Consumer medicine information

Eloctate

Efmoroctocog alfa

BRAND INFORMATION

Brand name

Eloctate

Active ingredient

Efmoroctocog alfa

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Eloctate.

SUMMARY CMI

ELOCTATE®

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 ELOCTATE?

ELOCTATE contains the active ingredient efmoroctocog alfa. Efmoroctocog alfa is a factor VIII protein necessary for forming clots in the blood and helps to control or prevent bleeding. ELOCTATE is used for the management of haemophilia A (congenital factor VIII deficiency).

For more information, see Section 1. Why am I using ELOCTATE? in the full CMI.

2. What should I know before I use ELOCTATE?

Do not use if you have ever had an allergic reaction to ELOCTATE, efmoroctocog alfa or other factor VIII replacement factors, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ELOCTATE? in the full CMI.

3. What if I am taking or using 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 or using other medicines? in the full CMI.

4. How do I use ELOCTATE?

  • Your doctor will decide what dose you will receive. Do not use more than the recommended dose.
  • ELOCTATE is administered by slow injection directly into your vein.
  • ELOCATE comes in a vial of sterile powder to cake and a pre-filled syringe containing solvent. These need to be mixed before use.

More instructions and how to use ELOCTATE can be found in Section 4. How do I use ELOCTATE? in the full CMI.

5. What should I know while using ELOCTATE?

Things you should do
  • Tell your doctor immediately if bleeding is not controlled after using ELOCTATE.
  • Tell your doctor immediately if you become pregnant.
  • Tell any other doctors, dentist, or pharmacist you visit that you are using ELOCTATE.
  • Keep all your appointments with your doctor and any blood tests.
Things you should not do
  • Do not stop using this medicine or change the dose without checking with your doctor.
Looking after your medicine
  • Store in the refrigerator at 2°C to 8°C. Do not freeze.
  • Store in a cool, dry place away from moisture, heat, or sunlight.
  • Keep ELOCTATE in the pack until it is time to use it.

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

6. Are there any side effects?

Less serious side effects include joint pain or swelling, muscle aches, tenderness or weakness, general feeling of discomfort, feeling hot or cold, headache, stomach pain, high or low blood pressure, dizziness, cough, light headedness, back pain, slow heartbeat, chest pain, rash and loss of taste. A serious side effect is an allergic reaction with symptoms of shortness of breath, wheezing or difficulty breathing, chest pain or discomfort, swelling of the face, lips tongue or other parts of the body rash or hives. 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

ELOCTATE®

Active ingredient: efmoroctocog alfa (recombinant coagulation factor VIII Fc fusion protein)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using ELOCTATE?

ELOCTATE contains the active ingredient efmoroctocog alfa. People with haemophilia A lack sufficient factor VIII to control bleeding. ELOCTATE works by replacing factor VIII to enable blood to clot.

ELOCTATE is used to:

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

ELOCTATE does not contain von Willebrand factor. Therefore, it is not suitable for use in Von Willebrand's disease.

2. What should I know before I use ELOCTATE?

Warnings

Do not use ELOCTATE if:

  • you have an allergy to ELOCTATE or other factor VIII replacement factors, or 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:

  • take any medicines for any other condition

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 ELOCTATE during pregnancy. Your doctor will discuss the risks and benefits of using it if you are pregnant.

Talk to your doctor if you are breastfeeding or plan to breastfeed. It is not known whether ELOCTATE passes into breast milk. Your doctor will discuss the risks and benefits of using it if you are breast-feeding.

3. What if I am taking or using other medicines?

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

Your doctor or Haemophilia Treatment Centre have more information on medicines to be careful with or avoid while using this medicine.

4. How do I use ELOCTATE?

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 what dose you will receive. This will depend on your individual need for replacement factor VIII therapy.
  • Your doctor may change the dose during your treatment.
  • Do not stop using ELOCTATE or change the dosage, without checking with your doctor unless you have an allergic reaction.

How to use it

ELOCTATE is administered by slow injection into your veins.

ELOCTATE is provided as a powder in a vial and a pre-filled syringe containing a sterile solvent also known as a diluent. These need to be mixed before use.

  • Mix the ELOCTATE powder with the diluent provided only when you are ready to use it. Do not shake ELOCTATE when mixing it. Shaking can damage this medicine.
  • If you mix the powder and solvent and are interrupted, you can keep the mixed product for a maximum of 6 hours if you store it below 30°C and protect it from direct sunlight. Do not put it in the freezer.
  • Always inspect ELOCTATE after is has been mixed and before use. It should be clear to slightly rainbow-like (opalescent) and colourless. Do not inject if the solution is discoloured or cloudy, or contains particles.
  • Refer to the leaflet in the pack for step-by-step instructions on how to prepare and inject ELOCTATE.
  • ELOCTATE is for single use in one patient only. Dispose of any unused solution, vials, and needles in a sharps bin. See additional information under, Getting rid of any unwanted medicine.

If you have any questions about how to use ELOCTATE, talk to your doctor, or Haemophilia Treatment Centre, or telephone 1800 818 806 (In Australia) or 0800 283 684 (In New Zealand).

If you forget to use ELOCTATE

If you miss your dose at the usual time, use your dose as soon as you remember and resume your normal dosing schedule.

Do not use a double dose to make up for the dose you missed.

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

If you use too much ELOCTATE

If you think that you or anyone else may have used too much ELOCTATE or have been given too much ELOCTATE, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using ELOCTATE?

Things you should do

Tell your doctor immediately if:

  • your bleeding is not controlled after using ELOCTATE.
  • you become pregnant while on treatment with ELOCTATE.

Before you use or take any other medicine, talk to your doctor or Haemophilia Treatment Centre.

If you are about to have any blood tests, tell your doctor that you are using ELOCTATE.

Keep all your appointments with your doctor so your progress can be checked and have any blood tests your doctor requests.

Remind any doctor, dentist, or pharmacist you visit that you are using ELOCTATE.

Things you should not do

  • Do not use more than the recommended dose.
  • Do not give ELOCTATE to anyone else even if they have the same condition as you.
  • Do not use ELOCTATE to treat any other complaints unless a doctor tells you to.
  • Do not stop using ELOCTATE or change the dosage without checking with your doctor.

