Consumer medicine information

Fasenra prefilled syringe and Fasenra pen

Benralizumab

BRAND INFORMATION

Brand name

Fasenra

Active ingredient

Benralizumab

Schedule

SUMMARY CMI

Fasenra^® prefilled syringe and Fasenra Pen™

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.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using FASENRA?

FASENRA contains the active ingredient benralizumab. FASENRA is used to treat a type of asthma - eosinophilic asthma – in adults and children aged 12 years and over.

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

2. What should I know before I use FASENRA?

Do not use if you have ever had an allergic reaction to FASENRA or any of the ingredients listed at the end of the CMI.

Do not use to treat acute asthma symptoms such as a sudden asthma attack. You will still need your reliever puffer/inhaler.

Tell your doctor if you have, or have had, an infection caused by parasites (eg parasitic worms) or if you live in/are travelling to an area where parasitic infections are common.

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 FASENRA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FASENRA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How FASENRA is given?

Your doctor or nurse may have recommended that you/your caregiver can give your subcutaneous (under the skin) injection, or it may be given to you by a healthcare professional.

The recommended dose is 30 mg (one injection - as either FASENRA PEN or FASENRA prefilled syringe) every 4 weeks for the first 3 doses, then one injection every 8 weeks after that.

Continue FASENRA for as long as your doctor tells you

More instructions can be found in Section 4. How FASENRA is given? in the full CMI.

5. What should I know while using FASENRA?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using FASENRA. If you have an Asthma Action Plan follow it closely at all times. If your asthma is uncontrolled or worsening tell your doctor.
Things you should not do	Do not stop using FASENRA unless your doctor advises you to. It is important to keep using FASENRA even if you feel well. Do not stop using/reduce the dose of your other asthma medicines unless your doctor advises you to
Looking after your medicine	Keep FASENRA in the refrigerator (2°C to 8°C). Do not freeze, shake or expose to heat. Protect from light. FASENRA may be kept at room temperature up to 25°C for no more than 14 days.

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

6. Are there any side effects?

Call your doctor or nurse straight away, or go straight to the Emergency Department at your nearest hospital if you have symptoms of an allergic reaction. Allergic reactions may occur within minutes or hours after an injection or may even occur several days after an injection.

Less serious side effects include headache, sore throat, fever/high temperature and injection site reactions.

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.

▼ This medicine is subject to additional monitoring in Australia. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems

FULL CMI

Fasenra^® prefilled syringe and Fasenra Pen™

Active ingredient: benralizumab

Consumer Medicine Information (CMI)

This leaflet provides important information about using FASENRA prefilled syringe and FASENRA PEN prefilled pen (collectively called FASENRA in this document). You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using FASENRA.

Where to find information in this leaflet:

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

1. Why am I using FASENRA?

FASENRA contains the active ingredient benralizumab, a humanised monoclonal antibody (a type of protein). Benralizumab works by binding to a specific receptor on eosinophils (a type of white blood cell) called the interleukin-5 (IL-5) receptor. Eosinophils may make your asthma worse by causing inflammation in the lungs. By binding to this receptor FASENRA reduces the number of eosinophils in your blood and lungs.

FASENRA is used in adults and adolescents (12 years of age and older) to treat a type of asthma - eosinophilic asthma - which is where patients have too many eosinophils in the blood and lungs. FASENRA is used together with other asthma medicines you take regularly to treat your asthma (inhaled corticosteroids plus other asthma medicines - for example a daily preventer puffer/inhaler).

If you are already using other asthma medicines (such as your daily preventer puffer/inhaler) but your asthma is not well controlled by these medicines, then FASENRA may help to reduce the number of asthma attacks (exacerbations) and may also make it easier for you to breathe normally. If you are taking medicines called oral corticosteroids (eg prednisolone) FASENRA may also help reduce the oral corticosteroid dosage you need to take each day to control your asthma.

You must not stop taking or reduce the dose of your other asthma medicines unless your doctor advises you to.

2. What should I know before I use FASENRA?

Warnings

Do not use FASENRA:

If you are allergic to benralizumab, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
To treat acute asthma symptoms such as a sudden asthma attack. You will still need your reliever puffer/inhaler.

Check with your doctor, nurse of pharmacist if you:

have, or have had, an allergic reaction to benralizumab
have, or have had, an infection caused by parasites (eg parasitic worms) or if you live in/are travelling to an area where parasitic infections are common as this medicine may weaken your ability to fight certain types of parasitic infections. The parasitic infection should be treated before you are given FASENRA
have any other medical conditions
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?

