Consumer medicine information

Hemlibra

Emicizumab

BRAND INFORMATION

Brand name

Hemlibra

Active ingredient

Emicizumab

Schedule

What is in this leaflet

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

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

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

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

What Hemlibra is used for

Hemlibra is used for routine prophylaxis in children, adolescents and adults with haemophilia A. This means it prevents bleeding or reduces the number of bleeding episodes. Hemlibra can be used for routine prophylaxis whether or not you have inhibitors to factor VIII.

Hemlibra contains the active substance emicizumab. This belongs to a group of medicines called monoclonal antibodies. Monoclonal antibodies are a type of protein that recognises and binds to a target in the body.

Haemophilia A is a bleeding condition present at birth, which is caused by missing or faulty factor VIII. Factor VIII is a blood clotting protein and blood does not clot normally when factor VIII is missing or not working properly.

Inhibitors to factor VIII develop in some people with haemophilia A after repeated use of factor VIII to prevent or treat bleeding. Inhibitors stop replacement factor VIII from working.

Hemlibra works like factor VIII, by binding to the same clotting factors, which helps your blood to clot. However, because emicizumab is different to factor VIII, it works whether or not inhibitors are present.

This medicine is used to prevent bleeding or reduce the number of bleeding episodes in people with haemophilia A ("routine prophylaxis"). It is not to be used "on-demand" to treat bleeds once they occur.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. This medicine is available only with a doctor's prescription.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you use Hemlibra

When you must not use it

Do not use Hemlibra if you have an allergy to:

emicizumab
any of the ingredients listed at the end of this leaflet
any other proteins that are of hamster origin.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

If you are on routine prophylaxis with another agent before changing to Hemlibra:

you must stop prophylaxis with bypassing agents the day before starting Hemlibra
you may continue prophylaxis with factor VIII for the first 7 days of treatment with Hemlibra

If you have haemophilia A with inhibitors, it is very important you talk to your doctor about when and how to use bypassing agents to treat bleeds while using Hemlibra.

Examples of bypassing agents include FEIBA-NF® and NovoSeven® RT.

Hemlibra increases the ability of your blood to clot. Therefore, the dose of bypassing agent or factor VIII needed to treat bleeds may be lower than the dose you used prior to starting Hemlibra (see "Using other medicines"). Your doctor will advise you.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start using Hemlibra.

Using other medicines

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

Some medicines and Hemlibra may interfere with each other. These include:

FEIBA-NF, factor VIII inhibitor bypassing fraction (also known as activated prothrombin complex concentrate, aPCC)
Any other blood product, including:
- NovoSeven®, recombinant coagulation factor VIIa (also known as activated factor VII or eptacog alfa)
- Any form of factor VIII

These medicines may be affected by Hemlibra or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Be aware there are serious and potentially life-threatening side effects of using FEIBA-NF while receiving Hemlibra.

Avoid using FEIBA-NF unless no other treatment options are available. However, if FEIBA-NF is required, talk to your doctor about how much to use. Do not use more than 50 units/kg of FEIBA-NF except under medical supervision.

Serious side effects were reported when FEIBA-NF was used in patients also receiving Hemlibra in a clinical trial (see 'Side Effects').

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use Hemlibra

Treatment with Hemlibra should be started under the supervision of a specialist doctor experienced in the treatment of haemophilia A.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your haemophilia doctor or nurse for help.

Each time you use Hemlibra, record the name and batch number of the medicine.

How much to use

The dose of Hemlibra is dependent on your weight and frequency of injection. Your haemophilia doctor or nurse will tell you how much to inject.

Weeks 1 to 4: The dose is 3 milligrams for every 1 kilogram you weigh, injected once a week
Week 5 and onwards: The dose will depend on whether you will continue to inject Hemlibra once a week or change to once every 2 weeks or once every 4 weeks.

How to inject

Hemlibra is given by injection under the skin (subcutaneously).

Your doctor or nurse will show you and/or your caregiver how to inject Hemlibra.

Also refer to the Instructions for Use provided in the box. The Instructions for Use describe how to prepare and administer an injection of Hemlibra.

Do not attempt self-injection until you are sure of how to do it. Once you and/or your caregiver have been trained, you should be able to inject this medicine at home, by yourself or with the help of a caregiver.

If a child would like to self-inject the medicine, the child’s healthcare provider and the parent or caregiver should agree on whether it is appropriate for them to do so.

Self-injection for children below the age of 7 years is not recommended.

Before using the medicine, check the solution for particles or discolouration. The solution should be colourless to slightly yellow. Do not use this medicine if you notice that it is cloudy, discoloured, or contains visible particles.

Do not inject Hemlibra into a vein or muscle. To correctly insert the needle under the skin, pinch a fold of loose skin at the clean injection site with your free hand. Pinching the skin is important to ensure that you inject under the skin (into fatty tissue) but not any deeper (into muscle). Injecting into a muscle could result in an uncomfortable injection.

Prepare and give the injection under clean and germ-free conditions using "aseptic technique".

A syringe, a transfer needle with filter and an injection needle are needed to withdraw Hemlibra solution from the vial into the syringe and inject it under the skin. Syringes, transfer needles and injection needles are supplied separately to the medicine.

Make sure that you use a new injection needle for each injection and dispose of it after a single use.

Use a 1 mL syringe to inject up to 1 mL of Hemlibra solution. Use a 2-3 mL syringe to inject greater than 1 mL and up to 2 mL of Hemlibra solution.

You will be given more information about this by your haemophilia doctor or nurse.

Where to inject

Your haemophilia doctor or nurse will show you and/or your caregiver which areas of the body should be injected with Hemlibra.

Only give an injection in the recommended places. The recommended places to inject yourself are: the front of the waist (lower abdomen) or the front of the thighs. If you have a caregiver, they can also inject Hemlibra into your upper outer arms.

Each time you inject, use a different recommended injection site.

Do not give injections where the skin is red, bruised, tender, hard, or areas where there are moles or scars.

When using Hemlibra, other medicines injected under the skin should be given in a different area.