Driving or using machines

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

Looking after your medicine

  • Keep ELOCTATE in the pack until it is time to use it, protected from light.
  • Store in the refrigerator at 2°C to 8°C. Do not freeze ELOCTATE.
  • If necessary, you can keep ELOCTATE out of the refrigerator for a single 6-month period. If out of the refrigerator, store the sealed carton in a cool, dry place below 30°C. Record the date ELOCTATE was removed from the refrigerator on the carton. Do not use ELOCTATE that has been out of the refrigerator for more than 6 months.
  • Once reconstituted, you can keep ELOCTATE at room temperature (below 30°C) for up to 6 hours. Protect the product from direct sunlight. Do not freeze.
  • Do not use ELOCTATE after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or damaged, return it to your Haemophilia Treatment Centre or Australian Red Cross Blood Service for disposal.

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If your doctor tells you to stop using this medicine or it is out of date, ask your Haemophilia Treatment Centre what to do with any 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, ask your doctor, Haemophilia Treatment Centre, or pharmacist if you have any further questions about side effects.

Less serious side effects in previously treated patients

Less serious side effectsWhat to do
Joint or muscle-related
  • Joint pain
  • Joint swelling
  • Aching muscles, muscle tenderness or weakness not caused by exercise
  • Back pain
Heart-related
  • High blood pressure
  • Low blood pressure including dizziness or lightheaded
  • Slow heartbeat
  • Chest pain
Others
  • General feeling of discomfort
  • Headache
  • Rash
  • Feeling cold
  • Feeling hot
  • Dizziness
  • Taste disturbance or loss of taste
  • Cough
  • Stomach pain
Speak to your doctor or Haemophilia Treatment Centre if you have any of these less serious side effects and they worry you.

Less serious side effects in previously untreated patients

Less serious side effectsWhat to do
  • 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 in both previously treated and previously untreated patients

Serious side effectsWhat to do
Factor VIII inhibition
  • easily bruising or bleeding due to factor VIII inhibition
Allergy-related
  • Swelling of your face, lips, tongue, or other parts of your body, rash or hives,
  • Shortness of breath, wheezing, difficulty breathing, chest pain or discomfort.
Stop using ELOCTATE and call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
These side effects are rare in previously treated patients.

ELOCTATE may increase the risk of abnormal blood clots forming in your body if you are at risk of developing blood clots.

Your body can make antibodies called “inhibitors” against ELOCTATE which may stop ELOCTATE from working properly.

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 as follows:
For Australia: Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems.
For New Zealand: Medsafe online at https://www.medsafe.govt.nz/safety/report-a-problem.asp

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 taking any of your medicines.

7. Product details

What ELOCTATE contains
Powder in a vial

Active ingredient
(main ingredient)		efmoroctocog alfa
Other ingredients
(inactive ingredients)
  • sucrose
  • sodium chloride
  • histidine
  • calcium chloride dihydrate
  • polysorbate 20
Potential allergensNot applicable

Solvent in a pre-filled syringe

Active ingredient
(main ingredient)		Not applicable
Other ingredients
(inactive ingredients)
  • sodium chloride
  • water for injections
Potential allergensNot applicable

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

ELOCTATE contains 14 mg of sodium per vial.

What ELOCTATE looks like

ELOCTATE consists of:

  • 1 vial of sterile ELOCTATE white to off-white powder to cake
  • 1 pre-filled syringe containing a clear and colourless solvent
  • 1 sterile vial adapter for mixing the powder and solvent

ELOCTATE is available in the following strengths:

  • 250 International Units (IU)
  • 500 International Units (IU)
  • 750 International Units (IU)
  • 1000 International Units (IU)
  • 1500 International Units (IU)
  • 2000 International Units (IU)
  • 3000 International Units (IU)

Who distributes ELOCTATE

In Australia:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall No.: 1800 818 806
Email: [email protected]

In New Zealand:

Sanofi-aventis new zealand limited
56 Cawley Street
Ellerslie, Auckland
New Zealand Free Call No.: 0800 283 684
Email: [email protected]

This leaflet was prepared in December 2022.

Australian Registration Numbers

ELOCTATE 250 IU Aust R 210521

ELOCTATE 500IU Aust R 210519

ELOCTATE 750 IU Aust R 210523

ELOCTATE 1000 IU Aust R 210525

ELOCTATE 1500 IU Aust R 210522

ELOCTATE 2000 IU Aust R 210524

ELOCTATE 3000 IU Aust R 210520

® ELOCTATE is a registered trademark of Bioverativ Therapeutics Inc.

eloctate-ccdsv12-cmiv8-05dec22

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Eloctate

Active ingredient

Efmoroctocog alfa

Schedule

Unscheduled

 

1 Name of Medicine

Efmoroctocog alfa.

2 Qualitative and Quantitative Composition

Each single-use vial contains nominally 250, 500, 1000, 2000, or 3000 International Units (IU) of efmoroctocog alfa.
Each pre-filled syringe contains 3 mL of solvent.
Efmoroctocog alfa is produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line, which has been extensively characterised. The HEK cell line expresses efmoroctocog alfa into a defined cell culture medium that does not contain any proteins derived from animal or human sources. The purification process utilises a series of chromatography and multiple viral clearance steps. The viral clearance steps include affinity chromatography, 15 nanometer virus-retaining nano-filtration step, and detergent viral inactivation. No human or animal derived additives are used in the purification and formulation processes.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and solvent for solution for injection.
Eloctate is formulated as a sterile, preservative-free, non-pyrogenic, lyophilised, white to off-white powder to cake, for intravenous (IV) administration in a single-use vial.
The liquid diluent (sterile water for injections) is in a pre-filled syringe.

4 Clinical Particulars

4.1 Therapeutic Indications

Eloctate is a long acting antihaemophilic factor (recombinant) indicated in adults and children with haemophilia A (congenital factor VIII deficiency) for:
Control and prevention of bleeding episodes.
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
Perioperative management (surgical prophylaxis).
Eloctate does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease.