Asthma action plan

Your doctor or nurse should give you a personal Asthma Action Plan to help manage your asthma. This plan will include what medicines to use regularly to control your asthma (eg preventer puffers/inhalers, as well as FASENRA), as well as what reliever medicines to use when you have sudden asthma attacks.

Ask your doctor, nurse or pharmacist if you have any questions about your personal Asthma Action Plan.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether the ingredients of FASENRA can pass into breast milk. The effects of FASENRA in pregnant women or their unborn babies are not known. Your doctor can discuss with you the risks and benefits involved.

Children

There is not enough information to recommend the use of FASENRA for children under the age of 12 years.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop. This includes all the medicines that you use for your asthma including preventer and reliever medicines.

Some medicines may interfere with FASENRA and affect how it works.

FASENRA has been used together with other commonly used asthma medicines. Do not suddenly stop taking your asthma medicines once you have started FASENRA. Some medicines (especially corticosteroids) must be stopped gradually, under the supervision of your doctor and based on your response to FASENRA.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FASENRA.

4. How FASENRA is given?

How much is given and how long to take it

Adults and adolescents (12 years and over)

30 mg (one injection - as either FASENRA PEN or FASENRA prefilled syringe)

every 4 weeks for the first 3 doses,
then one injection every 8 weeks after that

Continue FASENRA for as long as your doctor tells you.

FASENRA helps to control your asthma but does not cure it. It is important to keep taking your medicine even if you feel well.

How to give FASENRA

If your doctor or nurse have recommended that you/your caregiver can give your injection, make sure you/your caregiver reads the Instructions for Use leaflet included in each pack of FASENRA PEN and FASENRA prefilled syringes carefully before using FASENRA. Follow all directions given to you/your caregiver by your doctor or nurse carefully.

FASENRA is given as an injection into the fat layer just under the skin (subcutaneous)

The injections are usually given in your thigh or abdomen, however when given by someone else (for example a caregiver or your doctor, nurse or pharmacist), it may also be given in the upper arm.

Do not try to inject yourself in the arm.

After injecting FASENRA immediately throw away the used prefilled syringe or prefilled pen (autoinjector) in a special 'sharps' disposal container as instructed by your doctor, nurse or pharmacist.

If you forget to take FASENRA

If you have missed a dose of FASENRA contact your doctor, nurse or pharmacist as soon as possible. They will tell you what you need to do. You may need to reschedule your appointment if your injection is given to you by a doctor or nurse. If you/your caregiver give the injection, do not take your missed dose unless your doctor, nurse or pharmacist tell you to.

If you have trouble remembering your appointments or when to inject yourself, ask your doctor, nurse or pharmacist for some hints.

If you are given too much FASENRA

If FASENRA is given under the close supervision of a doctor, nurse or pharmacist it is unlikely that you will be given too much.

If you are concerned that you have been given too much FASENRA, tell your doctor, nurse or pharmacist immediately as you may need urgent medical attention.

If you think that you or anyone else may have taken too much FASENRA you should immediately:

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

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

5. What should I know while using FASENRA?

Things you should do

If you have an Asthma Action Plan follow it closely at all times. If your asthma is uncontrolled or worsening tell your doctor.

Remind any doctor, dentist, nurse, pharmacist or other health professional you visit that you are using FASENRA. If you are going to have surgery, tell the surgeon or anaesthetist that you are using FASENRA. It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are having this medicine. It may interfere with the results of some tests.

Keep all of your doctor's and/or hospital's appointments so that you don't miss any doses and your progress can be checked.

Things you should not do

Do not have FASENRA 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 having FASENRA unless your doctor advises you to. Interrupting or stopping FASENRA treatment may cause your asthma symptoms and asthma attacks to come back or become more frequent.
Do not stop using or reduce the dose of your other asthma medicines unless your doctor advises you to. Some medicines (especially corticosteroids) must be stopped gradually, under the supervision of your doctor and on your response to FASENRA.

Driving or using machines

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

Looking after your medicine

Keep FASENRA in the refrigerator at 2°C to 8°C. Do not freeze, shake or expose to heat. FASENRA should be kept sealed in the original package to protect it from light.

FASENRA may be kept at room temperature up to 25°C for no more than 14 days. This is important whether travelling by car, bus, train, plane or any other form of transport. FASENRA must be used within 14 days or discarded.

There is a space on the carton to write the date it is removed from the refrigerator.

Follow the instructions in the carton and Instructions for use leaflet on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effects	What to do
headache sore throat fever/high temperature injection site reactions (eg pain, redness, itching, swelling near where the injection was given).	Speak to your doctor, nurse of pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Allergic reaction - some of the symptoms of an allergic reaction may include:

rash, itching or hives on the skin
swelling of the face, lips, tongue or other parts of the body
shortness of breath, wheezing or difficulty breathing
fainting, dizziness, feeling lightheaded (due to a drop in blood pressure)

Allergic reactions may occur within minutes or hours after an injection or may even occur several days after an injection.

