Consumer medicine information

Adynovate

Rurioctocog alfa pegol

BRAND INFORMATION

Brand name

Adynovate

Active ingredient

Rurioctocog alfa pegol

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Adynovate.

SUMMARY CMI

ADYNOVATE®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ADYNOVATE?

ADYNOVATE contains the active ingredient rurioctocog alfa pegol. ADYNOVATE is used in the management of bleeding episodes in patients with haemophilia A (an inherited bleeding disorder caused by lack of blood clotting factor VIII). ADYNOVATE does not contain von Willebrand factor and is therefore not suitable for treating von Willebrand's disease. For more information, see Section 1. Why am I using ADYNOVATE? in the full CMI.

2. What should I know before I use ADYNOVATE?

Do not use if you have ever had an allergic reaction to ADYNOVATE, octocog alfa (a medicine called ADVATE), or you are allergic to mouse or hamster proteins or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have or have had any other medical conditions, if you have had or at risk of any heart problems, if you take any other medicines, or if you are pregnant or plan to become pregnant or if you are breastfeeding or plan to breastfeed. For more information, see Section 2. What should I know before I use ADYNOVATE? in the full CMI.

3. What if I am taking other medicines?

Tell your doctor or Haemophilia Treatment Centre if you are taking or using any other medicines including any that you get without a prescription from your pharmacy, supermarket, or health food shop. For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given ADYNOVATE?

  • ADYNOVATE injection will be prepared and administered by a qualified healthcare professional who is experienced in the care of patients with haemophilia. Some individuals may be trained to use ADYNOVATE at home.
  • Your doctor will decide on your dose of ADYNOVATE depending on your condition and body weight.
  • The frequency of infusions you receive, and how long you will use ADYNOVATE for, will depend on how well ADYNOVATE is working for you. Your doctor may change the dose you use during your treatment.
  • ADYNOVATE is given slowly by injection directly into your veins.
  • ADYNOVATE comes in a vial of drug powder and a diluent vial is also supplied. These need to be mixed before use.

More information can be found in Section 4. How do I use ADYNOVATE? in the full CMI.

5. What should I know while using ADYNOVATE?

Things you should do
  • Tell your doctor of Haemophilia Treatment Centre immediately if you notice
    - any sudden signs and symptoms of a severe, sudden allergic reaction.
    - your bleeding is not controlled or worsens after using ADYNOVATE.
  • Tell any doctors, dentists, or pharmacists you visit that you are using ADYNOVATE or if you are about to have any blood tests.
  • Keep all your appointments with your doctor and any blood tests.
Things you should not do
  • Do not give your medicine to anyone else, even if they appear to have the same condition as you.
  • Do not stop using your medicine or change the dosage without checking with your doctor.
Looking after your medicine
  • Keep ADYNOVATE in the pack until it is time to use it so that it is protected from light.
  • Keep ADYNOVATE in the refrigerator at 2°C to 8°C. Do not freeze.

For more information, see Section 5. What should I know while using ADYNOVATE? in the full CMI.

6. Are there any side effects?

A very common side effect is Headache. Common side effects include dizziness, nausea, diarrhoea, rash, hives. A serious side effect includes severe, sudden allergic reaction with signs or symptoms of rash or hives, wheals, or generalised itching, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing, tightness or discomfort in the chest, and dizziness, which may progress to difficulty in breathing, chest pain and fainting. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ADYNOVATE®

Active ingredient(s): rurioctocog alfa pegol

Consumer Medicine Information (CMI)

This leaflet provides important information about using ADYNOVATE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ADYNOVATE.

Where to find information in this leaflet:

1. Why am I using ADYNOVATE?
2. What should I know before I use ADYNOVATE?
3. What if I am taking other medicines?
4. How do I use ADYNOVATE?
5. What should I know while using ADYNOVATE?
6. Are there any side effects?
7. Product details

1. Why am I using ADYNOVATE?

ADYNOVATE contains the active ingredient rurioctocog alfa pegol (a PEGylated human recombinant DNA derived blood clotting factor VIII).

ADYNOVATE is used for the management of congenital haemophilia A (an inherited bleeding disorder caused by a lack of blood clotting factor VIII in the body).

ADYNOVATE is used to:

  • control and prevent bleeding episodes,
  • routinely prevent and reduce the frequency of bleeding episodes,
  • prevent or reduce bleeding before, during and after surgery.

The blood clotting factor VIII is essential for the blood to form clots and stop bleedings. In patients with inherited haemophilia A, there is a low level of factor VIII in the blood circulation.

ADYNOVATE is similar to the blood clotting factor VIII in human blood, and ADYNOVATE works as a replacement therapy so that blood can form clots at the site of bleeding.

ADYNOVATE is produced by recombinant DNA technology and has been modified chemically to prolong its duration of action.

This medicine helps to control your condition but does not cure it.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I use ADYNOVATE?

Warnings

Do not use ADYNOVATE if:

  • you have ever had an allergic reaction to ADYNOVATE, or octocog alfa (a medicine called ADVATE),
  • you are allergic to mouse or hamster proteins or if you have a known allergy to medicines of mouse or hamster origin,
  • you are allergic to any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have or have had any other medical conditions.
  • have had, or at risk of, any heart problems or conditions involving the blood vessels.
  • are on a controlled sodium diet.

ADYNOVATE may increase the risk of abnormal blood clots forming in your body if you have risk factors for developing blood clots.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. There is no information on the use of ADYNOVATE during pregnancy. Your doctor will discuss the risks and benefits of using ADYNOVATE if you are pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if ADYNOVATE passes into your milk and if it can harm your baby. Your doctor will discuss the risks and benefits of using ADYNOVATE if you are breast-feeding.