4.2 Dose and Method of Administration

For intravenous use only after reconstitution.
Treatment should be initiated and supervised by qualified healthcare professionals experienced in the diagnosis and treatment of haemophilia A. The ability of a patient to self-inject intravenously should be assessed.
See Directions for use provided at the end of this section for detailed reconstitution instructions.
Each vial of Eloctate has the recombinant FVIII potency in International Units stated on the label. It is recommended that prescribed doses of Eloctate are expressed as "International Units", written in full.
Careful control of replacement therapy is especially important in cases of life threatening bleeding episodes or major surgery (see Table 1 and Table 2).
Although dosing can be estimated by the guidelines below, it is recommended that standard routine laboratory tests such as factor VIII activity assays be performed (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Method of calculating initial estimated dose.

1 IU of Eloctate per kg bodyweight is expected to increase the circulating level of factor VIII by 2% [IU/dL].
Eloctate has been shown to have a prolonged circulating half-life. Although patients may vary in their pharmacokinetic (e.g. half-life, in vivo recovery) and clinical responses to Eloctate, the expected in vivo peak increase in factor VIII level expressed as IU/dL (or % of normal) or the required dose can be estimated using the following formulas:
IU/dL (or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg); or
Dose (IU) = body weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).
Dose adjustment may be necessary in paediatric patients under 12 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use). For patients 12 years of age or older, dose adjustment is not usually required.

Control and prevention of bleeding episodes.

Table 1 can be used to guide dosing in bleeding episodes:
Subsequent dosage and duration of treatment depends on the individual clinical response, the severity of the factor VIII deficiency, and the location and extent of bleeding (see Section 5.2 Pharmacokinetic Properties).

Perioperative management.

Careful control and monitoring of dose and duration of treatment is especially important in cases of major surgery. Verify target activity has been achieved prior to surgery. Table 2 can be used to guide dosing for perioperative management (surgical prophylaxis):

Routine prophylaxis.

For individualised prophylaxis, the recommended regimen is 50 IU/kg every 3-5 days. The dose may be adjusted based on patient response in the range of 25-65 IU/kg (see Section 5.2 Pharmacokinetic Properties). More frequent or higher doses up to 80 IU/kg may be required in children less than 12 years of age.
For weekly prophylaxis, the recommended dose is 65 IU/kg.

Directions for use.

Read all the instructions before you start. If you have any questions about this guide, ask your doctor or pharmacist. Your healthcare provider should show you or your caregiver how to reconstitute and administer Eloctate the first time Eloctate is used.
There are 5 steps, explained in this guide.
Take time to read through each section and keep this leaflet with your medicine as a reminder of what to do.

A. Setting up.

A1. First ensure that your work area is clean.
A2. Collect everything you will need. Check the expiry date on the Eloctate kit. If it is out of date, do not use it and contact your pharmacy immediately. If refrigerated, allow the vial of Eloctate and the pre-filled diluent syringe to warm to room temperature (15°C to 30°C) for approximately 30 minutes. Do not use heat sources (for example, hot water or a heater) to warm the contents.
A3. Wash your hands thoroughly with soap and water before performing the following procedures.
A4. Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.
A5. Remove the plastic cap from the Eloctate vial and wipe the rubber stopper of the vial with an alcohol wipe. Allow the rubber stopper to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface.
A6. Completely remove the backing from the vial adapter package by peeling back the lid. Do not remove the vial adapter from the package or touch the inside of the package or the adapter.
A7. Keep the vial on a flat surface. Hold the vial adapter package with one hand and using the other hand, place the vial adapter over the vial. The spike should be placed directly above the centre of the rubber stopper. Push the vial adapter straight down until the adapter spike punctures the centre of the vial stopper and is fully inserted.
A8. Lift the package cover away from the vial adapter and discard the cover.
A9. Take the plunger rod and syringe out of the package. Hold the plunger rod at the circular disk. Place the tip of the plunger rod into the end of the syringe. Turn in a clockwise direction until it is securely attached. Only use the diluent syringe provided to reconstitute the drug product.

B. Reconstituting the injection.

B1. With one hand, hold the diluent syringe right under the cap, and with the cap pointing up. Make sure you are holding the diluent syringe by the ridged part directly under the cap. Do not use if the cap has been removed or is not securely attached.
B2. With your other hand, grasp the cap and bend it at a 90° angle until it snaps off. After the cap snaps off, you will see the glass tip of the syringe. Do not touch the glass tip of the syringe or the inside of the cap.
B3. Be sure the vial is sitting on a flat surface. Insert the tip of the syringe into the adapter opening. Turn the syringe in a clockwise direction until it is securely attached to the adapter.
B4. Slowly depress the plunger rod to inject all of the diluent into the vial. The plunger rod may rise slightly after this process. This is normal.
B5. With the syringe still connected to the adapter, gently swirl the vial until the product is completely dissolved. The appearance of the solution should be clear to slightly opalescent and colourless. Do not shake. Do not use the reconstituted Eloctate if it contains visible particles or is cloudy.
B6. Make sure the plunger rod is completely depressed. Turn the vial upside-down. Slowly pull on the plunger rod to draw the solution into the syringe. Be careful not to pull the plunger rod completely out of the syringe.
B7. Gently unscrew the syringe from the vial adapter and dispose of the vial with the adapter still attached. Do not touch the syringe tip or the inside of the cap.
B8. Your Eloctate is now ready to be connected to your infusion tubing set. See section D. Giving the injection. Reconstituted Eloctate should be administered as soon as possible.

C. Pooling.

If you are using two or more reconstituted vials of Eloctate, you can follow these pooling steps.
C1. Be sure to leave the vial adapter attached to the vial, as you will need it for attaching a large luer lock syringe.
C2. Do not detach the diluent syringe or the large luer lock syringe until you are ready to attach the large luer lock syringe to the next vial (with vial adapter attached).
C3. Remove the diluent syringe from the vial adapter by turning it counter-clockwise until it is completely detached.
C4. Attach a separate large luer lock syringe by turning clockwise until it is securely attached.
C5. Slowly pull on the plunger rod to draw the solution into the syringe. Repeat this pooling procedure with each vial you will be using. Once you have pooled the required dose, proceed to administration using the large luer lock syringe.