Call your doctor or nurse straight away, or go straight to the Emergency Department at your nearest hospital. You may need urgent medical attention or hospitalisation.

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

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What FASENRA contains

Active ingredient (main ingredient)	Benralizumab, 30 mg
Other ingredients (inactive ingredients)	histidine histidine hydrochloride monohydrate trehalose polysorbate 20 water for injections

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

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

What FASENRA looks like

FASENRA PEN (AUST R 313902) contains 1 mL of solution in a clear glass type I prefilled syringe inside a pen (autoinjector). Its colour may vary from colourless to yellow, and it may contain white particles.

The pen includes a stainless-steel needle, with a FluoroTec (non-latex) coated plunger stopper and a needle safety guard inside the pen (autoinjector).

FASENRA PEN is available in packs containing 1 FASENRA PEN (a single dose).

FASENRA prefilled syringe (AUST R 285718) contains 1 mL of solution in a clear glass type I prefilled syringe. Its colour may vary from colourless to yellow, and it may contain white particles.

The glass prefilled syringe includes a stainless-steel needle, with a FluoroTec (non-latex) coated plunger stopper and a needle safety guard.

FASENRA prefilled syringe is available in packs containing 1 prefilled syringe (a single dose).

Who distributes FASENRA

Australia

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone:- 1800 805 342

New Zealand

AstraZeneca Limited
PO Box 87453, Meadowbank
Auckland 1742.
Telephone:- 09 306 5650

This leaflet was prepared 9 May 2022

The Australian Product Information document prepared for use by healthcare providers can be found on the Therapeutic Goods Administration (TGA) website – www.ebs.tga.gov.au. The New Zealand Data Sheet is available at www.medsafe.govt.nz

FASENRA and FASENRA PEN are trade marks of the AstraZeneca group of companies.

Doc ID-003812071 v5

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Fasenra

Active ingredient

Benralizumab

Schedule

1 Name of Medicine

Benralizumab.

2 Qualitative and Quantitative Composition

Each Fasenra prefilled syringe contains 30 mg benralizumab in 1 mL (30 mg/mL).
Each Fasenra Pen prefilled pen contains 30 mg benralizumab in 1 mL (30 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Clear to opalescent, colourless to yellow solution for injection in a prefilled syringe (Fasenra) or prefilled pen (Fasenra Pen).

4 Clinical Particulars

4.1 Therapeutic Indications

Fasenra is indicated as add-on therapy in patients aged 12 years and over with severe eosinophilic asthma (blood eosinophil count ≥ 300 cells/microL or ≥ 150 cells/microL if on oral corticosteroid treatment) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Fasenra should be prescribed by a health care professional in consultation with a specialist physician experienced in the diagnosis and treatment of severe asthma. Treatment with high-dose inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) should be optimised prior to commencement of treatment with Fasenra.

Adults and adolescents (12 years and over).

The recommended dose is 30 mg of Fasenra by subcutaneous injection every 4 weeks for the first 3 doses, and then every 8 weeks thereafter.
If an injection is missed on a planned date, dosing should resume as soon as possible on the indicated regime; a double dose must not be administered.
Fasenra is intended for long-term treatment. A decision to continue therapy should be made at least annually based on disease severity and level of exacerbation.

Special patient populations.

Renal impairment.

No dose adjustment is required for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations, Renal impairment).

Hepatic impairment.

No dose adjustment is required for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special patient populations, Hepatic impairment).

Use in the elderly.

No dose adjustment is required for elderly patients (see Section 5.2 Pharmacokinetic Properties, Special patient populations, Elderly (≥ 65 years old)).

Paediatric use.

The safety and efficacy of Fasenra in children below 12 years of age have not been established.

Method of administration.

Fasenra is for single use in one patient only. Discard any residue.
Fasenra is administered as a subcutaneous injection.
Administer Fasenra into the thigh or abdomen. If somebody else administers the injection, the upper arm can also be used. Do not administer into areas where the skin is tender, bruised, erythematous, or hardened.

Instructions for administration.

Do not shake. Do not use if frozen.
Prior to administration, if the Fasenra prefilled syringe/Fasenra Pen has been in the refrigerator allow Fasenra to reach room temperature (approximately 30 minutes).
Visually inspect Fasenra for particulate matter and discolouration prior to administration. Fasenra is clear, colourless to yellow, and may contain translucent or white to off white particles. Do not use Fasenra if liquid is cloudy, discoloured, or if it contains large particles or foreign particulate matter.
Additional information and instructions for the preparation and administration of Fasenra using the prefilled syringe or prefilled pen (Fasenra Pen) are given in the Instructions for Use booklet provided in each pack.