Following these recommendations will help reduce the risk of injection site reactions (see Side Effects).

How long to use it

Continue using your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep using your medicine even if you feel well.

If you forget to use it

If you forget your scheduled injection, inject the forgotten dose as soon as possible before the day of the next scheduled dose. Then, continue to inject the medicine as scheduled.

Do not inject a double dose on the same day to make up for a forgotten dose. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your haemophilia doctor or nurse.

If you have trouble remembering to use your medicine, ask your haemophilia doctor or nurse for some hints.

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much Hemlibra.

Do this even if there are no signs of discomfort or poisoning. This is because you may be at risk of developing side effects such as blood clots. You may need urgent medical attention.

While you are using Hemlibra

Things you must do

If you have haemophilia A with inhibitors, follow carefully your doctor's instructions about the use of bypassing agents when using Hemlibra. These may differ from before you started using Hemlibra.

If you are using bypassing agents, be aware of the possible symptoms of thrombotic microangiopathy (TMA) and blood clots which have occurred after use of FEIBA-NF in people receiving Hemlibra. Possible symptoms of TMA and blood clots are listed under 'Side Effects'.

If you are about to have any coagulation blood tests, tell your doctor that you are using this medicine. The presence of Hemlibra in the blood may interfere with some coagulation tests, leading to inaccurate results. Your doctor may need to do different tests which are not affected by Hemlibra.

Talk to your doctor immediately if you or your caregiver feels Hemlibra is no longer helping your condition (e.g. if you notice an increase in bleeds). Your doctor will try to understand what is causing this. It is uncommon, but it might mean that you have developed antibodies to Hemlibra, which caused Hemlibra to stop working. If Hemlibra is no longer helping, a change to your haemophilia treatment may be required.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

Always carry with you your Patient Alert Card. The card contains important information about your treatment. It will alert other healthcare professionals that you are being treated with Hemlibra and that special measures are needed with the use of bypassing agents and laboratory tests.

If you become pregnant while using this medicine, tell your doctor.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will check to make sure the medicine is working and discuss any unwanted side effects.

Things you must not do

Do not use Hemlibra to treat any other complaints unless your doctor tells you to.

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

Do not stop using your medicine or lower the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Hemlibra. This medicine helps most people with haemophilia A, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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

redness, itching, pain in the area the injection was given
headache
fever
joint pain
muscle aches
diarrhoea

The above list includes the more common side effects of Hemlibra.

Uncommonly, serious side effects have been reported when FEIBA-NF was used in patients with inhibitors also receiving Hemlibra:

Thrombotic microangiopathy (TMA) - a serious and potentially life-threatening condition where the lining of the blood vessels is damaged resulting in clots in small blood vessels. In some cases, this can cause damage to the kidneys and/or other organs.
Blood clots - blood clots may form. In rare cases, a blood clot can block a blood vessel and may be life-threatening.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

Confusion, weakness, swelling of arms and legs, yellowing of skin and eyes, abdominal or back pain, feeling sick (nausea), being sick (vomiting) or urinating less - may be signs of thrombotic microangiopathy (TMA)
Swelling, warmth, pain or redness - may be signs of a blood clot in a vein near the surface of the skin.
Headache, numbness in your face, eye pain or swelling or vision impairment - may be signs of a blood clot in a vein behind your eye.
Blackening of the skin - may be a sign of severe damage to the skin tissue.

Stop using Hemlibra and FEIBA-NF and talk to a doctor immediately if you or your caregiver notices any of the side effects listed above.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are uncommon.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using Hemlibra

Storage

Keep the vial in the box until it is time to use it. If you take the vial out of the box it may not keep well.

Keep Hemlibra in a refrigerator where the temperature is between 2°C to 8°C and it is not exposed to light.

Do not shake the vial and do not put it in the freezer.

Unopened vials may be kept at room temperature (below 30°C) for up to 7 days. After storage at room temperature, unopened vials may be returned back to the refrigerator. The total length of time the medicine is stored at room temperature should not be more than 7 days.

Do not use your medicine if it has been out of the refrigerator for more than 7 days or if the expiry date has passed.

Take the vial out of the refrigerator 15 minutes before use and allow it to reach room temperature before preparing an injection. Use Hemlibra straight away after transferring it from the vial to the syringe.

Do not refrigerate the solution in the syringe.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Dispose of used vials, needles, vial/ needle caps and used syringes in a sharps/puncture-proof container.

Product description

What it looks like

Hemlibra is a colourless to slightly yellow solution in single-use, clear glass vials containing emicizumab:

30 mg in 1 mL
60 mg in 0.4 mL
105 mg in 0.7 mL
150 mg in 1 mL

Each pack contains 1 vial.

Ingredients

Hemlibra contains emicizumab as the active ingredient. It also contains:

arginine
histidine
poloxamer
aspartic acid
water for injections

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Manufacturer

Hemlibra is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Numbers:

30 mg/1 mL: AUST R 293761
60 mg/0.4 mL: AUST R 293760
105 mg/0.7 mL: AUST R 293758
150 mg/1 mL: AUST R 293759

This leaflet was prepared on 19 May 2022.

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Hemlibra

Active ingredient

Emicizumab

Schedule

1 Name of Medicine

Emicizumab.

2 Qualitative and Quantitative Composition

Hemlibra 30 mg/1 mL solution for injection.

Each vial of 1 mL contains 30 mg of emicizumab at a concentration of 30 mg/mL.

Hemlibra 60 mg/0.4 mL solution for injection.

Each vial of 0.4 mL contains 60 mg of emicizumab at a concentration of 150 mg/mL.

Hemlibra 105 mg/0.7 mL solution for injection.

Each vial of 0.7 mL contains 105 mg of emicizumab at a concentration of 150 mg/mL.

Hemlibra 150 mg/1 mL solution for injection.

Each vial of 1 mL contains 150 mg of emicizumab at a concentration of 150 mg/mL.
Emicizumab is a humanised monoclonal modified IgG4 antibody with a bispecific antibody structure bridging factor IXa and factor X produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Solution for subcutaneous injection in single-use colourless glass vials.
Colourless to slightly yellow solution, adjusted to pH 6.0.

4 Clinical Particulars

4.1 Therapeutic Indications

Hemlibra is indicated for routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in adult and paediatric patients with haemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors.

4.2 Dose and Method of Administration

Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and/or bleeding disorders.
Treatment with bypassing agents should be discontinued the day before starting Hemlibra therapy (see Section 4.4). Factor VIII (FVIII) prophylaxis may be continued for the first 7 days of treatment with Hemlibra.

Dose.

The recommended loading dose is 3 mg/kg administered as a subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose from week 5, administered subcutaneously either: 1.5 mg/kg once weekly; or 3 mg/kg every two weeks; or 6 mg/kg every four weeks.
The maintenance dose should be selected based on physician and patient/caregiver dosing regimen preference to support adherence.
Duration of treatment. Hemlibra is intended for long-term prophylactic treatment.
Dosage adjustments during treatment. No dosage adjustments of Hemlibra are recommended.
Delayed or missed doses. If a patient misses a scheduled subcutaneous injection of Hemlibra, the patient should be instructed to take the missed dose as soon as possible before the day of the next scheduled dose. The patient should then administer the next dose on the usual scheduled dosing day. The patient should not take two doses on the same day to make up for a missed dose.
Special populations.

Paediatric populations.

No dose adjustments are recommended in paediatric patients. Currently available data are described in Section 5.1 and Section 5.2.

Elderly.

No dose adjustments are recommended in patients ≥ 65 years of age (see Section 4.4; Section 5.2).

Renal impairment.

No dose adjustments are recommended in patients with renal impairment (see Section 4.4; Section 5.2).

Hepatic impairment.

No dose adjustments are recommended in patients with hepatic impairment (see Section 4.4; Section 5.2).

Method of administration.

Hemlibra is a sterile, preservative-free, and ready to use solution that does not need to be diluted. Hemlibra is for subcutaneous use only.
The product is for single use in one patient only. Discard any residue. Once transferred from the vial to the syringe, the medicinal product should be used immediately since it does not contain any antimicrobial preservative.
Hemlibra should be administered using appropriate aseptic technique (see 'Instructions for handling'). The injection should be restricted to the recommended injection sites: the abdomen, the upper outer arms and the thighs (see Section 5.2). No data are available on injection at other sites of the body. Administration of Hemlibra subcutaneous injection in the upper outer arm should be performed by a caregiver or healthcare professional.
Alternating the site of injection may help prevent or reduce injection site reactions (see Section 4.8). Hemlibra subcutaneous injection should not be administered into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.
During treatment with Hemlibra, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites.
Administration by the patient and/or caregiver. Hemlibra is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient may self-inject Hemlibra, or the patient's caregiver may administer Hemlibra, if their physician determines that it is appropriate.
The physician and the caregiver should determine the appropriateness of a child self-injecting Hemlibra. However, self-administration is not recommended for children below 7 years of age.
Instructions for handling. Hemlibra is a colourless to slightly yellow solution. Hemlibra solution should be inspected visually to ensure there is no particulate matter or discolouration prior to administration. Hemlibra solution should be discarded if particulate matter is visible or the product is discoloured.
A syringe, a transfer needle or a vial adapter and an injection needle are needed to withdraw Hemlibra solution from the vial and inject it subcutaneously.
Please see below the selection criteria for the recommended device options.
A 1 mL syringe should be used for an injection up to 1 mL of Hemlibra solution. Administer doses of Hemlibra greater than 1 mL and up to 2 mL with a 2 mL to 3 mL syringe.
Refer to the Hemlibra 'Instructions for Use' for handling instructions when combining vials in a syringe. Do not combine different Hemlibra vial concentrations (30 mg/mL and 150 mg/mL) in a single injection to administer the prescribed dose.
Recommended criteria for syringes and needles are defined to ensure correct and safe administration of Hemlibra. These criteria are based on handling considerations (e.g. dosing accuracy, subcutaneous injection), Hemlibra characteristics (e.g. viscosity), and compatibility between Hemlibra and device materials.

1 mL syringe.

Criteria: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (in case not locally available, a syringe with Luer Slip tip can be used), graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic. When used together with a vial adapter, a syringe with Low Dead Space (LDS) plunger fulfilling the above criteria must be used.

2 to 3 mL syringe.

Criteria: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip (in case not locally available, a syringe with Luer Slip tip can be used), graduation 0.1 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic. When used together with a vial adapter, a syringe with LDS plunger fulfilling the above criteria must be used.

Transfer needle with filter.

Criteria: Stainless steel with Luer-Lock connection (in case not locally available, a needle with Luer Slip connection can be used), sterile, gauge 18 G, length 25 to 40 mm, blunt or single-bevel (or semi-blunt tip), single-use, latex-free, containing a 5 micrometre filter and non-pyrogenic, OR

Vial adapter with filter.

Criteria: Polypropylene with Luer-Lock connection, sterile, integrating a 5 micrometre filter, fitting 15 mm vial neck outer diameter, single-use, latex-free and non-pyrogenic.

Injection needle.

Criteria: Stainless steel with Luer-Lock connection (in case not locally available, an injection needle with Luer Slip connection can be used), sterile, gauge 26 G (acceptable range: 25 G to 27 G), length preferably 9 mm or maximally 13 mm, single-use, latex-free and non-pyrogenic, preferably including needle safety feature.
The following procedures should be strictly adhered to regarding the use and disposal of syringes:
Needles, syringes and vial adapter should never be reused.
Place all used needles, syringes, caps, vials and vial adapters into a sharps container (puncture-proof disposable container).

4.3 Contraindications

Hemlibra is contraindicated in patients with known hypersensitivity to emicizumab or to any of the excipients, or to patients with known hypersensitivity to hamster-derived proteins.

4.4 Special Warnings and Precautions for Use

In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded in the patient's medical record. Advise patients/caregivers to record the batch number of the product whenever Hemlibra is administered outside of a healthcare setting.

Thrombotic microangiopathy associated with Hemlibra and aPCC.

Cases of thrombotic microangiopathy (TMA) were reported from a clinical trial in patients receiving Hemlibra prophylaxis when on average a cumulative amount of > 100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more (see Section 4.8). Treatment for the TMA events included supportive care with or without plasmapheresis and haemodialysis. Evidence of improvement was seen within one week following discontinuation of aPCC. This rapid clinical improvement is distinct from the usual clinical course observed in atypical haemolytic uremic syndrome and classic TMAs, such as thrombotic thrombocytopenic purpura (see Section 4.8).
In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for 'Guidance on the use of bypassing agents in patients receiving Hemlibra prophylaxis'.
Patients receiving Hemlibra prophylaxis should be monitored for the development of TMA when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of TMA on a case-by-case basis.

Thromboembolism associated with Hemlibra and aPCC.

Thrombotic events were reported from a clinical trial in patients receiving Hemlibra prophylaxis when on average a cumulative amount of > 100 U/kg/24 hours of aPCC was administered for 24 hours or more. No cases required anticoagulation therapy, which is distinct from the usual treatment of thrombotic events. Evidence of improvement or resolution was seen after discontinuation of aPCC (see Section 4.8).
In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for 'Guidance on the use of bypassing agents in patients receiving Hemlibra prophylaxis'.
Patients receiving Hemlibra prophylaxis should be monitored for the development of thromboembolism (TE) when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms, imaging, and/or laboratory findings consistent with thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of thrombotic events on a case-by-case basis.

Guidance on the use of bypassing agents in patients receiving Hemlibra prophylaxis.

Treatment with bypassing agents should be discontinued the day before starting Hemlibra therapy.
Physicians should discuss with all patients and/or caregivers the exact dose and schedule of bypassing agents to use, if required while receiving Hemlibra prophylaxis.
Hemlibra increases the patient's coagulation potential. The bypassing agent dose required may therefore be lower than that used without Hemlibra prophylaxis. The dose and duration of treatment with bypassing agents will depend on the location and extent of bleeding and on the patient's clinical condition.
Avoid use of aPCC unless no other treatment options/alternatives are available. If aPCC is indicated in a patient receiving Hemlibra prophylaxis, the initial dose should not exceed 50 U/kg. If bleeding is not controlled with the initial dose of aPCC up to 50 U/kg, additional aPCC doses should be administered under medical guidance or supervision, and the total aPCC dose should not exceed 100 U/kg in the first 24 hours of treatment. Treating physicians must carefully weigh the risk of TMA and TE against the risk of bleeding when considering aPCC treatment beyond a maximum of 100 U/kg in the first 24 hours.
In pooled phase III clinical trials, there were 82 instances of aPCC treatment in patients receiving Hemlibra prophylaxis, of which eight instances (9.8%) consisted of on average a cumulative amount of > 100 U/kg/24 hours of aPCC for 24 hours or more. Two of the eight instances were associated with thrombotic events and three of the eight instances were associated with TMA (Table 1). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Of all instances of aPCC treatment, 68% consisted of a single infusion ≤ 100 U/kg.

In clinical trials, no cases of TMA or thrombotic events were observed with use of activated recombinant human factor VII (rFVIIa) alone in patients receiving Hemlibra prophylaxis.
Bypassing agent dosing guidance should be followed for at least 6 months following discontinuation of Hemlibra prophylaxis (see Section 5.2).

Immunogenicity.

Anti-emicizumab antibodies have been reported in a small number of patients treated with Hemlibra in clinical trials. Most patients found to have anti-emicizumab antibodies did not experience a change in emicizumab plasma concentrations or an increase in bleeding events; however, in uncommon (≥ 1/1,000 to < 1/100) cases, the presence of neutralizing anti-emicizumab antibodies with decreasing emicizumab concentration may be associated with loss of efficacy (see Section 4.8; Section 5.1).
In case of clinical signs of loss of efficacy (e.g. increase in breakthrough bleeding events), prompt evaluation by a physician should be sought to assess the etiology and a possible change in treatment should be considered.

Use in hepatic impairment.

The safety and efficacy of Hemlibra have not been specifically tested in patients with hepatic impairment. Patients with mild and moderate hepatic impairment were included in clinical trials. No data are available on the use of Hemlibra in patients with severe hepatic impairment. Hemlibra is a monoclonal antibody and is cleared via catabolism rather than by hepatic metabolism and a change in dose is not expected to be required for patients with hepatic impairment.

Use in renal impairment.

The safety and efficacy of Hemlibra have not been specifically tested in patients with renal impairment. There are limited data available on the use of Hemlibra in patients with mild to moderate renal impairment. No data are available on the use of Hemlibra in patients with severe renal impairment (see Section 5.2). Hemlibra is a monoclonal antibody and is cleared via catabolism rather than by renal excretion and a change in dose is not expected to be required for patients with renal impairment.

Use in the elderly.

The safety and efficacy of Hemlibra have not been specifically tested in a geriatric population. Clinical studies of Hemlibra included 13 patients aged 65 and over. Relative bioavailability decreased with older age, but no clinically important differences were observed in the pharmacokinetics of emicizumab between patients < 65 years and patients ≥ 65 years (see Section 5.2).

Paediatric use.

The safety and efficacy of Hemlibra have been established in paediatric patients. Use of Hemlibra in paediatric patients with haemophilia A (with or without FVIII inhibitors) is supported by two randomised studies and two single-arm studies (see Section 5.1).
All clinical trials included paediatric patients in the following age group: 47 adolescents (12 years to < 18 years). Only HAVEN 2 included paediatric patients in the following age groups: 55 children (2 years to < 12 years) and 5 infants and toddlers (14 months to < 2 years). Safety and efficacy results were consistent with those observed for adults (see Section 4.2; Section 5.1).
The steady-state plasma trough concentrations of emicizumab were comparable in adult and paediatric patients older than 6 months at equivalent weight-based doses. Lower concentrations of emicizumab were predicted in paediatric patients less than 6 months old (see Section 5.2).

Effects on laboratory tests.

Emicizumab restores the tenase cofactor activity of missing activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting, including the activated clotting time (ACT), activated partial thromboplastin time (e.g. aPTT) and all assays based on aPTT, such as one-stage FVIII activity, measure the total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway-based tests will yield overly shortened clotting times with Hemlibra, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single-factor assays based on aPTT, such as the one-stage FVIII activity assay (see Table 2). However, single-factor assays utilising chromogenic or immuno-based methods are unaffected by Hemlibra and may be used to monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below.
Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to Hemlibra but may overestimate the clinical haemostatic potential of Hemlibra. In contrast, assays containing bovine coagulation factors are insensitive to Hemlibra (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti-FVIII inhibitors.
Hemlibra remains active in the presence of inhibitors against FVIII and so will produce a false-negative result in clotting-based Bethesda assays for functional inhibition of FVIII. Instead, a chromogenic Bethesda assay utilising a bovine-based FVIII chromogenic test that is insensitive to Hemlibra may be used. Laboratory tests affected and unaffected by Hemlibra are shown in Table 2.
In summary, intrinsic pathway clotting-based laboratory test results in patients treated with Hemlibra should not be used to monitor Hemlibra activity, determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitor titres.
Due to the long half-life of Hemlibra, effects on coagulation assays may persist for up to 6 months after the last dose (see Section 5.2).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No adequate or well-controlled drug-drug interaction studies have been conducted with Hemlibra.
Clinical experience suggests that a drug interaction exists with Hemlibra and aPCC (see Section 4.4; Section 4.8).
There is a possibility for hypercoagulability with rFVIIa or FVIII with Hemlibra based on preclinical experiments. Emicizumab increases coagulation potential, therefore the coagulation factor dose required to achieve haemostasis may be lower than when used without Hemlibra prophylaxis.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Conventional fertility studies have not been performed with emicizumab. In general toxicity studies, no changes in the reproductive organs of male or female cynomolgus monkeys to suggest adverse effects on fertility were observed with emicizumab at subcutaneous doses of up to 30 mg/kg/week (yielding 11 times the plasma AUC in patients at the maximum recommended human dose) and at intravenous doses of up to 100 mg/kg/week (20 times the maximum clinical systemic exposure).
(Category B2)
There are no clinical studies of Hemlibra use in pregnant women. Animal reproduction studies have not been conducted with emicizumab. It is not known whether Hemlibra can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. As an IgG antibody, placental transfer of emicizumab is expected, increasing as pregnancy progresses. Hemlibra should be used during pregnancy only if the potential benefit for the mother outweighs the potential risk to the fetus.

Labour and delivery.

The safe use of Hemlibra during labour and delivery has not been established.
It is not known whether emicizumab is excreted in human milk. No studies have been conducted to assess the impact of emicizumab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered, along with the mother's clinical need for Hemlibra and any potential adverse effects on the breastfed infant from Hemlibra or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

There is no evidence that treatment with Hemlibra results in an increase in adverse reactions that might lead to the impairment of the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The following adverse drug reactions (ADRs) are based on pooled data from four phase III clinical trials (three adult and adolescent studies [HAVEN 1, HAVEN 3 and HAVEN 4] and one paediatric study [HAVEN 2]). A total of 373 male patients with haemophilia A received at least one dose of Hemlibra as routine prophylaxis in these studies. Two hundred and sixty-six patients (71%) were adults (≥ 18 years), 47 (13%) were adolescents (≥ 12 to < 18 years), 55 (15%) were children (≥ 2 to < 12 years) and 5 (1%) were infants and toddlers (≥ 14 months to < 2 years). The median duration of exposure across the studies was 34.1 weeks (range: 0.1 to 94.3 weeks).
Three patients (0.8%) in the pooled phase III clinical trials receiving Hemlibra prophylaxis withdrew from treatment due to ADRs, which were thrombotic microangiopathy, skin necrosis contemporaneous with superficial thrombophlebitis, and headache.
Adverse drug reactions from the pooled phase III clinical trials in patients who received Hemlibra are listed by MedDRA system organ class (Table 3). The corresponding frequency categories for each ADR are based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100).

Description of selected adverse drug reactions.

The most serious ADRs reported from the pooled phase III clinical trials with Hemlibra were thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinus thrombosis and superficial vein thrombosis contemporaneous with skin necrosis (see below; see Section 4.4).

Thrombotic microangiopathy.

In the pooled phase III clinical trials, thrombotic microangiopathy events were reported in 3/373 patients (< 1%) and in 3/31 patients (9.7%) who received at least one dose of aPCC. Each patient was reported to have received on average a cumulative amount of > 100 U/kg/24 hours of aPCC for 24 hours or more while receiving Hemlibra prophylaxis prior to the development of TMA events (presenting with thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity) (see Section 4.4). One patient resumed Hemlibra following resolution of TMA without recurrence.

Thrombotic events.

In pooled phase III clinical trials, serious thrombotic events were reported in 2/373 patients (< 1%) and in 2/31 patients (6.5%) who received at least one dose of aPCC. Each patient was reported to have received on average a cumulative amount of > 100 U/kg/24 hours of aPCC for 24 hours or more while receiving Hemlibra prophylaxis, prior to the development of the thrombotic events (see Section 4.4). One patient resumed Hemlibra following resolution of thrombotic event without recurrence.

Injection site reactions.

Injection site reactions (ISRs) were reported very commonly (20%) from clinical trials. All ISRs observed in the Hemlibra clinical trials were reported as being non-serious and mild to moderate in intensity and 95% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (11%), injection site pain (4%) and injection site pruritus (3%).

Immunogenicity.

In the pooled phase III clinical trials with Hemlibra, development of neutralizing anti-emicizumab antibodies associated with decreasing emicizumab concentration was uncommon (0.6%) (see Section 5.1). One patient, who developed neutralizing anti-emicizumab antibodies with decreasing emicizumab concentration, experienced loss of efficacy (manifest as breakthrough bleeding) after 5 weeks of treatment and later discontinued Hemlibra treatment (see Section 4.4; Section 5.1). Overall, the safety profile of Hemlibra was similar between those patients with anti-emicizumab antibodies (including neutralizing antibodies) and those without.

Post marketing.

The following adverse drug reactions have been identified from post marketing surveillance with Hemlibra (see Table 4). Adverse drug reactions from post marketing surveillance are listed by MedDRA system organ class.

Reporting of suspected adverse reactions.

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 is limited experience with overdose of Hemlibra. Accidental overdose may result in hypercoagulability. Patients who receive an accidental overdose should immediately contact their physician and be monitored closely.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Emicizumab bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective haemostasis.
Emicizumab has no structural relationship or sequence homology to FVIII and, as such, does not induce or enhance the development of direct inhibitors to FVIII.

Pharmacodynamic effect.

Haemophilia A is an X-linked hereditary disorder of blood coagulation due to a deficiency of functional FVIII and results in bleeding into joints, muscles or internal organs, either spontaneously or as result of accidental or surgical trauma. Prophylactic therapy with Hemlibra shortens the activated partial thromboplastin time (aPTT) and increases the reported FVIII activity (using a chromogenic assay with human coagulation factors). These two pharmacodynamic markers do not reflect the true haemostatic effect of emicizumab in vivo (aPTT is overly shortened and reported FVIII activity may be overestimated) but provide a relative indication of the pro-coagulant effect of emicizumab.
In an in vitro study of cytokine release that used the whole blood of healthy adults, the levels of cytokines induced by emicizumab were comparable to those induced by other antibodies known for their low cytokine-releasing potential.

Clinical trials.

The efficacy of Hemlibra for routine prophylaxis in patients with haemophilia A with or without inhibitors was evaluated in four clinical trials (three adult and adolescent studies [HAVEN 3, HAVEN 1 and HAVEN 4] and a paediatric study [HAVEN 2]).
Clinical trials in adult and adolescent patients.

HAVEN 3.

The HAVEN 3 study was a randomised, multicentre, open-label, phase III clinical trial in 152 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with haemophilia A without FVIII inhibitors who previously received either episodic ("on demand") or prophylactic treatment with FVIII. Patients received subcutaneous Hemlibra, 3 mg/kg once weekly for the first four weeks followed by either 1.5 mg/kg once weekly (Arms A and D), 3 mg/kg every two weeks (Arm B), or no prophylaxis (Arm C). Patients in Arm C could switch to Hemlibra (3 mg/kg once weekly for the first 4 weeks followed by 3 mg/kg every 2 weeks) after completing at least 24 weeks without prophylaxis. For Arms A and B dose up-titration to 3 mg/kg weekly was allowed after 24 weeks for patients who experienced two or more qualified bleeds (i.e. spontaneous and clinically significant bleeds occurring at steady state). Arm D patients could up-titrate after the second qualifying bleed. During the study, five patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly.
Eighty-nine patients previously treated with episodic ("on demand") FVIII were randomised in a 2:2:1 ratio to receive Hemlibra either once weekly (Arm A; N=36), every two weeks (Arm B; N=35) or no prophylaxis (Arm C; N=18), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Sixty-three patients previously treated with prophylactic FVIII were enrolled into Arm D to receive Hemlibra (1.5 mg/kg once weekly).
The primary objective of the study was to evaluate efficacy, based on number of bleeds requiring treatment with coagulation factors, of prophylactic Hemlibra administered weekly (Arm A) or every two weeks (Arm B) compared to no prophylaxis (Arm C) in patients previously treated with episodic FVIII (Table 5). Other objectives of the study included evaluation of the randomised comparison of Arms A or B and Arm C for the efficacy of Hemlibra prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds (Table 6). Patient treatment preference was also assessed using a preference survey.
The efficacy of Hemlibra prophylaxis was also compared with previous prophylactic FVIII treatment (Arm D) in patients who had participated in a non-interventional study (NIS) prior to enrolment (Table 7). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity as used in HAVEN 3.

HAVEN 1.

The HAVEN 1 study was a randomised, multicentre, open-label clinical trial in 109 adolescent and adult males (aged ≥ 12 years old and ≥ 40 kg) with haemophilia A with FVIII inhibitors who had previously received either episodic ("on demand") or prophylactic treatment with bypassing agents. In the study, patients received weekly Hemlibra prophylaxis (Arms A, C, and D) - 3 mg/kg once weekly for 4 weeks followed by 1.5 mg/kg once weekly thereafter - or no prophylaxis (Arm B). Patients randomised to Arm B could switch to Hemlibra prophylaxis after completing at least 24 weeks without prophylaxis. Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on Hemlibra prophylaxis for patients who experienced two or more qualified bleeds (i.e. spontaneous and clinically significant bleeds occurring at steady state). During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly.
Fifty-three patients previously treated with episodic ("on demand") bypassing agents were randomised in a 2:1 ratio to receive Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B), with stratification by prior 24-week bleed rate (< 9 or ≥ 9).
Forty-nine patients previously treated with prophylactic bypassing agents were enrolled in Arm C to receive Hemlibra prophylaxis. Seven patients previously treated with episodic ("on demand") bypassing agents who had participated in the NIS prior to enrolment but were unable to enrol in HAVEN 1 prior to the closure of Arms A and B were enrolled in Arm D to receive Hemlibra prophylaxis.
The primary objective of the study was to evaluate among patients previously treated with episodic ("on demand") bypassing agents the treatment effect of weekly Hemlibra prophylaxis compared with no prophylaxis (Arm A vs. Arm B) on the number of bleeds requiring treatment with coagulation factors over time (minimum of 24 weeks or date of discontinuation) (Table 5). Other secondary objectives of the randomised comparison of Arms A and B were the efficacy of weekly Hemlibra prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds and target joint bleeds (see Table 8), as well as assessing patient reported health-related quality of life (HRQoL) and health status (Tables 12 and 13).
The efficacy of weekly Hemlibra prophylaxis compared with previous prophylactic bypassing agents was also evaluated in patients who had participated in the NIS prior to enrolment (Arm C) (Table 9). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity as that used in HAVEN 1.

HAVEN 4.

Hemlibra was investigated in a single arm, multicentre, phase III clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with haemophilia A with or without FVIII inhibitors who had previously received either episodic ("on demand") or prophylactic treatment with FVIII or bypassing agents. Patients received Hemlibra prophylaxis - 3 mg/kg once weekly for four weeks followed by 6 mg/kg every four weeks thereafter.
The primary objective of the study was to evaluate the efficacy, based on treated bleeds, of Hemlibra prophylaxis administered every four weeks in maintaining adequate bleed control (Table 5). Other objectives were to evaluate the clinical efficacy of Hemlibra prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds (Table 11). Patient treatment preference was also assessed using a preference survey.
Efficacy results in adult and adolescent studies. The efficacy results of Hemlibra prophylaxis with respect to rate of treated bleeds (primary endpoint) in HAVEN 3, HAVEN 1 and HAVEN 4 are shown in Table 5.

HAVEN 3.

The efficacy results of Hemlibra prophylaxis compared with no prophylaxis with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in Table 6.

In the HAVEN 3 clinical trial intra-patient analysis, Hemlibra prophylaxis resulted in a statistically significant (p < 0.0001) reduction (68%) in bleed rate for treated bleeds compared with previous FVIII prophylaxis collected in the NIS prior to enrolment (Table 7).

HAVEN 1.

Additional analyses for HAVEN 1 to assess long term control of bleeds with Hemlibra prophylaxis were conducted using 12-week treatment intervals up to week 72. When Annualised Bleed Rate (ABR) for treated bleeds was assessed over 12-week intervals the mean ABRs decreased over time and the improvement was sustained up to week 72, while the median remained consistently at zero (Table 9). These data demonstrate the long term efficacy of Hemlibra prophylaxis. The mean and median calculated ABRs for treated bleeds are shown in Table 9.

In the HAVEN 1 clinical trial intra-patient analysis, Hemlibra prophylaxis resulted in a statistically significant (p=0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrolment (Table 10).

HAVEN 4.

Efficacy results for the HAVEN 4 clinical study are summarised below. Forty-one patients ≥ 12 years old were evaluated for efficacy with a median observation time of 25.6 weeks (range 24.1 - 29.4 weeks). The efficacy results of Hemlibra prophylaxis every four weeks with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in Table 11.

Patient-reported outcomes in adult and adolescent studies. The HAVEN adult and adolescent clinical studies evaluated patient-reported outcomes with several measures. The Haemophilia-Specific Quality of Life (Haem-A-QoL) questionnaire for adults (≥ 18 years) and its adolescent version (Haemo-QoL-SF, for 8 to < 18 years) assessed haemophilia-related quality of life in patients. For the Haem-A-QoL and Haemo-QoL-SF, the Physical Health Score (i.e. painful swellings, presence of joint pain, pain with movement, difficulty walking far and needing more time to get ready) and Total Score (summary of all scores) were protocol-defined endpoints of interest. To measure change in health status, the Index Utility Score (IUS) and the Visual Analog Scale (VAS) from the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) were examined.
In HAVEN 3 and HAVEN 4, an assessment of patient preference for treatment, the Emicizumab Preference Survey (EmiPref), was used.

HAVEN 1.

In HAVEN 1, HRQoL for patients aged ≥ 18 years was evaluated at week 25 based on the Haem-A-QoL questionnaire for adults (Table 13). The Haem-A-QoL is a valid and reliable measure of HRQoL. The Haem-A-QoL is a valid and reliable measure of HRQoL.

In HAVEN 1, patients' health status was assessed according to the EQ-5D-5L (Table 13). EQ-5D-5L is a valid and reliable measure of health status.

HAVEN 3 and HAVEN 4 patient preference.

In HAVEN 3 and HAVEN 4, patients who received Hemlibra (once weekly, every two weeks or every four weeks) reported whether they preferred subcutaneous Hemlibra, their prior intravenous (IV) treatment or had no preference at week 17. Of the patients in HAVEN 3 who responded to the preference questionnaire, 89 of 95 patients (93.7%) reported preferring Hemlibra to their prior IV treatment, and specifically 45 of 46 patients (97.8%) preferred Hemlibra to their prior prophylactic FVIII treatment. In HAVEN 4, all 41 patients (100%) responded to the preference questionnaire and reported preferring Hemlibra to their prior IV treatment.
In HAVEN 3 and HAVEN 4, the two reasons most frequently ranked by patients as the most important for their preference for Hemlibra were that the route of administration was easier and the frequency of treatments was lower.
Clinical trial in paediatric patients (HAVEN 2). In HAVEN 2, Hemlibra weekly prophylaxis was evaluated in a single-arm, multicentre, open-label clinical trial in paediatric patients (age < 12 years old, or 12 to 17 years old weighing < 40 kg) with haemophilia A with FVIII inhibitors. Patients received Hemlibra prophylaxis at 3 mg/kg once weekly for the first four weeks followed by 1.5 mg/kg once weekly thereafter.
The study evaluated the pharmacokinetics, safety and efficacy, including the efficacy of weekly Hemlibra prophylaxis compared with previous episodic and prophylactic bypassing agent treatment in patients who had participated in the NIS prior to enrolment (intra-patient comparison).

HAVEN 2 efficacy results (interim analysis).

At the time of the interim analysis, efficacy was evaluated in 59 paediatric patients who were < 12 years old and had been receiving weekly Hemlibra prophylaxis for at least 12 weeks, including 38 patients aged 6 to < 12 years, 17 patients aged 2 to < 6 years and 4 patients aged 14 months to < 2 years.
Annualised bleed rate and percent of patients with zero bleeds were calculated for 59 patients (Table 14). The median observation time for these patients was 29.6 weeks (range: 18.2 - 63 weeks).

In the intra-patient interim analysis, weekly Hemlibra prophylaxis resulted in a clinically meaningful (98%) reduction in bleed rate for treated bleeds in 18 paediatric patients who had at least 12 weeks of Hemlibra prophylaxis compared to their bleed rate collected in the NIS prior to enrolment (Table 15).

HAVEN 2 patient-reported outcomes.

In HAVEN 2, HRQoL for patients aged ≥ 8 to < 12 years was evaluated at week 25 based on the Haemo-QoL-SF questionnaire for children. The Haemo-QoL-SF is a valid and reliable measure of HRQoL (see Table 16).

In HAVEN 2, HRQoL for patients ages < 12 years was also evaluated at week 25 based on the Adapted InhibQoL with Aspects of Caregiver Burden questionnaire completed by caregivers. The Adapted InhibQoL is a valid and reliable measure of HRQoL (see Table 17).

Surgeries and procedures in the HAVEN clinical trials. There is limited experience with bypassing agent or FVIII use during surgeries and procedures in patients receiving Hemlibra prophylaxis. Bypassing agent or FVIII use during surgeries and procedures was determined by the investigator.

Immunogenicity.

As with all therapeutic proteins, there is the potential for an immune response in patients treated with Hemlibra. A total of 668 patients were tested for anti-emicizumab antibodies in the pooled phase III clinical trials, of which 5.1% of patients (34/668) tested positive for anti-emicizumab antibodies. Anti-emicizumab antibodies were neutralizing in vitro in 2.7% of patients (18/668). Of these, the neutralizing anti-emicizumab antibodies did not appear to have a clinically meaningful impact on the pharmacokinetics or efficacy of Hemlibra in 14 patients, while decreased emicizumab plasma concentrations were observed in 4 patients (0.6%). One patient (0.2%) from the HAVEN 2 clinical trial with neutralizing anti-emicizumab antibodies and decreased emicizumab plasma concentrations experienced loss of efficacy after 5 weeks of treatment and discontinued Hemlibra. Overall, the safety profile of Hemlibra was similar between those patients with anti-emicizumab antibodies (including neutralizing antibodies) and those without (see Section 4.4; Section 4.8). There was no clinically apparent impact of the presence of anti-emicizumab antibodies on safety.
The data reflects the number of patients whose test results were considered positive for antibodies to emicizumab using an enzyme-linked immunosorbent assay (ELISA) and/or for neutralizing anti-emicizumab antibodies using a FVIII chromogenic assay. Immunogenicity assay results may be influenced by several factors including assay sensitivity and specificity, sample handling, timing of sample collection, concomitant medicinal products and underlying disease. For these reasons, comparison of incidence of antibodies to emicizumab with the incidence of antibodies to other products may be misleading.

5.2 Pharmacokinetic Properties

The pharmacokinetics of emicizumab were determined via a non-compartmental analysis in healthy subjects and using a population pharmacokinetic analysis on a database composed of 389 patients with haemophilia A.

Absorption.

Following subcutaneous administration in haemophilia A patients, the absorption half-life was 1.6 days.
Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks in haemophilia A patients, mean trough plasma concentrations of emicizumab achieved 52.6 ± 13.6 microgram/mL at week 5. Sustained mean predicted trough plasma concentrations of emicizumab at steady-state were 51.1, 46.7 and 38.3 microgram/mL with the recommended maintenance doses of 1.5 mg/kg once weekly, 3 mg/kg every two weeks or 6 mg/kg every four weeks, respectively (Figure 1, Table 18).

Based on population PK simulations, the predicted mean (± SD) C_trough, C_max and ratios of C_max/C_trough at steady state for the recommended maintenance doses of 1.5 mg/kg once weekly, 3 mg/kg every two weeks or 6 mg/kg every four weeks are shown in Table 18.

Similar pharmacokinetic (PK) profiles were observed following once weekly dosing (3 mg/kg/week for 4 weeks followed by 1.5 mg/kg/week) in adults/adolescents (≥ 12 years) and children (< 12 years) (see Figure 2).

In healthy subjects, the absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% (upper arm) and 93.1% (thigh) depending on the injection site. Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh. Emicizumab can be administered interchangeably at these anatomical sites (see Section 4.2).

Distribution.

The apparent volume of distribution (V/F), estimated from the population PK analysis, in haemophilia A patients following multiple subcutaneous doses of emicizumab was 10.4 L.

Metabolism.

The metabolism of emicizumab has not been studied. IgG antibodies are mainly catabolised by lysosomal proteolysis and then eliminated from or reused by the body.

Excretion.

Following intravenous administration of 0.25 mg/kg in healthy subjects, the total clearance of emicizumab was 3.26 mL/kg/day (i.e. 0.228 L/day for a 70 kg adult) and the mean terminal half life was 26.7 days.
Following single subcutaneous injection in healthy subjects, the elimination half-life was approximately 4 to 5 weeks.
Following multiple subcutaneous injections in haemophilia A patients, the apparent clearance was 0.272 L/day and the elimination apparent half-life was 26.8 days.
Emicizumab exhibited dose-proportional pharmacokinetics in patients with haemophilia A over a dose range from 0.3 to 6 mg/kg once weekly following subcutaneous administration.

Pharmacokinetics in special populations.

Paediatrics.

The effect of age on the pharmacokinetics of emicizumab was assessed in a population pharmacokinetic analysis which included 5 infants and toddlers (14 months to < 2 years), 55 children (2 years to < 12 years) and 50 adolescents (12 to < 18 years) with haemophilia A. Age did not affect the pharmacokinetics of emicizumab in paediatric patients older than 6 months at equivalent weight-based doses (see Section 4.2). In paediatric patients less than 6 months old, the predicted concentrations of emicizumab were 19% to 33% lower than the older patients, especially with maintenance doses of 3 mg/kg once every two weeks or 6 mg/kg once every four weeks.