D. Giving the injection.

For intravenous use only after reconstitution. Eloctate is administered by intravenous (IV) infusion after reconstitution of the drug powder with the diluent.
Do not administer reconstituted Eloctate if it contains visible particles, is discoloured, or is cloudy.
D1. Attach the syringe to the connector end of the infusion set tubing by turning clockwise until it is securely attached. Do not administer reconstituted Eloctate in the same tubing or container with other medicinal products. Do not remove the protective needle cover until you are ready to insert the needle (see step D4).
D2. Apply a tourniquet and clean the skin area where you will perform the infusion using an alcohol wipe.
D3. Depress the plunger until all air is removed from the syringe and Eloctate has reached the end of the infusion set tubing. Do not push Eloctate through the needle.
D4. Remove the protective needle cover from the infusion set tubing. Insert the needle on the infusion set tubing into the vein. Remove the tourniquet. Always verify proper needle placement when performing intravenous administration.
D5. Slowly depress the plunger on the syringe to administer Eloctate. Eloctate should be injected intravenously over several minutes. The rate of administration should be determined by your comfort level. The small amount of drug product left in the infusion set will not affect treatment.
D6. After infusing Eloctate, flip the safety shield towards the needle. Remove the infusion set.

E. Post-infusion care and disposal.

E1. Place the wing and the safety shield between your thumb and index finger.
Press the safety shield against a hard surface until an audible click is heard.
E2. Use a sterile gauze to put pressure on the infusion site for several minutes. Apply an adhesive bandage if necessary.
E3. A sharps bin should be used for disposal of all unused solution, empty vials and used needles and syringes.

4.3 Contraindications

Eloctate is contraindicated in patients who have manifested severe hypersensitivity reactions, including anaphylaxis, to the product or its components.

4.4 Special Warnings and Precautions for Use

The clinical response to Eloctate may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined, and a sufficient dose of Eloctate should be administered to achieve a satisfactory clinical response. If the patient's plasma factor VIII level fails to increase as expected or if bleeding is not controlled after Eloctate administration, the presence of an inhibitor (neutralising antibodies) should be suspected, and appropriate testing performed (see Section 4.4 Special Warnings and Precautions for Use, Monitoring laboratory tests).

Anaphylaxis and severe hypersensitivity reactions.

Allergic type hypersensitivity reactions, including anaphylaxis, are possible with factor replacement therapies. Hypersensitivity reactions have been reported with Eloctate. Advise patients to discontinue use of Eloctate if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.

Neutralising antibodies (inhibitors).

Inhibitors have been reported with factor replacement therapy in the treatment of haemophilia A. Patients using Eloctate should be monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported with Eloctate in the treatment of haemophilia A, including in previously untreated patients (PUPs). If the patient's plasma factor VIII level fails to increase as expected or if bleeding is not controlled after Eloctate administration, the presence of an inhibitor (neutralising antibodies) should be suspected, and appropriate testing performed (see Section 4.4 Special Warnings and Precautions for Use, Monitoring laboratory tests).

Cardiovascular events.

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

Catheter-related complications.

If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteremia and catheter site thrombosis should be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).

Monitoring laboratory tests.

Monitor plasma factor VIII activity levels by performing the one stage clotting assay to confirm adequate factor VIII levels have been achieved and maintained, when clinically indicated (see Section 4.2 Dose and Method of Administration).
Monitor for the development of factor VIII inhibitors. If bleeding is not controlled with Eloctate and the expected factor VIII activity plasma levels are not attained, perform an assay to determine if factor VIII inhibitors are present (use Bethesda units to titre inhibitors).

Use in renal impairment.

Eloctate has not been studied in patients with renal impairment.

Use in hepatic impairment.

Specific studies of Eloctate in patients with hepatic impairment have not been performed.

Use in the elderly.

Clinical studies of Eloctate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for patients aged 65 and older should be individualised (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Safety, efficacy, and pharmacokinetics of Eloctate have been evaluated in previously treated paediatric and adolescent patients (PTPs). Safety and efficacy of Eloctate have been evaluated in PUPs < 6 years of age (median 0.58 year; range: 0.02-4.00 years) in study 4 (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). In adolescent patients 12 years of age and older, no dose adjustment is required. In comparison with adolescents and adults, children less than 12 years of age may have a higher clearance and a shorter half-life. These differences should be taken into account when dosing. More frequent or higher dosing may be needed in patients less than 12 years of age (see Section 5.2 Pharmacokinetic Properties, Paediatric pharmacokinetics).

Effects on laboratory tests.

No clinically meaningful changes were observed in any of the haematology or chemistry parameters.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are no known drug interactions reported with Eloctate. No drug interactions studies have been performed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been conducted in animals with efmoroctocog alfa. It is not known whether Eloctate can affect fertility or sperm development in haemophilia A patients. Animal studies have not identified adverse effects in male or female reproductive organs following treatment with efmoroctocog alfa.
(Category C)
Animal reproductive studies have not been conducted with efmoroctocog alfa, however efmoroctocog alfa has been shown to cross the placenta in small amounts in a placental transfer study in mice.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breastfeeding is not available. It is not known whether Eloctate can affect reproductive capacity. Fc fusion products, including efmoroctocog alfa, may pass through the placenta. The effects on the developing foetus are unknown.
Eloctate should be used during pregnancy only if the potential benefit justifies the potential risk.
 Lactation studies have not been conducted with Eloctate. It is not known whether efmoroctocog alfa is excreted into human milk. Caution should be exercised if Eloctate is administered to nursing mothers. Eloctate should be used only if clinically indicated.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Previously treated patients (PTPs).