4.3 Contraindications

Fasenra is contraindicated in patients who have known hypersensitivity to benralizumab or any of its excipients (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions).

4.4 Special Warnings and Precautions for Use

Fasenra should not be used to treat acute asthma exacerbations.
Patients should be instructed to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment.
Reduction in oral corticosteroids (OCS) dose, if appropriate, should be gradual and performed under the supervision of a physician. Abrupt discontinuation of OCS after initiation of Fasenra therapy is not recommended.

Hypersensitivity reactions.

Hypersensitivity reactions (e.g. anaphylaxis, angioedema, urticaria, urticaria papular, rash) have occurred following administration of Fasenra (see Section 4.8 Adverse Effects (Undesirable Effects)). These reactions may occur within hours of administration, but in some instances have a delayed onset (i.e. days). A history of serious hypersensitivity/anaphylaxis unrelated to benralizumab may be a risk factor for anaphylaxis following Fasenra administration.
In the event of a hypersensitivity reaction, Fasenra should be discontinued and appropriate therapy initiated.

Parasitic (helminth) infection.

Eosinophils may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if Fasenra may influence a patient's response against helminth infections.
Treat patients with pre-existing helminth infections before initiating therapy with Fasenra. If patients become infected while receiving treatment with Fasenra and do not respond to anti-helminth treatment, discontinue treatment with Fasenra until infection resolves.

Use in the elderly.

No dose adjustment is required for elderly patients (see Section 4.2 Dose and Method of Administration, Special patient populations, Use in the elderly; Section 5.2 Pharmacokinetic Properties, Special patient populations, Elderly (≥ 65 years old)).

Paediatric use.

The safety and efficacy of Fasenra in children below 12 years of age have not been established.
In Phase 3 studies SIROCCO/CALIMA, the treatment responses in adolescent patients (12 to 17 years of age) were less than that observed in adults, however they were not powered to detect a response in this sub-group. The adverse event profile in adolescents was generally similar to the overall population in these studies of up to 56 weeks duration as well as in a 108-week extension study (BORA).

Effects on laboratory tests.

As expected based on the mechanism of action of benralizumab, in the pivotal Phase 3 trials, following subcutaneous administration of benralizumab at the recommended dose blood eosinophils were reduced to a median absolute blood eosinophil count of 0 cells/microL. This magnitude of reduction was seen at the first observed time point, 4 weeks of treatment, and was maintained throughout the treatment period. Basophils also express IL-5Rα, and were also reduced.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In a randomized, double-blind parallel-group study of 103 patients aged between 12 and 21 years with severe asthma, the humoral antibody responses induced by seasonal influenza virus vaccination were similar between benralizumab 30 mg and placebo. Vaccine efficacy was not directly assessed in this study.
Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of benralizumab. There is no evidence of IL-5Rα expression on hepatocytes. Eosinophil depletion does not produce chronic systemic alterations of proinflammatory cytokines.
An effect of benralizumab on the pharmacokinetics of co-administered medications is not expected. Based on population pharmacokinetic analysis, commonly co-administered medications had no effect on the benralizumab clearance in patients with asthma.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been conducted with benralizumab in humans or animals.
Examination of surrogate fertility parameters (including organ weights and histopathology of reproductive tissues) in male and female cynomolgus monkeys treated with benralizumab at intravenous doses up to 25 mg/kg or at subcutaneous doses of up to 30 mg/kg once every 2 weeks for 9 months suggested no impairment of fertility. Systemic exposure (serum AUC) at the no adverse effect dose in monkeys was more than 400 times that in patients at the maximum recommended human dose.
(Category B1)
It is preferable to avoid the use of Fasenra during pregnancy, especially during the third trimester due to the potential for eosinophil depletion in the newborn. Administration of Fasenra to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.
IgG antibodies such as benralizumab are increasingly transported across the placenta as pregnancy progresses; therefore, greater fetal exposure occurs in the third trimester of pregnancy.
The effect of Fasenra on human pregnancy is unknown.
No adverse effects on pre- and post-natal survival, growth or development were observed in cynomolgus monkeys with maternal administration of intravenous doses of benralizumab (10 or 30 mg/kg) once every 2 weeks from early pregnancy (gestation day 20-22) to 1-month post-partum. Serum benralizumab levels in infants were 66% of maternal levels 7 days post-partum and declined over time (e.g. 10% of maternal levels 3 months post-partum). While there was no effect observed on the primary and secondary humoral immune responses to immunisation or levels of serum IgM, IgG and IgA in the offspring of the treated monkeys, there was a marked eosinophil depletion, consistent with significant placental transfer of benralizumab that resulted in pharmacologically active drug levels in infants. The immunological response to parasitic infection was not examined in the offspring.
It is unknown whether benralizumab is excreted in human milk. Since antibodies can be secreted in human milk a risk to the breastfed child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from benralizumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

Fasenra has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience - asthma.

A total of 895 patients received the recommended dose of Fasenra (30 mg every 4 weeks for the first 3 doses, and then every 8 weeks thereafter) within the 3 placebo-controlled Phase 3 clinical trials - 822 patients (including 38 adolescents) in SIROCCO and CALIMA (48 and 56-week duration respectively) and 73 patients (adults only) in a 28-week OCS sparing trial (ZONDA). Note - all 3 trials assessed 2 dosing regimens of Fasenra compared to placebo, however only the safety data for the recommended dosing regimen (Q8w; see Section 4.2 Dose and Method of Administration) has been presented below.
In clinical trials in patients with severe asthma with eosinophilic phenotype the most commonly reported adverse drug reactions during treatment were headache and pharyngitis.
Phase 3 exacerbation trials (SIROCCO and CALIMA). Table 1 presents the most common (≥ 3% frequency) adverse events regardless of causality from the two placebo-controlled trials (SIROCCO/CALIMA) in patients receiving the recommended dose (Q8w) of benralizumab. Table 2 presents the SIROCCO/CALIMA adverse drug reactions reported at a frequency less than 3%. All patients (including placebo) were on a background of high-dose ICS/LABA.

Adolescents (12 to 17 years of age).

The frequency, type and severity of adverse drug reactions in the adolescent population were observed to be similar to those seen in adults.
Phase 3 OCS sparing trial (ZONDA). In ZONDA all patients were taking daily OCS (7.5 to 40 mg per day) in addition to regular use of high-dose ICS/LABA. In general, the safety results in ZONDA were similar to those observed in SIROCCO and CALIMA.
Long-term safety. In a 56-week double blind, randomized, parallel-group extension trial (BORA) in patients with asthma from SIROCCO, CALIMA and ZONDA trials, 842 patients were treated with Fasenra at the recommended dose and remained in the trial. The overall adverse event profile was similar to the asthma trials described above. Additionally, in an open-label safety extension trial (MELTEMI) in patients with asthma from previous trials, 226 adult patients were treated with Fasenra at the recommended dose for up to 42.3 months. Combined with the treatment period in previous studies, this corresponds to median follow-up of 3.4 years (range 8.5 months - 5.3 years). The safety profile during this follow-up period was consistent with the known safety profile of Fasenra.
Adolescent patients aged 12 to 17 (n=61) from SIROCCO and CALIMA continued treatment with Fasenra (at the recommended dose) in BORA for up to 108 weeks. Safety was consistent with the predecessor trials.
Immunogenicity. Treatment with benralizumab, like other monoclonal antibodies, may result in an anti-drug antibody (ADA) response (see Section 5.1 Pharmacodynamic Properties, Immunogenicity). However, there is no apparent correlation of ADA development to efficacy or adverse events.

Post marketing experience.

In addition to the above, Table 3 describes adverse reactions that have been identified during post-approval use of Fasenra.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Doses of up to 200 mg were administered subcutaneously in clinical trials to patients with eosinophilic disease without evidence of dose-related toxicities.
There is no specific treatment for an overdose with benralizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Benralizumab is an antibody that binds to the alpha subunit of the human interleukin-5 receptor (IL-5Rα) with high affinity (16 picoM) and specificity. The IL-5 receptor is specifically expressed on the surface of eosinophils and basophils. The absence of fucose sugar units in the Fc domain of benralizumab results in high affinity (45.5 nanoM) for FcγRIII receptors on immune effectors cells such as natural killer (NK) cells leading to apoptosis of eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC).
Eosinophilic inflammation is an important component in the pathogenesis of asthma. Eosinophils are a rich source of proinflammatory mediators (e.g. eicosanoids, leukotrienes, cytokines) and granule proteins (e.g. eosinophil cationic protein, eosinophil peroxidase, eosinophil neurotoxin and major basic protein). Benralizumab, by enhanced ADCC, reduces eosinophilic inflammation.

Pharmacodynamic effects.

The pharmacodynamic response (blood eosinophil depletion) following repeat subcutaneous dosing was evaluated in asthma patients in a 12-week Phase 2 trial. Patients with mild-moderate asthma received 1 of 3 doses of benralizumab [25 mg (n=7), 100 mg (n=6) or 200 mg (n=6) subcutaneous] or placebo (n=6) every 4 weeks for a total of 3 doses. Median blood eosinophil levels at baseline were 400, 200, 120 and 200 cells/microL in the 25, 100, and 200 mg benralizumab and placebo groups, respectively. Blood eosinophil depletion was observed following subcutaneous administration of benralizumab at all dose levels and no depletion was observed in the placebo group. Twenty-four hours post-dosing, all benralizumab dosage groups demonstrated complete or near complete depletion of median blood eosinophil levels (0, 0 and 5 cells/microL respectively). There were no changes in median blood eosinophils in the placebo group. The effect on blood eosinophil depletion was maintained throughout the dosing period.
In a Phase 1 trial, the effect of benralizumab on eosinophils in airway mucosa was evaluated in asthmatic patients with 2.5% or more eosinophils in sputum. Patients received 100 or 200 mg subcutaneous benralizumab once every 4 weeks for 8 weeks (total benralizumab subcutaneous group n=9) or matching placebo (n=5). At the end of the 12-week treatment period, there was a median reduction from baseline in eosinophils in the airway mucosa of 96% in the total benralizumab subcutaneous group compared to a 47% reduction from baseline in the placebo group which was statistically significant (p=0.039).
In the Phase 1 trial, treatment with benralizumab was also associated with reductions in blood basophils, and in both Phase 1 and 2 trials eosinophil granule products such as serum eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP).
In the two pivotal Phase 3 asthma trials (SIROCCO and CALIMA), following subcutaneous administration of benralizumab at the recommended dose blood eosinophils were reduced to a median absolute blood eosinophil count of 0 cells/microL, which corresponds to a median reduction of 100% (see Section 5.1 Pharmacodynamic Properties, Clinical trials). This magnitude of reduction was seen at the first observed time point, 4 weeks of treatment, and was maintained throughout the treatment period. Maintenance of eosinophil depletion was observed throughout the 56-week extension phase (BORA extension trial) consistent with previous trials.

Immunogenicity.

Overall, treatment-emergent anti-drug antibody (ADA) response developed in 107 out of 809 (13%) of patients treated with Fasenra at the recommended dosing regimen during the 48 to 56-week treatment period. In a majority of the ADA positive patients, in vitro neutralizing antibodies were detected. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high ADA titers compared to antibody negative patients. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.
Following a second year of treatment of these patients from the Phase 3 placebo-controlled trials, an additional 18 out of 510 (4%) had newly developed treatment-emergent antibodies. Overall, in patients who were ADA positive in the predecessor trials, titers remained stable or declined in the second year of treatment. Consistent with predecessor trials, no evidence of an association of ADA with efficacy or safety was observed.
The data reflect the percentage of patients whose test results were positive for antibodies to benralizumab in specific assays. The observed incidence of antibody response is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to benralizumab with the incidence of antibodies to other products may be misleading.

Clinical trials.

Severe asthma.

The safety and efficacy of Fasenra as an add-on therapy in patients with severe asthma were evaluated in 3 randomised, double-blind, parallel-group, placebo-controlled Phase 3 clinical trials:
two replicate long-term exacerbation trials in adults and adolescents (12 years and older) with 48 and 56 weeks duration (SIROCCO and CALIMA respectively); and
one 28-week OCS reduction trial in adults (18 years and over (ZONDA)).
While all 3 trials assessed 2 dosing regimens compared to placebo, the recommended dosing regimen is Fasenra administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter (referred herein as Q8w; see Section 4.2 Dose and Method of Administration) as no additional benefit was observed with the more frequent dosing regimen (administered every 4 weeks). Only the results for the recommended Q8w dosing regimen have been presented below.
A total of 805, 881 and 148 patients were randomised to treatment with Fasenra Q8w and placebo in SIROCCO, CALIMA and ZONDA respectively. This included 84 adolescents (SIROCCO/CALIMA combined; 38 within the Fasenra Q8w arms and 4 within the placebo arms). See Table 4 for further details.

SIROCCO and CALIMA. Patients enrolled into SIROCCO and CALIMA were required to have a history of ≥ 2 asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months, an Asthma Control Questionnaire-6 (ACQ-6) score of ≥ 1.5 at screening and reduced lung function at baseline [pre-bronchodilator forced expiratory volume in 1 second (FEV₁) < 80% in adults and < 90% in adolescents] despite treatment with high dose ICS (SIROCCO) or with medium- or high-dose ICS (CALIMA) and their current standard of care. Medium- and high-dose ICS were defined as ≥ 250 microgram and ≥ 500 microgram/day fluticasone propionate dry powder formulation or equivalent respectively. The medium-dose ICS arm in CALIMA was assessed as a descriptive analysis only and has not been discussed further.
Patients were stratified 2:1 according to baseline blood eosinophils count (≥ 300 or < 300 cells/microL). The primary efficacy population (intent-to-treat (ITT)) in both studies was patients with a high-dose ICS/LABA and a baseline blood eosinophil count ≥ 300 cells/microL. Prespecified analyses were also conducted on the high-dose ICS/LABA populations with a baseline blood eosinophil count < 300 cells/microL (patients not included within the ITT population) and the full analysis set (FAS) for predefined eosinophil ranges. Table 5 provides a summary of the randomised patient numbers for the different analysis groups.

ITT population (high-dose ICS/LABA and baseline blood eosinophil count ≥ 300 cells/microL).

The primary endpoint for both trials was the annual asthma exacerbation rate ratio versus placebo within the primary efficacy population (ITT). Key secondary endpoints were FEV₁ and total asthma symptom score. Other lung function, symptom control and quality of life measures were also assessed.
Demographic, key respiratory and other baseline disease characteristics were balanced across the ITT treatment groups (Fasenra Q8w and placebo) in both trials. The demographic and patient characteristics in the ITT population were generally similar to the overall population for the two treatment arms, as well as the < 300 cells/microL subgroup.
Treatment with Fasenra Q8w significantly reduced the annual rate of exacerbations (primary endpoint) by 51% (SIROCCO) and 28% (CALIMA) compared to placebo (see Table 6). Similar reductions were observed compared to placebo for exacerbations requiring hospitalisations only (52%) and emergency room visits only (77%) in SIROCCO. In CALIMA, there were too few events in the placebo treatment arm to draw conclusions for exacerbations requiring hospitalisation or emergency room visits.
Clinically and statistically significant improvements in lung function were also observed with a 0.159 L (SIROCCO) and 0.116 L (CALIMA) increase in pre-bronchodilator FEV₁ relative to placebo (see Table 6). Compared with placebo, Fasenra Q8w provided consistent improvements over time in the mean change from baseline in FEV₁. Benefits of Fasenra Q8w on lung function were further supported by improvements in the mean change for morning and evening peak expiratory flow (PEF) from baseline compared to placebo.
Significant improvements were also observed for total asthma symptoms score and the Asthma Control Questionnaire (ACQ-6) after treatment with Fasenra Q8w relative to placebo (see Table 6). Significant improvements in quality of life, as measured by the Standardised Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(S)+12), were also demonstrated for Fasenra Q8w compared to placebo (see Table 6).

Baseline blood eosinophil subgroup analyses.

While efficacy benefits were observed with Fasenra compared to placebo irrespective of baseline eosinophil count, increasing baseline eosinophil counts were identified as a potential predictor of improved treatment response (see Figure 1).

Prior exacerbation history.

A subgroup analysis on prior exacerbation history within the ITT population indicated that a higher prior exacerbation history may also be a potential predictor of an improved treatment response. When considered alone, or in combination with a higher baseline eosinophil count, these factors may further identify patients who may achieve a greater response from treatment with Fasenra.
OCS dose reduction trials (ZONDA and PONENTE). ZONDA, a placebo-controlled study, and PONENTE, an open-label study, evaluated the effect of Fasenra on reducing the use of maintenance OCS.

ZONDA.

ZONDA included patients who were treated with daily OCS (7.5 to 40 mg/day) in addition to regular use of high-dose ICS/LABA with or without additional controller(s) to maintain asthma control. The definition of high-dose ICS was as per SIROCCO/CALIMA. There was an 8-week run-in period during which a patient's OCS dose was titrated to the minimum effective dose while maintaining asthma control. The baseline median OCS dose was 10 mg (range: 8-40 mg) for both treatment groups. Patients were also required to have blood eosinophil counts ≥ 150 cells/microL and a history of at least one exacerbation in the past 12 months. All patients were included in the analysis, including 20 patients with a baseline blood eosinophil count of ≥ 150-299 cells/microL (12 in Fasenra Q8w arm and 11 in the placebo arm).
Demographic, key respiratory and other baseline disease characteristics were balanced across the treatment groups (Fasenra Q8w and placebo).
The primary endpoint was percent (%) reduction from baseline of the final OCS dose during Weeks 24 to 28, while maintaining asthma control. Compared to placebo, patients receiving Fasenra Q8w achieved greater reductions in daily maintenance OCS dose while still maintaining asthma control. Reductions of ≥ 50% in the OCS dose were observed in 66% of patients receiving Fasenra Q8w compared to 37% for the placebo arm (see Table 7). The proportion of patients with a mean final OCS dose ≤ 5 mg at Weeks 24 to 28 were 59% for Fasenra Q8w and 33% for placebo (odds ratio 2.74 (95% CI: 1.41, 5.31), p=0.002). Patients with an optimized baseline OCS dose (12.5 mg or less) were eligible to achieve a 100% reduction in OCS dose during the study. A significant difference was observed in the percentage of eligible patients who achieved 100% reduction with Fasenra Q8w compared to placebo (52.4% vs 19.0%; Odds ratio 4.19 (95% CI: 1.58, 11.12), p=0.002).

Fasenra Q8w demonstrated a 70% reduction in the annual asthma exacerbation rate over 28 weeks compared with placebo (Rate ratio: 0.30 (95% CI: 0.17, 0.53), p < 0.001), and a 93% reduction in the annual asthma exacerbation rate associated with an emergency room visit or hospitalisations (Rate ratio: 0.07 (95% CI: 0.01, 0.63), p = 0.018) over 28 weeks compared with placebo.

PONENTE.

PONENTE enrolled 598 adult patients with severe asthma (blood eosinophil count ≥ 150 cells/microL at entry or ≥ 300 cells/microL in the past 12 months if study entry count was < 150 cells/microL) who were OCS-dependent. The primary endpoints included the proportion of patients who achieved a final OCS dose less than or equal to 5 mg while maintaining asthma control and taking into account adrenal function. The proportion of patients who achieved an OCS dose less than or equal to 5 mg (while maintaining asthma control and not limited by adrenal function) was 81.9%. Effects on OCS reduction were similar irrespective of blood eosinophil count at study entry (including patients with blood eosinophils < 150 cells/microL) and maintained over an additional period of 24 to 32 weeks.
Long term data. The long-term safety and efficacy of Fasenra was evaluated in a double-blind, randomised, parallel group, Phase 3, 56-week extension trial (BORA) in adult and adolescent (aged 12 years and older) patients from the predecessor studies - SIROCCO, CALIMA and ZONDA. The long-term safety of Fasenra was evaluated in an open-label safety extension trial MELTEMI (see Section 4.8 Adverse Effects (Undesirable Effects)).
BORA assessed the long-term effect of Fasenra on annual asthma exacerbation rate, lung function and ACQ-6, AQLQ(S)+12 at the 2 dosing regimens studied in the predecessor studies.
A total of 543 adult and adolescent patients were randomised to receive Fasenra Q8w in the predecessor trials and were treated and remained in the BORA extension trial - 512 from SIROCCO/CALIMA (full analysis set) and 31 from ZONDA.
The reduction in annual rate of asthma exacerbations observed in the placebo-controlled predecessor SIROCCO and CALIMA trials in patients with baseline blood eosinophil counts of ≥ 300 cells/microL who were taking high-dose ICS (ITT population) was maintained over the second year of treatment. In patients who received Fasenra in predecessor SIROCCO and CALIMA trials, 73% were exacerbation-free in the extension BORA trial. Similar maintenance of effect was observed throughout BORA in lung function, ACQ-6 and AQLQ(S)+12.
In a pre-specified pooled analysis, maintenance of the reduction in daily OCS dose was also observed over the extension trial in patients enrolled from ZONDA (Figure 2).

MELTEMI was designed as an open-label safety extension study, enrolling adult patients who completed at least 16 weeks in ZONDA (see Section 4.8 Adverse Effects (Undesirable Effects)). The safety of the 2 dosing regimens studied in the predecessor studies was evaluated in 446 patients who received at least 1 dose of Fasenra.

5.2 Pharmacokinetic Properties

The pharmacokinetics of benralizumab were dose-proportional in patients with asthma following subcutaneous administration over a dose range of 2 to 200 mg.

Absorption.

Following subcutaneous administration to patients with asthma, the absorption half-life was 3.5 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 59% and there was no clinically relevant difference in relative bioavailability in the administration to the abdomen, thigh or upper arm.

Distribution.

Based on population pharmacokinetic analysis, central and peripheral volume of distribution of benralizumab was 3.1 L and 2.5 L respectively for a 70 kg individual.

Metabolism.

Benralizumab is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue.

Excretion.

From population pharmacokinetic analysis, benralizumab exhibited linear pharmacokinetics and no evidence of target receptor-mediated clearance pathway. The estimated systemic clearance (CL) for benralizumab was at 0.29 L/day. Following subcutaneous administration, the elimination half-life was approximately 15.5 days.