3. What if I am taking other medicines?

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

There are no known interactions of ADYNOVATE with other medicines.

Your doctor or Haemophilia Treatment Centre have more information on medicines to be careful with or avoid if you have concerns.

4. How do I use ADYNOVATE?

How much to use

  • Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.
  • Your doctor will decide how much ADYNOVATE you use.
  • Your dose will depend on:
    - your body weight,
    - the amount of factor VIII your body is able to make,
    - how much, how often and where you are bleeding,
    - if your body have built up antibodies to ADYNOVATE.

How to use ADYNOVATE

  • Treatment with ADYNOVATE will be started in a hospital or Haemophilia Treatment Centre and supervised by your doctor who is experienced in the care of patients with haemophilia.
  • After starting ADYNOVATE treatment, some individuals may be trained to use ADYNOVATE at home.
  • ADYNOVATE is given by slow injection directly into your vein.

Do not attempt to inject ADYNOVATE by yourself unless you have received proper training by your doctor or Haemophilia Treatment Centre on how to use the product.

Preparing ADYNOVATE

  • ADYNOVATE is provided as a powder in a vial, and a diluent vial containing water for injections is also supplied in the pack. These vials need to be mixed together to form a clear solution before use.
  • Follow carefully the step-by-step instructions at the end of this leaflet or in the pack insert on how to prepare and inject ADYNOVATE.
  • Do not mix ADYNOVATE with any other medicines or solvent other than the water for injections diluent supplied with the pack.
  • Use only the reconstitution device provided with each pack to prepare the solution for injection.
  • After mixing the powder and the diluent, use the solution immediately. If the solution is not used straight way, you can keep the solution for a maximum of 3 hours when stored at room temperature (below 30°C).
  • Do not refrigerate the solution after it is prepared.
  • ADYNOVATE is for single use in one patient only.
  • Dispose of all unused solution, empty vials, and used needles and syringes into a sharps bin.

The step-by-step instructions can be found under Section 8. Instructions for use.

If you are unsure about how to prepare the medicine for use, contact your doctor or Haemophilia Treatment Centre.

Inspecting ADYNOVATE

  • Always inspect ADYNOVATE before use and after it has been mixed.
  • After mixing, the solution should be clear to colourless, and free from foreign particles.
  • Do not inject the solution if it is discoloured, or cloudy, or contains particles.

How often to use ADYNOVATE

Your doctor will tell you how often or at what intervals you will receive the injection.

The frequency of injections you receive, and how long you will use ADYNOVATE for, will depend on how well ADYNOVATE is working for you.

Continue using ADYNOVATE for as long as your doctor tells you. Usually, the replacement therapy with ADYNOVATE is a life-long treatment.

If you forget to use ADYNOVATE

Do not inject a double dose to make up for the forgotten dose.

If you inject a double dose, this may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or Haemophilia Treatment Centre.

If you use too much ADYNOVATE

If you think that you have used too much ADYNOVATE, you may need urgent medical attention.

You should immediately:

  • contact your doctor or Haemophilia Treatment Centre, or
  • go to the Emergency Department at your nearest hospital, or
  • phone the Poisons Information Centre by calling 13 11 26 (if you are in Australia), or by calling 0800 764 766 (if you are in New Zealand).

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ADYNOVATE?

Things you should do

  • Tell you other doctors, dentists and pharmacists you are using this medicine.
  • If you are about to have any blood tests, tell your doctor that you are using ADYNOVATE.
  • Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some blood tests before you start your treatment and from time to time during your treatment to monitor your progress.
  • Follow all instructions from your doctor. Your doctor may change the dose you use using your treatment.

Tell your doctor and/or Haemophilia Treatment Centre straight away if you notice:

  • any sudden signs and symptoms of a severe allergic response.
  • your bleeding is not controlled or worsens after using ADYNOVATE.

See additional information under Section 6. Are there any side effects?

Things you should not do:

  • Do not give your medicine to anyone else, even if they appear to have the same condition as you.
  • Do not use ADYNOVATE to treat any other complaints unless your doctor tells you to.
  • Do not stop using ADYNOVATE unless advised by your doctor or healthcare professional or unless you have an allergic reaction.
  • Do not change the dosage without checking with your doctor.
  • Do not use ADYNOVATE after the expiry date which is printed on the label after the word 'EXP'. The expiry date refers to the last day of the month.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ADYNOVATE affects you.

ADYNOVATE is not expected to have an influence on your ability to drive and use machines.

Looking after your medicine

  • Keep ADYNOVATE in the pack until it is time to use it. This will protect the medicine from light.
  • Keep ADYNOVATE in the refrigerator at 2°C to 8°C in a refrigerator. Do not freeze.
  • If necessary, you can keep ADYNOVATE out of the refrigerator for a single 3-month period when stored in the original packaging in a cool dry place at room temperature (below 30°C). The date that the product is removed from the refrigerator should be recorded on the carton.
  • Do not return the medicine to the refrigerator after it has been stored at room temperature.
  • Do not use any ADYNOVATE that has been out of the refrigerator for more than 3 months.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep ADYNOVATE out of reach of children.

Getting rid of any unwanted medicine

Medicines should not be disposed of via wastewater or household waste.

If your doctor tells you to stop using this medicine, or if the medicine is out of date, or if the medicine has not been stored properly, ask your doctor or Haemophilia Treatment Centre what to do with any unwanted medicine that is left over.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do

Very common:

  • headache

Common:

  • dizziness
  • nausea
  • diarrhoea
  • rash
  • hives

Uncommon:

  • flushing
  • redness of the eye
  • allergic reactions
  • easily bruising or bleeding due to development of factor VIII inhibitors
  • increase in some type of white blood cells
  • skin reactions at site of injection
  • itchy rash
Speak to your doctor or Haemophilia Treatment Centre if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do

Uncommon:

  • severe, sudden allergic reaction which may progress to anaphylaxis including shock

Signs or symptoms of an allergic response include:

  • rash, hives, wheals, or generalised itching,
  • swelling of your face, lips and tongue or any parts of the body,
  • shortness of breath, wheezing, difficulty in breathing,
  • tightness or discomfort in the chest, chest pain,
  • dizziness and fainting.
Stop the injection immediately.
Call your doctor or Haemophilia Treatment Centre straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Your body can make antibodies (also called "inhibitors") against ADYNOVATE, which may stop ADYNOVATE from working properly. Signs or symptoms may include easily bruising or bleeding, swelling and pain or tightness in joints.

Tell your doctor, Haemophilia Treatment Centre, or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems (if you are in Australia), or to Medsafe online at www.medsafe.govt.nz/safety/report-a-problem.asp (if you are in New Zealand).

By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor, Haemophilia Treatment Centre, or pharmacist before you decide to stop using any of your medicines.

7. Product details

What ADYNOVATE contains

This medicine is only available with a doctor's prescription.

Powder in a vial

Active ingredient
(main ingredient)		rurioctocog alfa pegol
Other ingredients
(inactive ingredients)		calcium chloride dihydrate
glutathione
histidine
mannitol
polysorbate 80
sodium chloride
trehalose dihydrate
trometamol

Diluent in a vial

Other ingredients
(inactive ingredients)		water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What ADYNOVATE looks like

ADYNOVATE is supplied as a white to off-white powder in a single-dose glass vial.

Each pack of ADYNOVATE contains:

  • 1 drug powder vial of ADYNOVATE
  • 1 diluent vial of water for injections (either a 5 mL diluent or a 2 mL diluent is provided to dissolve the powder for injection)
  • 1 reconstitution device (either BAXJECT II Hi-Flow or a pre-assembled BAXJECT III system is provided for mixing the powder and diluent).

ADYNOVATE is available in 7 strengths:

  • ADYNOVATE 250 IU ( 5 mL or 2 mL) - AUST R 273517
  • ADYNOVATE 500 IU (5 mL or 2 mL) - AUST R 278727
  • ADYNOVATE 750 IU (5 mL or 2 mL) - AUST R 300850
  • ADYNOVATE 1000 IU (5 mL or 2 mL) - AUST R 278728
  • ADYNOVATE 1500 IU (5 mL or 2 mL) - AUST R 300851
  • ADYNOVATE 2000 IU (5 mL) - AUST R 278729
  • ADYNOVATE 3000 IU (5 mL) - AUST R 300852

Not all presentations may be marketed.

Who distributes ADYNOVATE

ADYNOVATE is supplied in Australia by:

Takeda Pharmaceuticals Australia Pty Ltd
Level 39, 225 George Street
Sydney NSW 2000
Australia
Telephone: 1800 012 612
www.takeda.com/en-au

ADYNOVATE is supplied in New Zealand by:

Takeda New Zealand Pty Limited
Level 10, 21 Queen Street
Auckland 1010
New Zealand
Telephone: 0508 169 077
www.takeda.com/en-au

This leaflet was prepared in April 2023.

ADYNOVATE® is a registered trademark of Baxalta Incorporated.

TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

8. Instructions for use

IMPORTANT

  • Contact your doctor or Haemophilia Treatment Centre if you have any questions or if you experience any problems following this instruction guide.
  • These instructions are intended only as a visual aid for those patients who have been trained by their doctor or Haemophilia Treatment Centre on the proper way to self-inject the medicine.
  • Do not attempt to inject ADYNOVATE by yourself unless you have received proper training by your doctor or Haemophilia Treatment Centre on how to use the product.
  • Use only the water for injections (diluent) and the reconstitution device provided in the pack to prepare the solution for injection.
  • If more than one vial of ADYNOVATE is needed for the dose, mix each vial of ADYNOVATE using a separate BAXJECT II Hi-Flow or a separate preassembled BAXJECT III system supplied in each pack.
  • Follow the step-by-step instructions that is specific to the reconstitution device supplied with your ADYNOVATE.
  • After preparing ADYNOVATE, use the solution as soon as possible, within 3 hours after mixing.
  • Always inspect ADYNOVATE before use and after it has been mixed. After mixing, the solution should be clear to colourless.
  • Do not use the solution if it is discoloured, or cloudy, or contains particles.

Preparing ADYNOVATE using aseptic technique

In a quiet place, prepare a clean surface and gather all the materials you will need for the injection.

Remove ADYNOVATE from the refrigerator and check the expiry date on the package.

Wash your hands and put on clean exam gloves.

If you are self-injecting at home the use of gloves is optional.

Using the BAXJECT II Hi-Flow device

  1. Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.
  2. Allow the ADYNOVATE powder and diluent vials to reach room temperature before use.
  3. Remove plastic caps from the ADYNOVATE powder and diluent vials.
  4. Cleanse rubber stoppers with an alcohol wipe and allow to dry before use.
  5. Open the BAXJECT II Hi-Flow device package by peeling away the lid, without touching the inside (Figure A). Do not remove the device from the package.

  1. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B).

  1. Grip the BAXJECT II Hi-Flow package at its edge and pull the package off the device (Figure C). Do not remove the blue cap from the BAXJECT II Hi-Flow device. Do not touch the exposed purple plastic spike.

  1. Turn the system over so that the diluent vial is on top. Quickly insert the purple plastic spike fully into the ADYNOVATE powder vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the ADYNOVATE powder vial.

  1. Swirl gently until the ADYNOVATE powder is completely dissolved. The powder should dissolve rapidly (usually in less than 1 minute).

Do not refrigerate the solution after reconstitution.

Administration

  1. Remove the blue cap from the BAXJECT II Hi-Flow device (Figure E). Connect the syringe to the BAXJECT II Hi-Flow. Use of a Luer-lock syringe is recommended. 

  1. Turn the system upside down (ADYNOVATE powder vial now on top). Draw the reconstituted solution into the syringe by pulling the plunger back slowly (Figure F). Do not draw air into the syringe.

  1. Disconnect the syringe; attached a needle suitable for intravenous injection. If more than one vial of ADYNOVATE is to be used, the contents of multiple vials may be drawn into the same syringe.
  2. Administer the dose by injecting the solution directly into the vein over a period of up to 5 minutes (maximum infusion rate of 10 mL per min).

Using the BAXJECT III system

The ADYNOVATE powder vial and the diluent vial are supplied preassembled with the BAXJECT III reconstitution device within a sealed blister package.

Do not use if the lid is not completely sealed on the blister packaging.

  1. Take the sealed blister out from the pack and allow the ADYNOVATE powder and diluent vials to reach room temperature before use.
  2. Open the blister package by peeling away the lid. Remove the preassembled BAXJECT III system from the blister.
  3. Place the pre-assembled BAXJECT III system on a flat surface with the diluent vial on top (Figure 1). The diluent vial has a blue stripe. Do not remove the blue cap until instructed in a later step.

  1. Hold the lower end of the pre-assembled BAXJECT III system with one hand, and use the other hand to press down firmly on the diluent vial until the system is fully collapsed and the diluent flows down into the ADYNOVATE powder vial (Figure 2). Do not tilt the system until all the diluent is completely transferred to the ADYNOVATE powder vial.

  1. Check to make sure the diluent transfer is complete. Swirl gently until all the ADYNOVATE powder is dissolved (Figure 3). The powder should dissolve rapidly (usually in less than 1 minute).

Make sure all the ADYNOVATE powder is completely dissolved, otherwise the undissolved powder will not pass through the device filter.

Do not refrigerate the solution after reconstitution.

Administration

  1. Remove the blue cap from the BAXJECT III device. Connect the syringe to the BAXJECT III device. Use of a Luer-lock syringe is recommended.
  2. Turn the system upside down (ADYNOVATE powder vial now on top). Draw the reconstituted solution into the syringe by pulling the plunger back slowly. Do not draw air into the syringe.
  3. Disconnect the syringe; attach a needle suitable for intravenous injection. If more than one vial of ADYNOVATE is to be used, the contents of multiple vials may be drawn into the same syringe.
  4. Administer the dose by injecting the solution directly into the vein over a period of up to 5 minutes (maximum infusion rate 10 mL per min).

ADYNOVATE® and BAXJECT® are registered trademarks of Baxalta Incorporated.

TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Adynovate

Active ingredient

Rurioctocog alfa pegol

Schedule

Unscheduled

 

1 Name of Medicine

Rurioctocog alfa pegol.

2 Qualitative and Quantitative Composition

Adynovate 250, 500, 750, 1000, 1500, 2000 and 3000 International Units (IU).
Adynovate [rurioctocog alfa pegol, Recombinant Coagulation Factor VIII (rch), PEGylated] is supplied in single-use vials containing nominal potencies of 250, 500, 750, 1000, 1500, 2000 or 3000 IU per vial with a diluent vial containing sterile water for injections for reconstitution to 2 mL or 5 mL.
The 5 mL diluent of water for injections is available for Adynovate 250, 500, 750, 1000, 1500, 2000 or 3000 IU.
The 2 mL diluent of water for injections is available for Adynovate 250, 500, 750, 1000 or 1500 IU.
The amounts of the inactive ingredients are constant in all strengths.

Excipient(s) with known effect.

Each vial of Adynovate contains 0.45 mmol (10 mg) sodium, see Section 4.4 Special Warnings and Precautions for Use.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection with diluent.
Adynovate is formulated as a sterile, non-pyrogenic, white to off-white, lyophilised powder for intravenous injection after reconstitution with water for injections.

4 Clinical Particulars

4.1 Therapeutic Indications

Adynovate is a long-acting antihaemophilic factor (recombinant) indicated in haemophilia A (congenital factor VIII deficiency) patients for:
Control and prevention of bleeding episodes.
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
Perioperative management (surgical prophylaxis).
Adynovate is not indicated for the treatment of von Willebrand disease.

4.2 Dose and Method of Administration

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

Treatment monitoring.

During the course of treatment, appropriate determination of factor VIII levels (by one-stage clotting or chromogenic assays) is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.

Dosage.

The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.
The number of units of factor VIII administered is expressed in IU, which is related to the current WHO concentrate standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or preferably in IU (relative to an International Standard for factor VIII in plasma).
One IU of factor VIII activity is equivalent to that quantity of factor VIII in one mL of normal human plasma.

On demand treatment.

The calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dL. The required dose is determined using the following formula:
Required units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5.
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dL) in the corresponding period.
Table 1 can be used to guide dosing in bleeding episodes and surgery:

Prophylaxis.

For long term prophylaxis, the recommended dose is 40 to 50 IU per kg bodyweight of Adynovate twice weekly in 3 to 4 day intervals. Dose and/or frequency should be adjusted to provide the necessary coverage to prevent bleeding. In some cases, doses up to 60 IU per kg can be used.

Paediatric population.

On demand treatment dosing in paediatric patients (< 12 years of age) does not differ from adult patients. Higher doses or more frequent dosing may be required in some children.
For prophylactic therapy in patients under the age of 12, the recommended dose is 40 to 60 IU per kg bodyweight of Adynovate twice weekly in 3 to 4 day intervals. In some cases, doses up to 80 IU per kg can be used.

Method of administration.

Adynovate should be administered via the intravenous route.
Adynovate should be administered at room temperature not more than 3 hours after reconstitution.
Reconstituted products should be visually inspected for particulate matter and discolouration prior to administration. The solution should be clear to colourless. Do not administer if particulate matter or discolouration or cloudiness is found.
Adynovate does not contain antimicrobial preservative. It is for single use in one patient only. Discard any residue.
The rate of administration should be determined to ensure the comfort of the patient up to a maximum of 10 mL/min.
After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH of 6.7 to 7.3. The osmolality is ≥ 380 mOsmol/kg.

Preparation and reconstitution.

Use aseptic technique.

Using the BaxJect II Hi-Flow device.

For reconstitution use only with the water for injections and the reconstitution device provided in the pack.
1. Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.
2. Allow the vials of Adynovate and diluent to reach room temperature before use.
3. Remove plastic caps from the Adynovate and diluent vials.
4. Cleanse rubber stoppers with an alcohol wipe and allow to dry prior to use.
5. Open the BaxJect II Hi-Flow device package by peeling away the lid, without touching the inside. Do not remove the device from the package.
6. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper.
7. Grip the BaxJect II Hi-Flow package at its edge and pull the package off the device. Do not remove the blue cap from the BaxJect II Hi-Flow device. Do not touch the exposed purple plastic spike.
8. Turn the system over so that the diluent vial is on top. Quickly insert the purple plastic spike fully into the Adynovate vial stopper by pushing straight down. The vacuum will draw the diluent into the Adynovate vial.
9. Swirl gently until Adynovate is completely dissolved. Do not refrigerate after reconstitution.

Using the BaxJect III system.

Do not use if the lid is not completely sealed on the blister.
1. If the product is still stored in a refrigerator, take the sealed blister (contains powder and diluent vials preassembled with the system for reconstitution) from the refrigerator and let it reach room temperature.
2. Wash your hands thoroughly using soap and warm water.
3. Open the Adynovate package by peeling away the lid. Remove the BaxJect III system from the blister.
4. Place Adynovate on a flat surface with the diluent vial on top. The diluent vial has a blue stripe. Do not remove the blue cap until instructed in a later step.
5. With one hand holding Adynovate in the BaxJect III system, press down firmly on the diluent vial with the other hand until the system is fully collapsed and the diluent flows down into the Adynovate vial. Do not tilt the system until the transfer is complete.
6. Verify that the diluent transfer is complete. Swirl gently until all material is dissolved. Be sure that the Adynovate powder is completely dissolved, otherwise not all reconstituted solution will pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should be clear, colourless and free from foreign particles.

Administration.

Remove the blue cap from the BaxJect II Hi-Flow/ BaxJect III device. Connect the syringe to the BaxJect II Hi-Flow/ BaxJect III device. Use of a Luer-lock syringe is recommended. Do not inject air.
Turn the system upside down (Adynovate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly.
Disconnect the syringe; attach a suitable needle and inject intravenously. If a patient is to receive more than one vial of Adynovate, the contents of multiple vials may be drawn into the same syringe.
A separate BaxJect II Hi-Flow device is required to reconstitute each vial of Adynovate with the diluent.
Administer Adynovate over a period of less than or equal to 5 minutes (maximum infusion rate 10 mL per min).

4.3 Contraindications

Known life-threatening hypersensitivity reaction, including anaphylaxis, to Adynovate, to the parent molecule Advate (octocog alfa), to mouse or hamster protein, or other constituents of Adynovate.

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Hypersensitivity reactions are possible with Adynovate. Allergic-type hypersensitivity reactions including anaphylaxis have been reported with recombinant antihaemophilic factor VIII products, including Adynovate and its parent molecule, Advate. Immediately discontinue administration and initiate treatment as clinically appropriate if hypersensitivity reactions occur.

Inhibitor formation.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.

Cardiovascular events.

In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increase the cardiovascular risk.

Catheter-related complications in treatment.

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.

Excipient related considerations.

After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients on a controlled sodium diet.
It is strongly recommended that every time Adynovate 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.

Use in the elderly.

Clinical studies of Adynovate did not include subjects aged 65 and over.

Paediatric use.

The listed precautions apply both to adults and children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Adynovate on fertility have not been established.
(Category B2)
The safety of Adynovate for use in pregnant women has not been established. Animal reproduction studies with recombinant factor VIII, including Adynovate, have not been conducted. Healthcare professionals should balance the potential risks and only prescribe Adynovate if clearly needed.
 The safety of Adynovate for use in lactating women has not been established. It is not known if Adynovate or its metabolites are excreted in human milk. Healthcare professionals should balance the potential risks and only prescribe Adynovate to a breastfeeding woman if clearly needed.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely after treatment with factor VIII and may in some cases progress to severe anaphylaxis (including shock).
Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

Tabulated list of adverse reactions.

The safety of Adynovate has been evaluated in 6 multi-centre, prospective, open label clinical trials and 1 ongoing study in 365 previously treated and untreated patients with severe haemophilia A (factor VIII < 1% of normal), who received at least one dose of Adynovate. Table 2 lists the adverse drug reactions (ADRs) reported during clinical studies.

Description of selected adverse reactions.

Immunogenicity.

Inhibitor development.

Formation of neutralising antibodies (inhibitors) to factor VIII can occur following administration of factor VIII products.
Clinical trial subjects were monitored for neutralising (inhibitory) antibodies to factor VIII. None of the subjects who participated in one or more of 6 completed clinical trials in previously treated patients (PTPs) developed persistent neutralising (inhibitory) antibodies against factor VIII of ≥ 0.6 BU/mL (based on the Nijmegen modification of the Bethesda assay). One patient developed a transient FVIII inhibitor at the lowest limit of positivity (0.6 BU) during personalised prophylaxis targeting a FVIII level of 8-12%. From an ongoing study in previously untreated patients < 6 years with severe haemophilia A, preliminary reports on 9 cases of factor VIII inhibitor development associated with treatment with Adynovate were received.

Binding antibodies to factor VIII, PEG-factor VII, PEG and CHO protein.

Immunogenicity was also evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein using validated ELISA assays. No subject developed persistent treatment-emergent binding antibodies against factor VIII, PEG-factor VIII or PEG. There was no causal relationship between observed adverse events and binding antibodies except in one subject, a PUP where a causal relationship can neither be confirmed nor ruled out based on available data. No subject had pre-existing or treatment-emergent antibodies to CHO protein.
The detection of antibodies that are reactive to Factor FVIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to rurioctocog alfa pegol with the incidence of antibodies to other products may be misleading.
Hypersensitivity. Hypersensitivity reactions are possible with Adynovate (Table 2). Allergic-type hypersensitivity reactions, including anaphylaxis, are rare complications of treatment with recombinant factor VIII, including the parent molecule, Advate.
Paediatric population. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Class reactions. Adverse reactions include: Anaphylactic reaction, Hypersensitivity, Factor VIII inhibition.

Post-marketing adverse reactions.

Following is a list of ADRs which have been observed in post-marketing:

Immune system reactions.

Anaphylactic reaction.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

There has been no reported clinical adverse experience that could be associated with overdosage.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Adynovate is a full-length recombinant human coagulation factor VIII with an extended half-life. The therapeutic activity of Adynovate is derived from its parent molecule, octocog alfa (Advate), which is produced by recombinant DNA technology from a Chinese hamster ovary cell line. The octocog alfa molecule is then covalently conjugated with the PEG reagent, which targets lysine residues. The PEG moiety is conjugated to the octocog alfa molecule to increase the plasma half-life through the reduction of the LRP-1 receptor-mediated clearance of the factor VIII molecule.

Pharmacodynamic effects.

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

Clinical trials.

The safety, efficacy, and PK of Adynovate were evaluated in a multicentre, open-label, prospective, non-randomised, two-arm clinical trial that compared the efficacy of a twice weekly prophylactic treatment regimen to on-demand treatment and determined haemostatic efficacy in the treatment of bleeding episodes. A total of 137 male PTPs (12 to 65 years of age) with severe haemophilia A received at least one infusion with Adynovate. Twenty five of the 137 subjects were adolescents (12 to less than 18 years of age).
Subjects received either prophylactic treatment (n = 120) with Adynovate at a dose of 40-50 IU per kg twice weekly or on-demand treatment (n = 17) with Adynovate at a dose of 10-60 IU per kg for a 6-month period. The mean (SD) dose per prophylaxis infusion was 44.4 (3.9) IU per kg with a median dosing interval of 3.6 days. There were 91 out of 98 (93%) subjects previously treated prophylactically prior to enrolment, who experienced a reduction in dosing frequency during routine prophylaxis in the study, with a median reduction of 33.7% (approximately one more day between doses). One hundred eighteen (118) of 120 (98%) prophylaxis subjects remained on the starting recommended regimen without dose adjustment, and 2 subjects increased their dose to 60 IU/kg during prophylaxis due to bleeding in target joints.

On-demand treatment and control of bleeding episodes.

A total of 518 bleeding episodes were treated with Adynovate in the per-protocol population, i.e. dosed according to the protocol specific dosing requirements. Of these, 361 bleeding episodes (n = 17 subjects) occurred in the on-demand arm and 157 (n = 61 subjects) occurred in the prophylaxis arm. The median total dose to treat all bleeding episodes in the per protocol population was 30.9 (Q1: 21.6; Q3: 45.3) IU per kg. The median dose per infusion to treat all bleeding episodes in the per-protocol population was 29 (Q1: 20.0; Q3: 39.2) IU per kg. The median dose per infusion to treat a minor, moderate, or severe/major bleeding episode in the per-protocol population was 25.5 (Q1: 16.9; Q3: 37.6) IU/kg, 30.9 (Q1: 23.0; Q3: 43.1) IU/kg, or 36.4 (Q1: 29.0; Q3: 44.5) IU/kg, respectively.
A total of 591 bleeding episodes were treated with Adynovate in the treated population, which was identical to the safety analysis set of subjects assigned to routine prophylaxis or on demand treatment with Adynovate and who received at least one dose of the product. Of these, 361 bleeding episodes (n = 17 subjects) occurred in the on-demand arm and 230 bleeding episodes (n = 75 subjects) occurred in the routine prophylaxis arm. Efficacy in control of bleeding episodes is summarised in Table 3.

Routine prophylaxis.

A total of 120 subjects (treated population) received a twice a week regimen in the prophylaxis arm, and an additional 17 subjects were treated episodically in the on-demand arm. In the treated population, the median [mean] annualised bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [4.7] while on a twice a week prophylaxis regimen (Table 4). In the per-protocol population, the median [mean] annualised bleed rate (ABR) in the on demand treatment arm was 41.5 [40.8] compared to 1.9 [3.7] while on a twice a week prophylaxis regimen. Using a negative binomial model to estimate the ABR, there was a significant reduction in the ABR (p < 0.0001) for subjects in the prophylaxis arm compared to the on-demand arm.
In the treated population, the median [mean] ABR for the 23 adolescent subjects age 12 to < 18 years of age on routine prophylaxis was 2.1 [5.2] compared to a median [mean] ABR of 1.9 [4.6] for the 97 subjects 18 years and older. Reduction in ABR between the treatment arms was observed regardless of baseline subgroups examined, including age, presence or absence of target joints, and pre-study treatment regimen. The majority of the bleeding episodes during prophylaxis (95%) were of minor/moderate severity. Forty-five out of 120 subjects (38%) experienced no bleeding episodes and 68 out of 120 subjects (57%) experienced no joint bleeding episodes in the prophylaxis arm. Of those subjects who were compliant to regimen (per-protocol population), 40 out of 101 subjects (40%) experienced no bleeding episodes. All subjects in the on-demand arm experienced a bleeding episode, including a joint bleeding episode.

Routine prophylaxis study in paediatric subjects (< 12 years of age).

The safety and efficacy of Adynovate was evaluated in a total of 73 paediatric PTPs with severe haemophilia A, of which 66 subjects were dosed (32 subjects aged < 6 years and 34 subjects aged 6 to < 12 years) in a separate paediatric study. The prophylactic regimen was 40 to 60 IU/kg of Adynovate twice a week. The median [mean] overall ABR was 2.0 [3.61] for the 66 subjects in the treated population and the median [mean] ABRs for spontaneous and joint bleeding episodes were both 0 [1.18 and 1.12, respectively]. Of the 66 subjects treated prophylactically, 25 (38%) experienced no bleeding episodes, 44 (67%) experienced no spontaneous bleeding episodes, and 48 (73%) experienced no joint bleeding episodes.
Of the 70 bleeding episodes observed during the paediatric study, 82.9% were controlled with 1 infusion and 91.4% were controlled with 1 or 2 infusions. Control of bleeding was rated excellent or good in 63 out of 70 (90%) bleeding episodes. The definitions of excellent or good in the paediatric study were unchanged as compared to the previously conducted prophylaxis study in adolescent and adult subjects.

Long-term prophylaxis treatment in paediatric and adult subjects.

The long-term safety and efficacy of Adynovate in prophylaxis and treatment of bleeding episodes was evaluated in 216 paediatric and adult PTPs with severe haemophilia A who had either previously participated in other Adynovate studies or were naive to Adynovate. In the treated population, subjects received a fixed-dose twice-weekly regimen of 40 to 50 IU/kg if aged ≥ 12 years or of 40 to 60 IU/kg if aged < 12 years. The dose was adjusted up to 80 IU/kg twice weekly if required to maintain factor VIII trough levels of > 1%. Subjects that opted for a personalised (pharmacokinetically-tailored) prophylactic regimen received doses up to 80 IU/kg per infusion that targeted factor VIII trough levels of ≥ 3% at least twice weekly. ABR per prophylactic regimen, bleeding site and etiology are presented in Table 5.
Long-term haemostatic efficacy was evaluated in 910 bleeding episodes treated with Adynovate and was rated excellent or good in 88.5% of bleeding episodes. Across age categories and for both the fixed-dose and the PK-tailored dose regimen, > 85% of bleed treatments were rated excellent or good. The majority of bleeding episodes were treated with one (74.0%) or two (15.4%) infusions.

Personalised prophylaxis PROPEL clinical trial in adolescents and adult subjects.

The safety and efficacy of Adynovate was evaluated in a prospective, randomised, open label multicentre study in 121 (115 randomised) adolescents (12-18 years old) and adult PTPs with severe haemophilia A for a 12 months treatment period. The study compared 2 PK guided prophylactic dosing regimens of Adynovate that targeted factor VIII trough levels of 1-3% dosed twice weekly (N=57) or 8-12% dosed every other day (N=58), by assessing the proportions of subjects achieving a total ABR of 0 in the second 6-month study period as the primary efficacy endpoint.
The average prophylactic doses administered in the 1-3% and 8-12% trough arms were 3,866.1 IU/kg per year [mean (SD) infusions/week = 2.3 (0.58)] and 7,532.8 IU/kg per year [(mean (SD) infusions/week = 3.6 (1.18)], respectively. After dose adjustment during the first 6-month period of prophylaxis, median trough levels in the second 6-month period (based on the one-stage clotting assay and calculated to the end of the planned infusion interval) ranged from 2.10 IU/dL to 3.00 IU/dL in the 1-3% trough level arm and from 10.70 IU/dL to 11.70 IU/dL in the 8-12% trough level arm, demonstrating that dosing in the 2 prophylaxis regimens was generally adequate to achieve and maintain the desired factor VIII trough levels.
The primary endpoint of the study, proportion of subjects who had a total ABR of 0 during the second 6 month period, was not reached in the ITT patient population (p=0.0545) but was reached in the per-protocol population (nominal p value of 0.0154). The proportions of randomised subjects with total ABRs of 0 during the second 6-month study period and the secondary efficacy outcome measures, spontaneous ABRs and spontaneous annualised joint bleeding rates (AJBRs) of 0 during the second 6-month study period, are presented in Table 6.
The secondary efficacy outcome measures (total ABRs, spontaneous ABRs and spontaneous AJBRs during the second 6-month study period), are presented in Table 7.
A total of 242 bleeding episodes in 66 subjects were treated with Adynovate; 155 bleeds in 40 subjects in the 1-3% trough level arm and 87 bleeds in 26 subjects in the 8-12% trough level arm. The majority of bleeds (86.0%, 208/242) were treated with 1 or 2 infusions; and bleed treatment at resolution of the bleeding episode was rated excellent or good in 84.7% (205/242) of bleeds.

Perioperative management study.

A total of 21 major surgical procedures and 5 additional minor surgeries were performed and assessed in 21 unique subjects in the surgery study. For major surgeries, the preoperative loading dose ranged from 36 IU/kg to 109 IU/kg (median: 63 IU/kg); and postoperative total dose ranged from 186 IU/kg to 1320 IU/kg (median: 490 IU/kg). The median total dose for major surgeries was 553 IU/kg (range: 248-1394 IU/kg) and the median total dose of minor surgeries was 106 IU/kg (range: 76-132 IU/kg).
Perioperative haemostatic efficacy was rated as excellent (blood loss less than or equal to that expected for the same type of procedure performed in a non-haemophilic patient, and required blood components for transfusions less than or similar to that expected in non-haemophilic population) for all 26 (21 major, 5 minor) procedures. The median (IQR) observed intraoperative blood loss (n = 14) was 10.0 (20.0) mL compared to the predicted average blood loss (n = 14) of 150.0 (140.0) mL for major orthopaedic surgeries.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of Adynovate was evaluated in a crossover study with Advate in 26 subjects (18 adults and 8 adolescents) and in 22 subjects (16 adults and 6 adolescents) after 6 months of treatment with Adynovate. A single dose of 45 ± 5 IU/kg was utilised for both products. In the paediatric study, a single dose of 60 ± 5 IU/kg was utilised for both Advate and Adynovate to evaluate PK in 31 paediatrics subjects (< 6 years and 6 to < 12 years of age). Plasma factor VIII activity was measured by the one stage clotting assay and chromogenic assay as shown in Table 8 to Table 11.
Adynovate has an extended half-life of 1.4 to 1.5-fold compared to recombinant full length human coagulation factor VIII (Advate) in the adolescent and adult population, as determined based on one-stage clotting and chromogenic assays, respectively. The half life extension in the paediatric population was 1.3 to 1.5-fold using both the one stage clotting and chromogenic assays. An increase in AUC and a decrease in clearance as compared to the parent molecule, Advate, were also observed. Incremental recovery was comparable with both products. The change in PK parameters was similar in both the adult and adolescent populations and between one-stage clotting and chromogenic substrate assays.

Paediatric pharmacokinetics.

Pharmacokinetic parameters calculated from 39 subjects less than 18 years of age (intent to treat analysis) are available for 14 children (1 to less than 5 years), 17 older children (6 to less than 12 years) and 8 adolescent subjects (12 to < 18 years of age), as shown in Table 10. The mean clearance (based on body weight) of Adynovate was higher and the mean half-life was lower in children less than 12 years of age than adults.
A higher dose may be required in children less than 12 years of age.
The PK data demonstrates that Adynovate has an extended circulating half-life.

5.3 Preclinical Safety Data

Genotoxicity.

No studies on genotoxicity have been performed with Adynovate.

Carcinogenicity.

No studies on carcinogenicity have been performed with Adynovate.

6 Pharmaceutical Particulars

6.1 List of Excipients

Calcium chloride dihydrate, Glutathione, Histidine, Mannitol, Polysorbate 80, Sodium chloride, Trehalose dihydrate, Trometamol, Water for injections (diluent).

6.2 Incompatibilities

Incompatibilities were not assessed as part of the registration of this medicine. Adynovate must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

6.4 Special Precautions for Storage

Store Adynovate in powder form at 2°C to 8°C.
Do not freeze.
Adynovate may be stored at room temperature not to exceed 30°C for a period of up to 3 months not to exceed the expiration date. If stored at room temperature, record the end date of the 3-month storage at room temperature on the carton when Adynovate is removed from refrigeration.
After storage at room temperature, do not return the product to the refrigerator.
Do not use beyond expiration date printed on the carton or vial.
Store vials in their original box and protect them from extreme exposure to light.
After reconstitution, do not refrigerate the solution. Use the reconstituted solution immediately or within 3 hours after reconstitution. Discard any remaining solution.

6.5 Nature and Contents of Container

Each pack contains a powder vial and a vial containing 2 mL or 5 mL diluent (both type I glass closed with chlorobutyl rubber stoppers). The product is supplied in either one of the following configurations:
Adynovate with BaxJect II Hi-Flow device: Each pack contains a powder vial, a vial containing diluent and a device for reconstitution (BaxJect II Hi-Flow).
Adynovate in BaxJect III system: Each pack contains a ready to use BaxJect III system in a sealed blister (the powder vial and the vial containing diluent are preassembled with the system for reconstitution).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Adynovate is comprised of 2,332 amino acids [molecular weight (MW) 280 kDa] covalently conjugated with a polyethylene glycol (PEG) reagent (MW 20 kDa).

CAS number.

1417412-83-9.

7 Medicine Schedule (Poisons Standard)

Unscheduled (Exempted).

Summary Table of Changes