Eloctate has been evaluated in five completed studies (Study 1, 2, 3 and two pharmacokinetic studies) in PTPs with severe haemophilia A (< 1% endogenous FVIII activity or a genetic mutation consistent with severe haemophilia A). A total of 276 subjects have been treated with Eloctate. Sixty-nine (25.06%) were paediatric subjects < 12 years of age, 25 (9.1%) were adolescents (12 to < 18 years of age), and 182 (65.9%) were adults (18 years of age and older). There were 200 subjects treated for at least 104 weeks (2 years), 151 subjects treated for at least 156 weeks (3 years) and 107 subjects treated for at least 208 weeks (4 years). The total number of exposure days (EDs) was 80,848 with a median of 294 (range 1-735) EDs per subject. The subjects received a total of 80,024 injections with a median of 303.5 injections of Eloctate (range 1-755) per subject.
Adverse drug reactions (ADRs) are considered adverse events assessed as related to treatment with Eloctate.
ADRs were reported in 11 of 276 (4.0%) subjects treated with routine prophylaxis or episodic (on demand) therapy. The ADRs with an incidence ≥ 0.5% for Eloctate were arthralgia, malaise, myalgia, headache and rash. No serious ADRs were reported in subjects who received Eloctate. No age specific differences in ADRs were observed between paediatric and adult subjects. ADRs in PTPs are summarized in Table 3.
One (1) subject was withdrawn from a study due to an adverse drug reaction of rash. In the studies, no inhibitors were detected and no events of anaphylaxis were reported.

Previously untreated patients (PUPs).

Eloctate safety was also evaluated in 1 completed study (Study 4) in 103 subjects with severe haemophilia A (< 1% endogenous FVIII activity). At enrolment, the median age was 0.58 year (range: 0.02-4 years). Overall, the median number of weeks on treatment was 64.24 weeks (range: 0.0-206.8 weeks). The number of subjects with at least 10 exposure days (EDs) was 87 (84.5%), at least 20 EDs was 85 (82.5%), and at least 50 EDs was 81 (78.6%).
Adverse events were monitored for a total of 140.44 subject-years. ADRs were reported in 29 of 103 (28.2%) subjects treated with Eloctate. ADRs in PUPs are summarised in Table 4.

Immunogenicity.

No PTPs developed neutralising antibodies (inhibitors) to Factor VIII in clinical studies (Study 1, 2, 3 and two pharmacokinetic studies).
In Study 4 in PUPs, development of neutralising antibodies (inhibitors) was observed in 28 subjects, 14 of them had a high-titre inhibitor. Based on subjects with an inhibitor test following an exposure day (ED) milestone or who developed an inhibitor at any time during the study, the incidence of Factor VIII inhibitor development was:
28/90 subjects (31.11%) with at least 10 EDs;
28/86 subjects (32.56%) with at least 50 EDs.
The median time to inhibitor development for the 28 subjects was 9 EDs (interquartile range: 6.5-12).

Post marketing experience.

In postmarketing experience, the following adverse reactions have been reported: Factor VIII inhibitors development; hypersensitivity.

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

No symptoms of overdose have been reported. 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.

The factor VIII/von Willebrand factor (FVIII/VWF) complex consists of 2 molecules (FVIII and von Willebrand factor) with different physiological functions. Upon activation of the clotting cascade, FVIII is converted to activated FVIII (FVIIIa) and released from VWF. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X on phospholipid surfaces, and which ultimately converts prothrombin to thrombin and leads to the formation of a fibrin clot.
Haemophilia A is an X-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII activity and results in profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a result of accidental or surgical trauma. The FVIII portion of efmoroctocog alfa is a glycoprotein comparable to the 90 + 80 kDa form of endogenous FVIII that is found in human plasma. When injected, efmoroctocog alfa binds to von Willebrand factor in an individual's circulation, and replaces all functions of the missing FVIII.
Eloctate (efmoroctocog alfa) is a long-acting, fully recombinant fusion protein comprised of recombinant B domain-deleted human factor VIII (BDD FVIII) covalently linked to the Fc domain of human IgG1, and is produced by recombinant DNA technology.
The other portion of efmoroctocog alfa is the Fc region of human IgG1 that binds to the neonatal Fc receptor (FcRn). This receptor is expressed throughout life and is part of a naturally occurring pathway that protects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation, resulting in their long plasma half-life. Binding to FcRn delays lysosomal degradation and allow for longer plasma half-life of efmoroctocog alfa than endogenous FVIII.
Haemophilia A is a bleeding disorder characterised by a deficiency of functional clotting factor VIII (FVIII), which leads to a prolonged clotting time in the activated partial thromboplastin time (aPTT) assay, a conventional in vitro test for the biological activity of FVIII. Treatment with Eloctate normalises the clotting time over the effective dosing period.
Eloctate is used as a replacement therapy to increase plasma levels of factor VIII, thereby enabling a temporary correction of the factor deficiency and the bleeding tendency.

Clinical trials.

The safety, efficacy, and pharmacokinetics of Eloctate was evaluated in two multinational, open label, pivotal studies in PTPs; a phase 3 study in adults and adolescents (study 1) and a phase 3 paediatric study (study 2). Patients from these studies could subsequently enroll in the long-term extension study (study 3). The safety and efficacy of Eloctate was also evaluated in PUPs with severe haemophilia A (study 4).
Previously treated patients (PTPs).

Study 1.

Study 1 compared the efficacy of each of 2 prophylactic treatment regimens to episodic (on demand) treatment; determined haemostatic efficacy in the treatment of bleeding episodes; and determined haemostatic efficacy during perioperative management in subjects undergoing major surgical procedures.
The study enrolled a total of 165 previously treated male patients with severe haemophilia A (< 1% endogenous FVIII activity or a genetic mutation consistent with severe haemophilia A). PTPs were defined as those patients having at least 150 documented prior exposure days to any recombinant and/or plasma derived FVIII, and/or cryoprecipitate products, excluding fresh frozen plasma. Subjects were aged 12-65, including 13 adolescent subjects aged 12 to 17 years. Hepatitis C virus (HCV) status was positive in 82 of 165 (49.7%) subjects on study. Of the 165 enrolled subjects, 164 received at least 1 dose of Eloctate, and 163 were evaluable for efficacy. A total of 153 subjects (92.7%) completed the study.
Subjects on prophylaxis regimens prior to entering the study were assigned to the individualised prophylaxis arm. Those subjects on episodic (on demand) therapy prior to entry either entered the individualised prophylaxis arm or were randomised to the weekly prophylaxis or episodic (on demand) arms. Subjects requiring surgery could receive perioperative management (surgical prophylaxis) with Eloctate during the study. Subjects were followed for up to 54 weeks.
Of the 118 subjects enrolled in the individualised prophylaxis arm, 117 received Eloctate starting with a twice weekly regimen consisting of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The dose and interval were adjusted within the range of 25-65 IU/kg every 3-5 days to maintain trough between 1 and 3% above baseline or higher as clinically indicated to prevent bleeding. The median dosing interval was 3.51 days (interquartile range, 3.17, 4.43) and the median total weekly dose was 77.90 IU/kg (interquartile range 72.35, 91.20). For 112 subjects with ≥ 6 months on study, approximately 30% achieved a mean dosing interval of ≥ 5 days during the last three months on study. Subjects were on study for a median period of 32.1 weeks (range, 9, 54).
Twenty-four (24) subjects in the weekly prophylaxis arm were to receive 65 IU/kg of Eloctate once weekly. Twenty-three (23) subjects were evaluable for efficacy due to the withdrawal of one subject prior to entering the efficacy period. Subjects were on study for a median period of 28 weeks (range, < 1, 38).
Twenty-three (23) subjects in the episodic (on demand) arm received Eloctate as needed, for the treatment of bleeding episodes. Subjects were on study for a median period of 28.9 weeks (range, 15, 32).

Study 2.

Study 2 enrolled a total of 71 previously treated male paediatric patients with severe haemophilia A (< 1% endogenous FVIII activity or a genetic mutation consistent with severe haemophilia A). Of the 71 enrolled subjects, 69 received at least 1 dose of Eloctate and were evaluable for efficacy. Subjects were less than 12 years of age (35 were < 6 years of age and 34 were 6 to < 12 years of age).
Sixty-nine (69) subjects received Eloctate on an individualised prophylactic dose regimen starting with a twice weekly regimen consisting of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The dose could be adjusted within the range of 25-80 IU/kg with a minimum allowable interval of every 2 days to maintain trough between 1 and 3% above baseline or as clinically indicated to prevent bleeding. The median dosing interval was 3.49 days (interquartile range, 3.46 to 3.51 days) with no difference in the median dosing interval between age cohorts. 89.9% of subjects remained on a twice weekly interval. The median weekly dose of Eloctate for subjects < 6 years of age was 91.63 IU/kg (interquartile range, 84.72 to 104.56 IU/kg). For subjects in the 6 to < 12 years of age cohort, the median weekly dose was 86.88 IU/kg (interquartile range, 79.12 to 103.08 IU/kg).

Study 3.

Study 3 was an open-label, multicentre, long-term study in PTPs with haemophilia A who had completed Study 1, Study 2, or any other study. The study evaluated the long-term safety and efficacy of routine prophylaxis, on-demand treatment, and perioperative management with Eloctate. During the study, subjects could change treatment groups. Subjects < 12 years of age entering from another study were not offered weekly or on-demand treatment options until they reached 12 years of age.
The majority of subjects stayed on their treatment regimen throughout the extension study, with 21 subjects (22.6%) switching treatment regimens once or twice during the study. Fifteen subjects were part of the surgery subgroup.
Of the 240 subjects in Study 3 (aged 2-66), 190 subjects participated in the individualised prophylaxis arm. Subjects enrolled in individualised prophylaxis had dosing that was 25-65 IU/kg every 3 to 5 days, or dosing 2 times per week at 20 IU/kg to 65 IU/kg on Day 1 and 40-65 IU/kg on Day 4. In paediatric subjects, doses could be adjusted up to a maximum prophylactic dose of 80 IU/kg and the interval decreased to every 2 days, as clinically indicated to prevent bleeding.
Thirty-four (34) subjects received weekly prophylaxis during Study 3. Subjects on the weekly prophylaxis regimen received 65 IU/kg of Eloctate once weekly.
Twenty-six (26) subjects received the personalized prophylaxis regimen. Subjects were enrolled in the personalized prophylaxis regimen if optimal prophylaxis could not be achieved using either of the above options. Dosing of Eloctate was adjusted to meet the needs of individual subjects.
Thirteen (13) subjects received episodic (on-demand) treatment as needed, for the treatment of bleeding episodes. See Tables 5 and 6.
Previously untreated patients (PUPs).

Study 4.

Study 4 evaluated the safety and efficacy of Eloctate in prevention and treatment of bleeding episodes in PUPs. The study enrolled 108 PUPs < 6 years old with severe haemophilia A (< 1% endogenous FVIII activity), of whom 103 received at least one dose of Eloctate. At enrolment, the median age was 0.58 year (range: 0.02-4 years), 77.7% of subjects were < 1 year old, and median weight was 8.65 kg (range: 3.5-16.1 kg). Overall, the median number of weeks on Eloctate was 64.24 weeks (range: 0.0-206.8 weeks), including immune tolerance induction (ITI). The median number of weeks for the episodic treatment regimen was 23.57 weeks (range: 0.4-107.8 weeks) and for the prophylactic treatment regimen, the median number of weeks was 43.97 weeks (range: 0.0-96.6 weeks). Overall, the median number of EDs was 100 days (range: 0-649 days), including ITI.
Subjects could be treated episodically (optional), until a prophylactic regimen was initiated. Subjects who developed a high-titre inhibitor or select subjects with a low-titre inhibitor with poorly controlled bleeding were eligible to undergo the ITI regimen.
Eighty-nine PUPs received prophylaxis with Eloctate. The recommended initial dose on the prophylactic regimen was 25-80 IU/kg at 3-5-day intervals, with adjustments to dosing and dosing intervals based on pharmacokinetic data, levels of physical activity, and bleed patterns. For subjects on prophylaxis, the median average weekly dose was 101.4 IU/kg (range: 28.5-776.3 IU/kg) and the median dosing interval was 3.87 days (range: 1.1-7 days).
Efficacy in routine prophylaxis.

Study 1 (≥ 12 years).

Using a negative binomial model to calculate the annualized bleeding rate (ABR), there was a statistically significant reduction in annualised bleed rate (ABR) of 92% (p < 0.001, 95% CI: 87%, 95%) for subjects in the individualised prophylaxis arm and a statistically significant reduction of 76% (p < 0.001, 95% CI: 54%, 88%) for subjects in the weekly prophylaxis arm compared to the episodic (on demand) arm.
Fifty-three (53) of 117 (45.3%) subjects experienced no bleeding episodes while on individualised prophylaxis and 4 of 23 (17.4%) subjects experienced no bleeding episodes while on weekly prophylaxis.
A comparison of the median ABRs in subjects evaluable for efficacy is summarized in Table 7.

Study 2 (< 12 years).

For paediatric subjects, 32 (46.4%) experienced no bleeding episodes (18 subjects (51.4%) < 6 years of age and 14 subjects (41.2%) 6 to < 12 years of age). A comparison of the median ABRs in paediatric subjects evaluable for efficacy is summarized in Table 8.

Study 3 (extension study): (≥ 12 years).

For adult and adolescent subjects enrolled from Study 1, forty (40) subjects on prophylaxis had 0 bleeding episodes. Thirty-five of 110 subjects (31.8%) on individualised prophylaxis, 2 of 27 subjects (7.4%) on weekly prophylaxis, 3 of 21 subjects (14.3%) on personalised prophylaxis, and 3 of 13 subjects (23.1%) on episodic treatment had no bleeding episodes. A summary of the median ABRs in subjects evaluable for efficacy is summarised in Table 9.

< 12 years.

For paediatric subjects enrolled from Study 2, three (3) of 29 subjects (10.3%) on individualised prophylaxis had no bleeding episodes. A summary of the median ABRs in paediatric subjects evaluable for efficacy is summarised in Table 10.

Study 4.

A summary of the median (IQR) ABRs in PUPs evaluable for efficacy is presented in Table 11.
Immune tolerance induction (ITI). The use of Eloctate for ITI has been investigated in 15 PUPs who had developed inhibitors (12 with high-titre inhibitors and 3 with low-titre inhibitors). Among these 15 subjects, 5 subjects met the criteria for complete success (3 with low-titre and 2 with high-titre) and came off study. No subjects relapsed during ITI tapering or relapse monitoring. Two subjects had partial success, and 3 subjects (all with high-titre inhibitors) terminated ITI early due to lack of efficacy. Five subjects had ITI ongoing at the end of the study, including 1 subject who developed a recurrent positive inhibitor titre during ITI. There is experience from real world use of Eloctate for ITI.
Efficacy in control of bleeding.

Study 1 (≥ 12 years).

A total of 757 new bleeding events were observed during the study. Assessment of response to each injection was recorded by subjects at 8 to 12 hours post-treatment. A 4 point rating scale of excellent, good, moderate, and no response was used to assess response. Bleeding episodes are summarized in Table 12.

Study 2 (< 12 years).

A total of 86 new bleeding events were observed during the study. Assessment of response to each injection was recorded by subjects at 8 to 12 hours post-treatment. A 4 point rating scale of excellent, good, moderate, and no response was used to assess response. Bleeding episodes are summarised in Table 13.
The haemostatic efficacy in treatment of bleeds was rated as excellent or good in 89.4% of all evaluable injections and 92.6% for all evaluable first injections.

Study 3: adult and adolescent study (12 to 71 years).

A total of 757 bleeding events were observed in 106 subjects. The majority of the bleeding episodes were spontaneous and localised in joints. The median total dose to treat a bleeding episode was 27.35 IU/kg (interquartile range: 22.73-32.71). Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. Efficacy in control of bleeding episodes in subjects over 12 is summarised in Table 14.

Paediatric study (1 to 11 years).

A total of 86 bleeding events were observed by 69 subjects during the study. Assessment of response to each injection was recorded by subjects at 8 to 12 hours post treatment. Efficacy in control of bleeding episodes in subjects < 12 years old is summarised in Table 15.

Study 4.

A summary of efficacy in control of bleeding in PUPs is presented in Table 16.
Efficacy in perioperative management (surgical prophylaxis).

Major surgeries.

Haemostasis was evaluated in forty-eight (48) surgeries in thirty-four (34) subjects from Study 1 and Study 3. There was 1 major surgery evaluated in the paediatric study (Study 2) and 2 major surgeries evaluated during the pharmacokinetic studies. Thirty-nine (39) surgeries (81.3%) required a single injection of rFVIIIFc to maintain haemostasis.
Haemostatic response was assessed in forty-four (44) major surgical procedures in thirty-one (31) subjects. Nine (9) major surgical procedures were performed in nine subjects in study 1. In an extension study, a total of 35 major surgical procedures were assessed for haemostatic response in 23 subjects. The investigators postoperatively assessed haemostasis using a 4 point scale of excellent, good, fair, and poor/none. The haemostatic response was rated as excellent or good in 100% of major surgeries.
Haemostatic response to dosing during surgery and postoperatively for Study 1 and Study 3 is summarized in Table 17.

Minor surgeries.

A haemostatic assessment of 69 minor surgical procedures in 58 subjects was conducted with a 100% excellent or good response in Study 1, Study 2, and Study 3.
In study 2, a total of 7 minor surgeries were performed in 7 paediatric subjects (2 surgeries in the < 6 years of age cohort and 5 in the 6 to < 12 years of age cohort). Minor surgeries included port removal, port placement, dental extraction, colonoscopy, and endoscopy. An investigator's assessment of haemostasis was collected at least 24 hours following surgery. Haemostasis was rated as excellent for 5 minor surgeries and as good for 2 minor surgeries.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of Eloctate (rFVIIIFc) versus Advate (octocog alfa) (rFVIII) was evaluated following a 10 minute IV infusion in 28 evaluable subjects (≥ 15 years) in study 1. The subjects underwent a washout period of at least 96 hours (4 days) prior to receiving a single dose of 50 IU/kg of Advate. PK sampling was conducted predose followed by assessments at 6 time points up to 72 hours (3 days) postdose. Following a washout period of 96 hours (4 days), the subjects received a single dose of 50 IU/kg of Eloctate. PK samples were collected predose and then subsequently at 7 time points up to 120 hours (5 days) postdose. A repeat PK evaluation of Eloctate was conducted at week 14.
Pharmacokinetic parameters for Eloctate were estimated based on the plasma FVIII activity over the time profile (see Figure 1) based on a one stage clotting assay. For Eloctate, the maximum activity (Cmax) was observed following the end of the infusion. The geometric mean increase in circulating FVIII activity from preinfusion level was 2.24 IU/dL per IU/kg and the elimination half-life was 19 hours. The 1.5-fold prolongation of half-life for Eloctate relative to Advate was consistent across subjects over the range of half-lives. The Eloctate PK profile was stable over repeated dosing as shown by comparable PK parameters at week 14.
A summary of PK parameters after a 50 IU/kg dose for Eloctate and Advate are presented in Table 18.

Paediatric pharmacokinetics.

Pharmacokinetic (PK) parameters of Eloctate (rFVIIIFc) were determined for adolescents 12 to less than 18 years of age in study 1 and for children less than 12 years of age in study 2 (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
PK parameters were evaluated following a 10 minute IV infusion in 11 evaluable adolescents who received a single dose of Eloctate. PK samples were collected predose and then at multiple time points up to 120 hours (5 days) postdose. In a separate study, PK parameters were evaluated following a 5 minute IV infusion in 54 evaluable children (less than 12 years of age) who received a single dose of Eloctate. PK samples were collected predose and then at multiple time points up to 72 hours (3 days) postdose. PK parameters for Eloctate were estimated based on the plasma FVIII activity over time profile. A post hoc analysis in paediatric subjects on previous Advate therapy (n = 15) demonstrated that half-life prolongation of Eloctate relative to Advate (approximately 1.5-fold) is consistent with adult and adolescent subjects.
Table 19 presents the PK parameters calculated from the paediatric data of 65 subjects less than 18 years of age. Compared to adults and adolescents clearance appeared to be higher and half-life appeared to be shorter in children less than 12 years of age. This may result in a need for dose adjustments in children less than 12 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Population pharmacokinetics.

A population PK model was developed based on FVIII activity data from 249 subjects of all ages (≤ 65 years of age) and weighing between 13.4 kg and 132.4 kg in three clinical studies (16 subjects in a phase 1/2a study, 164 subjects in study 1, and 69 subjects in study 2). The population estimate for the typical CL and steady-state volume of distribution of Eloctate are 1.56 dL/h and 35.7 dL, respectively. The model was used to predict the activity time profile following a single dose of Eloctate in patients with severe haemophilia A (see Table 20, see Table 21, see Table 22). In addition the model was used to predict trough activity for three different prophylaxis regimens (see Table 23).
A dosing regimen of 50 IU/kg every 5 days is predicted to yield troughs above 1 IU/dL in 42.6% of individuals ≥ 12 years of age.
Eloctate has been evaluated in 249 male haemophilia A PTPs ≤ 65 years of age and weighing between 13.4 kg and 132.4 kg. Bodyweight, a surrogate for age, affected clearance and volume of distribution. After accounting for weight, age did not impact PK.
No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on Eloctate disposition.
Race and ethnicity have no observed effect on the pharmacokinetics of Eloctate.

5.3 Preclinical Safety Data

Genotoxicity.

Efmoroctocog alfa has not been evaluated in mutagenicity or chromosomal aberration assays since it is a replacement protein factor for coagulation.

Carcinogenicity.

No animal studies investigating carcinogenicity effects of efmoroctocog alfa have been conducted since it is a replacement factor for coagulation activity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder.

Sucrose; sodium chloride; histidine; calcium chloride dihydrate; polysorbate 20.

Solvent.

Water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

4 years. The expiry date can be found on the packaging.

Reconstituted solution.

The reconstituted product can be stored at room temperature (up to 30°C) for 6 hours. Protect product from direct sunlight. If product is not used within 6 hours, it must be discarded. The appearance of the reconstituted product should be clear to slightly opalescent and colourless.

6.4 Special Precautions for Storage

Protect from light. Unopened vials should be stored under controlled refrigeration (2°C - 8°C). Do not freeze.
The product may be stored at room temperature (up to 30°C) for a single 6 month period. The date that the product is removed from refrigeration should be noted on the carton. The product must be used or discarded before the end of this period.
Eloctate does not contain any preservative or antimicrobial agent and is for use in one patient on one occasion only.
Dispose of all the materials in accordance with local requirements.
For storage conditions of the reconstituted medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

A powder vial (type 1 glass) with a stopper (butyl) and a flip-off seal (aluminium), 3 mL solvent in a pre-filled syringe (type 1 glass) with a plunger stopper (butyl), a tip-cap (butyl), and a sterile vial adapter reconstitution device. Eloctate is available in 5 vial sizes - 250 IU, 500 IU, 1000 IU, 2000 IU and 3000 IU. Actual factor VIII activity in International Units is stated on the label of each Eloctate carton and vial.
3 mL diluent in a pre-filled syringe (type I glass) with a plunger stopper (butyl), a tipcap (butyl), and a sterile vial adaptor reconstitution device.

Pack size.

1 vial with powder; 1 pre-filled syringe with solvent; 1 vial adapter.

6.6 Special Precautions for Disposal

Any unused medicine should be disposed of by taking to your local pharmacy. The syringe and needle cap should be disposed of in a sharps container.

6.7 Physicochemical Properties

Eloctate (efmoroctocog alfa) (rhu) is a long-acting, fully recombinant fusion protein consisting of a human coagulation factor VIII (FVIII) covalently linked to the Fc domain of human immunoglobulin G1 (IgG1). The factor VIII portion of efmoroctocog alfa has a primary amino acid sequence and post-translational modifications that are comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted). The Fc domain of efmoroctocog alfa contains the hinge, CH2 and CH3 regions of IgG1. Efmoroctocog alfa contains 1890 amino acids with an apparent molecular weight of approximately 220 kilodaltons.

CAS number.

1270012-79-7.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes