction).

If you are uncertain as to whether you have such an allergy, raise this concern with your doctor.

Do not use it after the expiry date (‘Expiry’) printed on the carton and label.

Do not use NovoThirteen® if the packaging is torn, shows signs of tampering or does not look quite right.

Before you start to use it

Tell your doctor if you:

  • have, or have ever had, a higher risk of blood clots forming (thrombosis), as NovoThirteen may increase the severity of a pre-existing blood clot;
  • are allergic to rFXIII, yeast protein or to any of the ingredients in NovoThirteen®;
  • are using other blood clotting factors. It is not recommended to use NovoThirteen® and recombinant factor VIIa (another blood clotting factor) together;
  • are pregnant or trying to become pregnant;
  • are breast-feeding or planning to breast-feed.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • blood clots (thrombosis);
  • liver disease or liver damage

Contact your doctor immediately:

  • If you experience unexpected bleeding during your treatment with NovoThirteen®. Your doctor will prescribe an alternative treatment to treat the bleeding.

Antibodies with neutralising effect against NovoThirteen® could decrease the effectiveness of the treatment and thereby result in unexpected spontaneous bleeding episodes. Neutralising antibodies have not been seen in clinical trials with NovoThirteen®.

Tell your doctor if you plan to have surgery.

If you have not told your doctor/s about any of the above, tell him/them before you use NovoThirteen®.

Taking other medicines

Do not use NovoThirteen® and blood clotting factor concentrates at the same time.

Tell your doctor before you use NovoThirteen® and medicines used to reduce the dissolving of blood clots.

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Immediately before you use it

Make sure that:

  • the packaging is not damaged or torn;
  • the protective tamper-proof plastic caps are in place, and are not loose or missing;
  • the NovoThirteen® powder in the vial is white and the solvent is a clear colourless solution;
  • the vials are not damaged

Using NovoThirteen®

How to use NovoThirteen®

Start of treatment with NovoThirteen® should be supervised by a doctor with experience in rare bleeding conditions. Following treatment cycles should also be supervised by a doctor for a period of time. Always use this medicine exactly as your doctor has told you. Check with your doctor or healthcare professional if you are not sure.

NovoThirteen® is given as an injection into a vein. Solvent must be added (reconstitution) to the vial of NovoThirteen® powder before the solution is injected. The solution should be clear and colourless.

Reconstitution and injection:
Please refer to the user instructions.

NovoThirteen® is for single use in one person only. Once NovoThirteen® has been prepared for injection, it should be used immediately. Discard your vial after use.

If the reconstituted product is not used immediately it should be used within 3 hours if stored at temperatures below 25°C or within 24 hours if stored at 2 - 8°C. If it is left longer, the medicine may no longer be sterile and the amount of activated rFXIII will increase. Activated rFXIII may increase the risk of getting a blood clot (thrombosis).

Once NovoThirteen® has been reconstituted it must not be frozen. If the reconstituted product does freeze it must not be used and must be discarded.

When and how much to use

NovoThirteen® is given as an injection into a vein. Your dose will depend on your body weight. The usual dose is 35 IU for each kilogram of body weight. The injections are given once a month (every 28 +/- 2 days).

Based on the concentration of NovoThirteen® solution, the dose volume to be injected (in millilitres) can be calculated from this formula:

Dose volume in millilitres = 0.042 x your body weight in kg.

Use in small children
If you need to give NovoThirteen® to a child weighing less than 24 kg you should dilute the reconstituted NovoThirteen® with 6.0 mL of sodium chloride 0.9% solution for injection. This makes the dosing of small children easier. For more information see section ‘Dilution of the reconstituted product with sodium chloride 0.9% solution for injection’ in the NovoThirteen® user instruction.

The dose volume for the use in small children can be calculated from this formula

Dose volume in mL = 0.117 x body weight in kilograms.

Your doctor may adapt the dose if this is deemed necessary.

The reconstituted NovoThirteen® should be administered as a slow bolus intravenous injection at a rate not higher than 2 mL/minute.

For more information on how to get your injection ready, see ‘NovoThirteen® User Instructions’.

For more information about how to inject NovoThirteen® contact your doctor

After you use it

  • Do not refill NovoThirteen® vials.
  • Healthcare professionals, relatives and other carers should follow general precautionary measures for removal and disposal of needles to eliminate the risk of needle stick injury.

How long to use it

Do not stop using NovoThirteen® without consulting your doctor. Your doctor will explain what might happen if you stop treatment and discuss other options with you.

If you use too much (overdose)

If you are given or if you give yourself too much NovoThirteen® you should contact your doctor immediately. Your doctor will take appropriate action.

If you have any concerns about taking this medicine, ask your doctor or haemophilia nurse.

If you forget to use it

You should contact your doctor who will take the appropriate action. Do not take a double dose to make up for a forgotten dose.

While you are using NovoThirteen®

Things you must do

You and your doctor should monitor your bleeding. Tell your doctor or nurse if your bleeding gets worse.

Contact your doctor immediately:

  • If you experience unexpected bleeding during your treatment with NovoThirteen®. Your doctor may prescribe an alternative treatment to treat the bleeding.
  • If you experience unexpected spontaneous bleeding during treatment with Factor XIII containing products. Antibodies against NovoThirteen® could decrease the effectiveness of the treatment and thereby result in unexpected spontaneous bleeding episodes. Contact your doctor immediately if bleeding occurs.

Things you must not do

Do not give NovoThirteen® to anyone else, even if they have the same condition as you.

Do not use NovoThirteen® to treat any other complaints.

Do not stop using NovoThirteen®, or adjust the dosage, without checking with your doctor.

Side effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • local reaction around the injection site such as redness, itchiness, tenderness, pain or discomfort
  • pain in the legs or arms
  • frequent infections, such as fever, severe chills, sore throat or mouth ulcers which may be symptoms of a lack of white blood cells

The above list includes the more common side effects of your medicine.

Contact your doctor immediately, or go to the accident and emergency department at your nearest hospital if you have an allergic reaction. The signs might include:

  • sudden signs of allergy, such as rash, hives or itching, swelling of the face, lips, tongue or other parts of the body
  • pinkish, itchy swellings on the skin
  • shortness of breath, wheezing or difficulty breathing
  • low blood pressure (cold clammy skin, rapid weak heartbeat)
  • feeling dizzy and sweating

These are serious side effects and you may need urgent medical attention.

Your doctor will have more information about unwanted effects of NovoThirteen®.

Tell your doctor or haemophilia nurse as soon as possible if you notice any side effects or do not feel well while you are using NovoThirteen®.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or haemophilia nurse to answer any questions you have.

Storage

NovoThirteen® must be stored at 2-8ºC. It should not be frozen. If the product freezes it should be discarded. NovoThirteen® must only be used if the package is undamaged and the use by (‘expiry’) date marked on the pack has not passed.

Protect from light.

Never use NovoThirteen® after the expiry date printed on the label and carton. The expiry date refers to the last day of that month.

Never use NovoThirteen® vials if the solution is not clear and colourless when reconstituted with the solvent.

Keep out of the reach of children.

Product Description

NovoThirteen® can only be obtained from a hospital or haemophilia treatment centre.

This leaflet does not tell you all that is known about NovoThirteen®. If you have any questions about NovoThirteen®, ask your doctor or nurse.

What it looks like

NovoThirteen® is supplied as a white powder, in a glass vial. The powder must be dissolved with the solvent before it is used.

Ingredients

The active ingredient in NovoThirteen® is recombinant coagulation factor XIII (rFXIII), which is also called catridecacog (rys). NovoThirteen® is made by genetic engineering.

Each vial contains 2500 IU (International Units) (15.0 mg) of rFXIII. Each vial also contains sodium chloride, sucrose, polysorbate 20 and L-histidine.

Sodium hydroxide and hydrochloric acid are used to adjust the pH.

The solvent vial contains water for injections. After reconstitution, 1 mL of the solution contains 833 IU catridecacog (activated).

Manufacturer

NovoThirteen® is made in Denmark and supplied in Australia by:

Novo Nordisk Pharmaceuticals Pty. Ltd.
Level 10
118 Mount Street
North Sydney, NSW, 2060
This leaflet was prepared in October 2023.

Australian Registration Numbers: AUST R 201776

NovoThirteen® is a registered trademark of Novo Nordisk HealthCare AG, Switzerland.

NovoCare® is a registered trademark of Novo Nordisk A/S.

© 2023
Novo Nordisk A/S

For further information call the NovoCare® Customer Care Centre on 1800 668 626 (Australia).

www.novonordisk.com.au

NovoThirteen® User Instructions

To reconstitute and administer this product the following tools are needed: a 10 ml syringe or a syringe of convenient size according to the injection volume, alcohol swabs, the included vial adaptor and an infusion set (tubing, butterfly needle).

Preparing the solution

Check the name and the colour of the package to make sure it contains the right product as well as that the product has not passed the expired date.

Always use an aseptic technique. Before starting, wash your hands. Bring the powder and solvent vials to a room temperature not above 25°C, by holding them in the hands until they feel as warn as your hands. Remove the plastic caps from the two vials. If the caps are loose or missing, do not use the vials. Clean the rubber stoppers on the vials with alcohol swabs and allow them to dry before use. Do not touch the rubber stoppers after wiping them.

A

The product is reconstituted using the vial adaptor included.Remove the protective paper from the vial adaptor without taking the vial out of the protective cap. If the protective paper is not fully sealed, or if it is broken, do not use the vial adaptor. Place the solvent vial on a flat solid place and attach the vial adaptor to the solvent vial (water for injection). Take care not to touch the spike on the vial adaptor.

B

Once attached, remove the protective cap from the vial adaptor by lightly squeezing the protective cap with your thumb and index finger as shown.

C

Pull the plunger to draw in a volume of air that is equal to the amount of solvent in the solvent vial (mL equals cc on the syringe).

D

Screw the syringe securely onto the vial adaptor on the solvent vial. Inject air into the vial by pushing the plunger until you feel a clear resistance.

E

Hold the syringe with the solvent vial upside down. Pull the plunger to draw the solvent into the syringe.

F

Remove the empty solvent vial by tipping the syringe with the vial adaptor.

G

Click the vial adaptor, still attached to the syringe, onto the powder vial. Hold the syringe slightly tilted with the vial facing downwards. Push the plunger slowly to inject the solvent into the powder vial. Make sure not to aim the stream of solvent directly at the powder as this will cause foaming.

H

Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause foaming.

NovoThirteen® should be inspected visually for extraneous (for any foeign) particulate matter and discolouration prior to administration. In the event of either beubg observed, discard the medicinal product.

Reconstituted NovoThirteen® is a clear, colourless solution. If a larger dose is needed, repeat the procedure in a separate syringe until the required dose is reached.

Important Information

Once prepared, NovoThirteen® for injection should be used immediately. This is because the medicine may no longer be sterile. Also the amount of non-proteolytically activated rFXIII in the medicine will increase. Non-proteolytically activated NovoThirteen® may increase the risk of getting a blood clot (thrombosis).

If the reconstituted product is not used immediately it should be used within 3 hours and can be stored at room temperature (below 25°C) during this time. Any unused product stored at room temperature for 3 hours should be discarded.

If the reconstituted product is not administered immediately, it should be stored in the refrigerator at 2°C - 8°C for no longer than 24 hours.

The reconstituted product must not be frozen. If the reconstituted product does become frozen it must not be used and must be discarded.

In case a dilution of the reconstituted NovoThirteen® is needed, proceed to the section ‘Dilution of the reconstituted product with sodium chloride 0.9%, solution for injection’.

Injecting the solution

I

Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have been pushed out by the pressure in the vial). Hold the syringe with the vial upside down and pull the plunger to draw up the amount calculated for the injection.

J

Unscrew the vial adaptor with the vial. The product is now ready for injection in the vein. Follow the injection procedure as instructed by your healthcare professional.

Following reconstitution the product should be administered separately and not mixed with infusion solutions nor be given in a drip.

The preparation should be administered as a slow bolus intravenous injection at a rate not higher than 2 mL/minute.

K

Safely dispose of the syringe, vial adaptor, infusion set and vials. Any unused medicinal product or waste material should be disposed of in accordance with local requirements or as instructed by your healthcare professional.

Dilution of the reconstituted product with sodium chloride 0.9%

If dilution of the reconstituted NovoThirteen® is necessary in order to be able to handle the dosing of children below 24 kg the reconstituted NovoThirteen® should be diluted with 6.0 mL 0.9% sodium chloride (see section ‘Using NovoThirteen® - Use in small children’).

User instruction on how to dilute the reconstituted NovoThirteen®

To dilute the reconstituted NovoThirteen® the following tools are needed: a vial containing sodiuk chloride 0.9% solution for injection, a 10 mL syringe, alcohol swabs.

General instruction for dilution

The dilution should be performed in accordance with aseptic rules.

Carefully draw 6.0 mL sodium chloride 0.9%, solution for injection, into the 10 mL syringe.

Slowly inject the 6.0 mL sodium chloride 0.9%, solution for injection, into the reconstituted NovoThirteen® vial.

Gently swirl to mix the solution.

The diluted solution is a clear, colourless solution. Check the injection solution for particulate matter and for discolouration. If either is noticed, please discard.

Ask your doctor for advice before the reconstituted NovoThirteen® is diluted with sodium chloride 0.9%, solution for injection.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

NovoThirteen

Active ingredient

Catridecacog

Schedule

Unscheduled

 

1 Name of Medicine

Recombinant human factor XIII (rFXIII) 2500 IU (15 mg) powder and solvent for solution for injection.

2 Qualitative and Quantitative Composition

NovoThirteen contains catridecacog, a recombinant coagulation factor XIII A-subunit with a molecular mass of approximately 83.2 kDa. Catridecacog is produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology, without the use of animal derived materials.
One vial of NovoThirteen contains 2500 IU catridecacog per 3 mL, after reconstitution, corresponding to a concentration of 833 IU/mL. The specific activity of rFXIII is approximately 165 IU/mg protein.
The potency of this medicinal product is expressed in international units (IU). These units are not interchangeable with the units used to express the potency for other FXIII-containing products.

3 Pharmaceutical Form

NovoThirteen is supplied as a white lyophilised powder to be reconstituted with solvent for injection. The solvent is clear and colourless. The reconstituted solution has a pH of approximately 8.0.

4 Clinical Particulars

4.1 Therapeutic Indications

NovoThirteen is indicated for routine prophylaxis of bleeding in patients with congenital Factor XIII A-subunit deficiency.

4.2 Dose and Method of Administration

Treatment should be initiated and continued for a period of time under the supervision of a doctor experienced in the treatment of rare bleeding disorders. The congenital factor XIII A-subunit deficiency should be confirmed by appropriate diagnostic procedures.
For detailed instructions for reconstitution and administration of NovoThirteen, refer to the Instructions for Use leaflet.

Dosage.

Dose and dose interval.

The recommended dose is 35 IU/kg body weight (bw) once monthly (every 28 days ± 2 days), administered as an intravenous bolus injection. The dose volume in millilitres for patients weighing at least 24 kg can be calculated from the formula below:
Dose volume in mL = 0.042 x subject bw (kg).
Dose adjustment can be considered necessary by the physician in certain situations where the prevention of bleeding is not appropriately covered by the recommended 35 IU/kg/month dose. This dose adjustment should be based on FXIII activity levels.
Monitoring FXIII activity levels using a standard FXIII activity assay is recommended.
Low FXIII activity levels may indicate development of antibodies (see Section 4.4 Special Warnings and Precautions for Use, Inhibitor formation) in which case further treatment should only be performed under close patient supervision.
The amount of NovoThirteen is calculated upon body weight. When NovoThirteen is administered to small children weighing less than 24 kg, the reconstituted NovoThirteen should be diluted with 6.0 mL of sodium chloride 0.9% solution for injection (see Special additional instructions for small children weighing less than 24 kg).

Special additional instructions for small children weighing less than 24 kg.

If the body weight is less than 24 kg, the reconstituted NovoThirteen can be further diluted with 6.0 mL of sodium chloride 0.9%, solution for injection. To use the formula below the reconstituted product should be diluted with 6.0 mL of sodium chloride 0.9%, solution for injection.
Dose volume in mL of diluted product = 0.117* x Body weight in kilograms.
*The calculation of the correction factor 0.117 is related to the exact quantity of the product and not the nominal value of the product.
The potency of this medicinal product is expressed in international units (IU).
Although expressed in the same unitage (IU), the posology of NovoThirteen is different from the dosing schedule of the other FXIII containing products.

Method of administration.

NovoThirteen user instructions. To reconstitute and administer this product the following tools are needed: a 10 mL syringe or a syringe of convenient size according to the injection volume, alcohol swabs, the included vial adaptor and an infusion set (tubing, butterfly needle).

Preparing the solution.

Check the name and the colour of the package to make sure it contains the right product as well as that the product has not passed the expired date.
Always use an aseptic technique. Before starting, wash your hands. Bring the powder and solvent vials to a temperature not above 25°C, by holding them in the hands until they feel as warm as your hands. Remove the plastic caps from the two vials. If the caps are loose or missing, do not use the vials. Clean the rubber stoppers on the vials with alcohol swabs and allow them to dry before use. Do not touch the rubber stoppers after wiping them.
A. The product is reconstituted using the vial adaptor included.
Remove the protective paper from the vial adaptor without taking the vial out of the protective cap. If the protective paper is not fully sealed, or if it is broken, do not use the vial adaptor. Place the solvent vial on a flat solid place and attach the vial adaptor to the solvent vial (water for injection). Take care not to touch the spike on the vial adaptor.
B. Once attached, remove the protective cap from the vial adaptor by lightly squeezing the protective cap with your thumb and index finger.
C. Pull the plunger to draw in a volume of air that is equal to the amount of solvent in the solvent vial (mL equals cc on the syringe).
D. Screw the syringe securely onto the vial adaptor on the solvent vial. Inject air into the vial by pushing the plunger until you feel a clear resistance.
E. Hold the syringe with the solvent vial upside down. Pull the plunger to draw the solvent into the syringe.
F. Remove the empty solvent vial by tipping the syringe with the vial adaptor.
G. Click the vial adaptor, still attached to the syringe, onto the powder vial. Hold the syringe slightly tilted with the vial facing downwards. Push the plunger slowly to inject the solvent into the powder vial. Make sure not to aim the stream of solvent directly at the powder as this will cause foaming.
H. Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause foaming.
NovoThirteen should be inspected visually for extraneous (for any foreign) particulate matter and discolouration prior to administration. In the event of either being observed, discard the medicinal product.
Reconstituted NovoThirteen is a clear, colourless solution.
If a larger dose is needed, repeat the procedure in a separate syringe until the required dose is reached.

Important information.

Once prepared NovoThirteen for injection should be used immediately. This is because the medicine may no longer be sterile. Also the amount of non-proteolytically activated rFXIII in the medicine will increase. Non-proteolytically activated NovoThirteen may increase the risk of getting a blood clot (thrombosis).
If the reconstituted product is not used immediately it should be used within 3 hours and should be stored at room temperature (below 25°C) during this time.
Any unused product stored at room temperature for 3 hours should be discarded.
If the reconstituted product is not administered immediately, it should be stored in the refrigerator at 2°C - 8°C for no longer than 24 hours.
The reconstituted product must not be frozen. If the reconstituted product does become frozen it must not be used and must be discarded.
In case a dilution of the reconstituted NovoThirteen is needed, proceed to the section 'Dilution of the reconstituted product with sodium chloride 0.9%, solution for injection'.

Injecting the solution.

I. Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have been pushed out by the pressure in the vial). Hold the syringe with the vial upside down and pull the plunger to draw up the amount calculated for the injection.
J. Unscrew the vial adaptor with the vial. The product is now ready for injection in the vein. Follow the injection procedure as instructed by your healthcare professional.
Following reconstitution the product should be administered separately and not mixed with infusion solutions nor be given in a drip.
The preparation should be administered as a slow bolus intravenous injection at a rate not higher than 2 mL/minute.
K. Safely dispose of the syringe, vial adaptor, infusion set and vials. Any unused medicinal product or waste material should be disposed of in accordance with local requirements or as instructed by your healthcare professional.
Dilution of the reconstituted product with sodium chloride 0.9%, solution for injection. If dilution of the reconstituted NovoThirteen is necessary in order to be able to handle the dosing of children below 24 kg, the reconstituted NovoThirteen should be diluted with 6.0 mL 0.9% sodium chloride (see Special additional instructions for small children weighing less than 24 kg).

User instruction on how to dilute the reconstituted NovoThirteen.

To dilute the reconstituted NovoThirteen the following tools are needed: a vial containing sodium chloride 0.9%, solution for injection, a 10 mL syringe and alcohol swabs.

General instruction for dilution.

The dilution should be performed in accordance with aseptic rules.
Carefully draw exactly 6.0 mL sodium chloride 0.9%, solution for injection, into the 10 mL syringe.
Slowly inject the 6.0 mL sodium chloride 0.9%, solution for injection, into the reconstituted NovoThirteen vial.
Gently swirl to mix the solution.
The diluted solution is a clear, colourless solution. Check the injection solution for particulate matter and for discolouration. If either is noticed, please discard.
After dilution, proceed to the step 'Injecting the solution'.
Ask your doctor for advice before the reconstituted NovoThirteen is diluted with sodium chloride 0.9%, solution for injection.

4.3 Contraindications

NovoThirteen is contraindicated in patients with a known hypersensitivity to, rFXIII or any of the excipients of NovoThirteen.

4.4 Special Warnings and Precautions for Use

General.

NovoThirteen should not be used for prophylactic treatment of bleeding in patients with congenital FXIII B-subunit deficiency. FXIII B-subunit deficiency is associated with a much reduced half-life of the administered pharmacologically active A-subunit. The subunit deficiency of patients should be known prior to treatment.
The on-demand treatment of acute bleeds or breakthrough bleeds with NovoThirteen was allowed per protocol in the late phase clinical development programme. One patient was treated on demand in a phase 3b extension study (F13CD-3720). Also, on-demand treatment is followed in a non-interventional post-authorisation safety study (NN1841-3868). Until further results are available, alternative treatment should be considered in such situations.
As NovoThirteen contains a recombinant protein it may cause allergic reactions including anaphylactic reaction. Patients should be informed of the early signs of hypersensitivity reactions (including hives, generalised urticaria, tightness of the chest, wheezing, hypotension) and anaphylaxis. If allergic or anaphylactic-type reactions occur, the administration should be immediately discontinued and further treatment with NovoThirteen should not be given.
Recombinant FXIII may contain trace amounts of yeast protein and therefore care should be taken when administering NovoThirteen to patients with known allergy to yeast.

Inhibitor formation.

Inhibitor formation to NovoThirteen therapy has not been detected in clinical trials. Inhibitors may be suspected in the event of lack of therapeutic response observed as bleeding or demonstrated by laboratory findings including FXIII activity that fails to reach expected levels. In the event that inhibitors are suspected analysis for antibodies should be performed.
Patients known to have neutralising antibodies to FXIII should not be treated with NovoThirteen without close monitoring.

Thromboembolic risk.

The reconstituted medicinal product must be handled in accordance with Section 4.2 Dose and Method of Administration. Incorrect storage of the product after reconstitution must be avoided as it may result in loss of sterility and in increased levels of non-proteolytically activated rFXIII. Increased levels of non-proteolytically activated rFXIII may increase the risk of thrombosis.
In case of predisposition to conditions of thrombosis, caution should be exercised due to the fibrin-stabilising effect of NovoThirteen. A stabilisation of the thrombus might occur, resulting in increased risk of vessel occlusions.

Use in hepatic impairment.

Patients with hepatic impairment have not been studied. NovoThirteen may not be effective in patients with hepatic impairment if the hepatic impairment is severe enough to result in decreased levels of FXIII B-subunits. FXIII activity levels should be monitored in patients with severe hepatic impairment.

Use in renal impairment.

Patients with renal insufficiency requiring dialysis have not been studied in clinical trials.

Use in elderly.

There is limited clinical experience administering NovoThirteen to elderly patients (≥ 65 yrs) with congenital FXIII deficiency.

Paediatric use.

Analyses of data from paediatric patients included in clinical trials have not identified difference in treatment response according to age.

Monitoring and laboratory tests.

Monitoring NovoThirteen activity levels using a standard FXIII activity assay is recommended.
If during monitoring FXIII activity fails to reach expected levels or if reduced therapeutic effect is observed, analysis for antibodies should be performed.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There is no clinical data available on interaction between rFXIII and other medicinal products.
A potential synergistic effect of combined treatment with rFXIII and rFVIIa in an advanced cardiovascular model in cynomolgus monkey resulted in exaggerated pharmacology (thrombosis and death) at a lower dose level than when administering the individual compounds.
Based on a non-clinical study it is not recommended to combine rFXIII and rFVIIa.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The potential effect on fertility has not been studied in animals. No effects on reproductive organs have been seen in non-clinical studies.
(Category B2)
There is no clinical data on the use of NovoThirteen in pregnant women. NovoThirteen has not been studied in pregnant animals. The risk to humans is not known. However, based on the therapeutic need, the use of NovoThirteen as replacement therapy may be considered during pregnancy.
 It is unknown whether rFXIII is excreted in human breast milk. The excretion of rFXIII drug substance in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with NovoThirteen should be made taking into account the benefit of breast-feeding to the child and the benefit of NovoThirteen therapy to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machinery were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

In clinical trials, NovoThirteen has been administered to 82 patients with congenital factor XIII A-subunit deficiency (3112 doses of NovoThirteen). 21 patients were between the age of 6 to less than 18 years old and 6 patients were less than 6 years old (total of 986 exposures in paediatric subjects on NovoThirteen). The most frequent adverse event is headache reported in 37% of patients.

Tabulated list of treatment emergent adverse events.

Adverse events reported by more than 10% of the patients who participated in clinical trials (F13-1663, F13CD-1725, F13CD-3720, F13CD-3760 and F13CD-3835, 82 patients exposed in total) are presented in Table 1.

Tabulated list of adverse reactions.

Frequency descriptions of adverse reactions (assessed to be possibly or probably related to rFXIII) identified from 82 patients with congenital FXIII deficiency exposed in phase 3 clinical trials are presented in Table 2, by system organ class. Within each grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions from post-marketing sources.

In a post-authorisation safety study transient non-neutralising antibodies were seen in a child with congenital FXIII deficiency after several years of treatment with NovoThirteen. No clinical findings were associated with these antibodies.

Description of selected adverse reactions.

One patient with a pre-existing neutropenia experienced a mild aggravation of neutropenia and leucopenia during treatment with NovoThirteen. Following discontinuation of NovoThirteen the patient's neutrophil count returned to levels similar to those prior to treatment with NovoThirteen.
Non-neutralising antibodies have been seen in 4 of the 82 exposed patients with congenital FXIII deficiency. The four events of non-neutralising antibodies occurred in patients below the age of 18 (age 8, 8, 14 and 16). These antibodies were seen at the start of treatment with NovoThirteen. All four patients received at least 2 doses of NovoThirteen. Three of the patients discontinued the study and returned to their previous treatment. One continued to receive NovoThirteen and the antibodies were no longer detected following repeated exposure. The antibodies had no inhibitory effect and the patients did not experience any adverse events or bleeding in association with these antibodies. Antibodies were transient in all patients.
One healthy subject developed binding antibodies after receiving the first dose of NovoThirteen. The antibodies had no inhibitory activity, and the subject did not experience any adverse events or bleeding in association with these antibodies. The antibodies were no longer detected at a 6-month follow up.
In all cases, the non-neutralising antibodies were found to be of no clinical significance.

Paediatric population.

In clinical studies, adverse reactions were more frequently reported in patients from 6 to less than 18 years of age than in adults. Adverse reactions were more frequently reported in patients aged from 6 to less than 18 years old than in adults. Three patients under 18 years experienced serious adverse reactions (non-neutralising antibodies) in comparison to no serious adverse reactions in patients over 18 years.
In patients below 6 years, no anti-rFXIII antibodies, no thromboembolic adverse events or other safety issues were reported.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

In reported cases of NovoThirteen overdose, a dose up to 2.3 times the recommended dose did not result in clinical symptoms being observed.
For information on the management of overdose contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

FXIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of haemostasis through cross-linking of fibrin and other proteins in the fibrin clot.
At present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII. The results of standard coagulation tests are normal, as it is the quality of the clot that is affected. A clot solubility assay is widely used as an indicator of FXIII deficiency, but the assay is qualitative, and when performed correctly the test is positive only when the FXIII activity in the sample is close to zero.
In plasma, FXIII circulates as a heterotetramer [A2B2] composed of 2 FXIII A-subunits and 2 FXIII B-subunits held together by strong non-covalent interactions. The FXIII B-subunit acts as carrier molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When FXIII A-subunit is bound to FXIII B-subunit [A2B2], the half-life of the FXIII A-subunit [A2] is prolonged. FXIII is a pro-enzyme (pro-transglutaminase), which is activated by thrombin in the presence of Ca2+. The enzymatic activity resides with the FXIII-A subunit. Upon activation, the FXIII A-subunit dissociates from the FXIII B-subunit and thereby exposes the active site of the FXIII A-subunit. The active transglutaminase cross-links fibrin and other proteins resulting in increased mechanical strength and resistance to fibrinolysis of the fibrin clot and contributes to enhanced platelet and clot adhesion to the injured tissue.
rFXIII is a pro-transglutaminase (rFXIII [rA2] homodimer) which is identical to the human FXIII A-subunit [A2]. rFXIII A-subunit binds to free human FXIII B-subunit resulting in a heterotetramer [rA2B2] with a similar half-life to endogenous [A2B2]. rFXIII is activated by thrombin in the presence of Ca2+. Activated rFXIII increases the mechanical strength of fibrin clots, thereby retarding fibrinolysis in a dose-dependent manner. rFXIII enhances platelet adhesion to the site of injury. Thus, rFXIII has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII.

Clinical trials.

A pivotal prospective, open-label, single-arm phase 3 trial (F13CD-1725) including 41 patients with FXIII A-subunit deficiency was conducted to investigate the haemostatic efficacy of NovoThirteen in patients with congenital FXIII deficiency, as reflected by the rate of bleeding episodes requiring treatment with a FXIII-containing product. The dosing scheme used was 35 IU/kg/month (every 28 days ± 2 days) administered as an intravenous bolus injection.
Five bleeding episodes requiring treatment with a FXIII-containing product have been observed in four patients during treatment with NovoThirteen in the trial.
The mean rate of treatment requiring bleeds was determined to be 0.138 per subject year, when calculated for all 41 patients. In the primary endpoint analysis, the age-adjusted rate (number per subject year) of treatment-requiring bleeds during the rFXIII treatment period was 0.048/year (95% CI: 0.009-0.250; model-based estimate corresponding to the mean age of 26.4 years).
In the F13CD-1725 extension trial F13CD-3720, the age-adjusted rate of bleeds that required treatment with a FXIII-containing product was estimated to be 0.021 bleeds per subject year with a 95% CI of [0.0062; 0.073] (model-based estimate corresponding to a mean age of the trial population of 31.0 years).
The crude bleeding rate in the two trials, F13CD-1725 and F13FC-3720, not adjusted for age, were 0.138 and 0.043 respectively, corresponding to a total of 13 bleeds over 223 subject-years and a pooled rate of 0.058.
Comparing with retrospectively collected data from patients with congenital FXIII deficiency, the bleeding frequency in the F13CD-1725 trial is numerically lower than the bleeding frequency for patients on regular replacement therapy (n=60) (on average approximately 0.3 treatment-requiring bleeds/year) and significantly lower than the rate of 2.91 treatment-requiring bleeds/year in patients receiving on-demand treatment (n=16).

Paediatric population.

Six children (less than 6 years old) and 21 children between the age of 6 to less than 18 years old have been treated with NovoThirteen for a total of 986 exposures.
Children above 6 years were investigated through the pivotal phase 3 trial (F13CD-1725) and the extension study (F13CD-3720) assessing the safety and efficacy of monthly replacement therapy with NovoThirteen.
The 6 patients below 6 years were investigated through a single dose pharmacokinetic phase 3b trial (F13CD-3760) and then, included in the long-term follow-up trial (F13CD-3835) assessing the safety and the efficacy of monthly replacement therapy with NovoThirteen.
NovoThirteen was well tolerated and no thromboembolic adverse events or FXIII treatment requiring bleeding episodes were reported in patients below 6 years during the 17 years of cumulative follow-up, representing a total of 214 doses. Results of safety laboratory parameters and other safety-related examinations did not indicate clinically relevant changes as a result of the rFXIII administration. No anti-rFXIII antibodies were detected in any of the patients.
The suggested dose of 35 IU/kg has shown to be appropriate to provide haemostatic coverage in children with congenital FXIII A-subunit deficiency. NovoThirteen was well tolerated in this population.

Post-marketing.

A post-marketing surveillance programme is collecting safety data on the use of NovoThirteen for the treatment of congenital Factor XIII deficiency.

5.2 Pharmacokinetic Properties


Assessment of the pharmacokinetics properties of rFXIII in healthy subjects and in patients with congenital FXIII deficiency was based on assays developed to measure plasma concentrations of FXIII subunits (individual dimers or complexes) and FXIII activity. ELISA methods were developed to measure free B2, A2 in complex with B2 [rA2B2, A2B2] and total A2 [rA2, A2, rA2B2, A2B2]. The total FXIII activity from both endogenous and exogenous protein was measured by the Berichrom assay. See Figure 1.
rFXIII has shown to have the same pharmacokinetic properties as endogenous FXIII A-subunit [A2] following binding to endogenous FXIII B-subunit [B2].
When rFXIII [rA2] is administered to FXIII A-subunit deficient patients or to healthy subjects, rA2 forms a heterotetramer complex [rA2B2] with free B-subunit resulting in a rapid decrease of the plasma concentration of free B-subunit after rFXIII administration. In parallel to this, a rapid increase is observed for the concentration of the heterotetramer [rA2B2, A2B2]. After the initial decline, the pool of free B-subunit increases gradually following administration of rFXIII. Following administration of 20, 50 or 75 U/kg (corresponding to 24, 60 and 89 IU/kg, respectively) of rFXIII to patients, the plasma concentrations of free B-subunit were essentially restored to pre-dose levels within 72 hours.
The resulting half-life observed in clinical single-dose pharmacokinetic trials in healthy subjects (UKHV-1) was in the range of 218 to 321 hours (9-13 days) based on FXIII activity (Berichrom), total A2 (ELISA) and A2B2 (ELISA). Plasma clearance was observed to be in the range of 0.15 to 0.25 mL/h/kg. Pharmacokinetic parameters of rFXIII obtained in patients with congenital FXIII deficiency (CD-1) were comparable to those in healthy subjects (UKHV-1).
In a single dose trial, of 35 IU/kg of rFXIII, in healthy male subjects the following geometrical mean values of pharmacokinetics parameters were estimated based on baseline-adjusted Berichrom data. Clearance was 0.13 mL/h/kg, the half-life was 11.1 days and volume of distribution at steady state was 47.1 mL/kg. The initial baseline-adjusted geometrical mean activity at 30 minutes post-dosing was 0.85 IU/mL (CV=24.2%) which decreased to 0.11 IU/mL (CV=85.5%) 28 days post-dose. The mean AUC0-28days was 220.3. IU*h/mL (CV=23.8%) and the mean AUC∞ 277.6 IU*h/mL (CV=47.2%).
In a pharmacokinetic trial 6 children (age 1 to less than 6 years old) with congenital FXIII A-subunit deficiency were exposed to one single i.v. dose of NovoThirteen 35 IU/kg. The geometric mean half-life of FXIII was approximately 16 days (range: 10 to 25 days). In this trial, the mean clearance in children was 0.15 mL/h/kg.
The PK results have been summarized in Table 3 for the clinical studies F13CD-1725, F13CD-3720 and F13CD-3760. In summary, systemic exposure to rFXIII activity (AUC0-30days) in children aged 1 to < 6 years with congenital FXIII deficiency was similar to that in adults with the condition.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been performed with NovoThirteen since FXIII is an endogenous protein.

Carcinogenicity.

No carcinogenicity studies have been conducted with NovoThirteen since FXIII is an endogenous protein.

6 Pharmaceutical Particulars

6.1 List of Excipients

NovoThirteen powder contains the following excipients: sodium chloride, sucrose, polysorbate 20, L-histidine, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment).
Solvent contains: water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2-8°C. Refrigerate. Do not freeze. Store in the original package in order to protect from light. Do not use after the expiry date.
For storage conditions of the reconstituted product, see Section 4.2 Dose and Method of Administration.

6.5 Nature and Contents of Container

Each NovoThirteen pack contains:
a single use glass vial containing 2500 IU white, lyophilised powder for solution for injection;
a single use glass vial containing solvent (water for injection) for NovoThirteen for reconstitution, containing 3.2 mL;
a sterile vial adaptor for reconstitution.
The vials are made of type 1 glass. The powder vial is sealed with a freeze drying rubber stopper made of chlorobutyl. The solvent vial is sealed with a rubber disc made of bromobutyl.
The closed vials are equipped with a tamper-evident snap-off cap which is made of plastic.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Pharmacotherapeutic group: Antihaemorrhagics Blood Coagulation factor, ATC code: B02BD11.

CAS number.

CAS number: 606138-08-3.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes