Consumer medicine information

Beovu

Brolucizumab

BRAND INFORMATION

Brand name

Beovu

Active ingredient

Brolucizumab

Schedule

SUMMARY CMI

Beovu^®

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 receiving Beovu?

Beovu contains the active ingredient brolucizumab. Beovu is used to treat eye conditions in adults 1) neovascular (wet) age-related macular degeneration (AMD) or wet AMD, 2) diabetic macular oedema (DME).

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

2. What should I know before I am given Beovu?

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

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

For more information, see Section 2. What should I know before I am given Beovu? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Beovu 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 will I be given Beovu?

Beovu is given by an ophthalmologist (eye doctor) as an injection into the eye under a local anaesthetic.
The recommended dose is 6 mg (0.05 mL) of brolucizumab.

More instructions can be found in Section 4. How will I be given Beovu? in the full CMI.

5. What should I know while I am given Beovu?

Things you must do	Remind any doctor, dentist or pharmacist you visit that you are using Beovu. Tell your doctor if you experience signs of inflammation or infection or you become pregnant.
Driving or using machines	Do not drive or operate machinery if your vision is poor, either because of your disease or because of the treatment.
Drinking alcohol	There are no known interactions between Beovu and alcohol.
Looking after your medicine	Your ophthalmologist (eye doctor) will treat you with Beovu. There is no need to store this medicine at home.

For more information, see Section 5. What should I know while I am given Beovu? in the full CMI.

6. Are there any side effects?

The most common side effects are: eye irritation, clouding of the lens, dry eye, abnormal sensation in the eye, pain or irritation at the site of the injection, increased tear production, redness or itching of the eye, small particles or spots in your vision (floaters), allergic reactions (rash, itching, redness of the skin).

The most serious side effects are: redness or worsening redness of the eye, eye pain, sensitivity to light, any vision changes, including sudden vision loss, seeing flashes of light with floaters (seeing spots or cobwebs), progressing to blurred vision or loss of sight, stroke and heart attack.

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. 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

Beovu^®

Active ingredient(s): brolucizumab (rbe)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

1. Why am I receiving Beovu?
2. What should I know before I am given Beovu?
3. What if I am taking other medicines?
4. How will I be given Beovu?
5. What should I know while I am given Beovu?
6. Are there any side effects?
7. Product details

1. Why am I receiving Beovu?

Beovu contains the active ingredient brolucizumab. It is a prescription medicine that is injected into the eye by your ophthalmologist (eye doctor) to treat eye conditions which may impact your vision. It belongs to a group of medicines called anti-neovascularization agents ("anti-VEGF").

Beovu is used to treat eye conditions in adults which may cause decreased vision such as:

Wet age-related macular degeneration (wet AMD)
Diabetic macular oedema (DME)

Beovu may slow down disease progression and thereby maintain, or even improve your vision.

If you have any questions about Beovu, how it works or why this medicine has been prescribed for you, ask your doctor.

Your doctor may have prescribed it for another reason. It is available only with a doctor's prescription.

This medicine is not addictive.

There is not enough information to recommend the use of this medicine for children or adolescents.

2. What should I know before I am given Beovu?

Warnings

You must not be given Beovu if:

you are allergic (hypersensitive) to brolucizumab, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
you have an active or suspected infection in or around the eye.
you experience pain or redness in your eye.

Check with your doctor if you:

have glaucoma.
have a history of seeing flashes of light or floaters (dark floating spots) and if you have a sudden increase of size and number of floaters.
have a prior history of eye diseases or eye treatments.
if you have a history of sudden vision loss due to blockage of blood vessels in the back of the eye (retinal vascular occlusion) or inflammation of blood vessels in the back of the eye (retinal vasculitis) in the last year
ever had a stroke or heart attack. Signs of a stroke may include weakness or numbness of limbs or face, difficulty speaking or swallowing. Signs of a heart attack may include chest pain, which may spread to the neck and shoulders.
had a surgery or surgery is planned on your eye within the previous or next four weeks.
take any medicines for any other condition.

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant, think you are pregnant or plan to become pregnant. Your doctor can discuss with you the risks and benefits involved. It is recommended that you use effective contraception during Beovu treatment and for at least one month after the last injection of Beovu.

Talk to your doctor if you are breastfeeding or plan to breastfeed. Beovu is not recommended during breast feeding and for at least one month after the last injection when stopping treatment with Beovu. It is not known whether Beovu passes into breast milk.

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.

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

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

4. How will I be given Beovu?

How Beovu is given

Beovu is given by your ophthalmologist (eye doctor) as an injection into your eye (intravitreal injection).

Before the injection, your doctor will use a disinfectant eyewash to clean your eye carefully, to prevent infection. Your doctor will also give you an eye drop (local anesthetic) to numb the eye to reduce or prevent any pain you might have with the injection.

Follow the 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, ask your doctor for help. It is important to see your doctor regularly when on treatment with Beovu.

How much is given

The recommended dose is 6 mg (0.05 mL) of brolucizumab.

When it is given

Wet AMD

You will be treated with one injection per month for the first three months.
After that, you may get one injection every eight (2 months) to twelve weeks (3 months). The treatment interval between two doses should not be less than every eight weeks (2 months). Your doctor will determine your treatment interval based on the condition of your eye.

DME

You will be treated with one injection every six weeks for the first five injections.
After that, you may get one injection every twelve or sixteen weeks (3 or 4 months). Your doctor will determine your treatment interval based on the condition of your eye; some patients may need treatment every eight weeks (2 months). The treatment interval between two doses should not be less than every eight weeks (2 months).

Follow the instructions provided and use Beovu until your doctor tells you to stop.

How long does Beovu treatment continue

Beovu is used to treat chronic eye diseases, therefore this is a long-term treatment, possibly continuing for months or years. Your doctor will check that the treatment is having the desired effect during your regularly scheduled visits. Your doctor may also check your eyes during a visit without an injection.

If you have questions about how long you will receive Beovu, talk to your doctor.

If a scheduled Beovu injection is missed

If you miss an appointment for Beovu treatment, contact your doctor as soon as possible. Your doctor will decide when you should be given your next dose.

Missing an injection may reverse the visual improvement you may have experienced.

Before stopping Beovu treatment

Speak with your doctor before stopping treatment.

Stopping treatment may increase your risk of vision loss and reverse the visual improvement you may have experienced.

If you are given too much Beovu

If you are given more Beovu than you need, your doctor will check the pressure in your eye and may need to treat it if it is increased. If you are unwell after receiving Beovu contact your doctor.

5. What should I know while I am given Beovu?

Things you must do

Tell your doctor immediately if you notice any of the following symptoms during or after Beovu is injected:

develop redness of the eye or worsening eye redness, eye pain, increased discomfort, any change in vision (such as sudden vision loss, blurred or decreased vision), an increased number of small particles also commonly referred to as floaters, seeing spots or cobwebs in your vision, increased sensitivity to light, nausea or vomiting, develop sudden vision loss, which could be a sign of retinal vascular occlusion. All of these could be symptoms of a serious eye condition and may result in your doctor discontinuing your treatment with Beovu.
develop serious eye infection or eye disorder as it can sometimes develop after an injection into the eye.
notice any bruising or unexplained bleeding. There is a theoretical increased risk of bleeding with this group of medicines (anti-VEGF).
the systemic use of VEGF inhibitors, substances similar to those contained in Beovu, is potentially related to the risk of blood clots blocking blood vessels (arterial thromboembolic events), which may lead to heart attack or stroke. There is a theoretical risk of such events following injection of Beovu into the eye
become pregnant while being treated with this medicine, tell your doctor immediately.

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

Furthermore it is important for you to know that:

the safety and efficacy of Beovu when administered to both eyes at the same time has not been studied and use in this way may lead to an increased risk of experiencing side effects
injections with Beovu may cause an increase in eye pressure (intraocular pressure) in some patients within 30 minutes of the injection. Your doctor will monitor this after each injection
your doctor will check whether you have other risk factors that may increase the change of a tear or detachment of one of the layers at the back of the eye (retinal detachment or tear; and retinal pigment epithelial detachment or tear), in which case Beovu must be given with caution.

Things you must not do

Driving or using machines

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

Do not drive or operate machinery if your vision is poor, either because of your disease or because of the treatment. After your injection with Beovu, you may experience some temporary vision problems (example - blurry vision). If you are affected, do not drive, operate machinery or do anything else that could be dangerous until your vision is normal.

Looking after your medicine

The information on how to store Beovu is meant for your doctor, who will be storing, handling, and injecting Beovu.

If you have to store Beovu:

Pre-filled syringe

Keep it in a refrigerator (2°C to 8°C). Do not freeze it.
Keep the pre-filled syringe in the sealed blister and in the outer carton in order to protect from light.
Prior to use, the unopened blister may be kept at room temperature (25°C) for up to 24 hours.

Vial

Keep it in a refrigerator (2°C to 8°C). Do not freeze it.
Keep the vial in the outer carton in order to protect from light.
Prior to use, the unopened vial may be kept at room temperature (25°C) for up to 24 hours.

Do not store Beovu or any other medicines

in the bathroom or near a sink, or
in the car or on window sills

Keep the medicine where young children cannot reach it.

Getting rid of any unwanted medicine

You must not be given 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 safe disposal.

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.

The side effects associated with the administration of Beovu are either due to the medicine itself or the injection procedure and mostly affect the eye.

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

Less serious side effects

Less serious side effects	What to do
Injection site reactions such as: eye irritation, clouding of the lens, a feeling of having something in the eye, dry eye, abnormal sensation in the eye eye discomfort, pain or irritation at the site of the injection, increased tear production, redness or itching of the eye, small particles or spots in your vision (floaters) allergic reactions (rash, itching, redness of the skin)	Speak to your doctor if you have any of these less serious side effects and they worry you

Serious side effects

Serious side effects	What to do
Eye infection symptoms such as: bloodshot eye, bleeding in the eye (retinal haemorrhage, conjunctival haemorrhage), inflammation or infection of the eyelid margins, visual disturbance, blurred or decreased sharpness of vision, blindness (temporary or otherwise) discharge of the eye with itching, redness and swelling (conjunctivitis) small marks on the surface of the eye, swelling of a section of the eye ( uveitis, iritis, iridocyclitis, conjunctivitis), swelling or irritation of the eyelid, eyelid pain, sac of pus on the eye detachment of one of the layers at the back of the eye (vitreous detachment) tear of the retina at the back of the eye (retinal tear) increase in eye pressure	Tell your doctor as soon as possible if you notice any of these side effects
Worsening of eye inflammation or infection such as: inflammation of blood vessels in the back of the eye (retinal vasculitis), redness or worsening redness of the eye (retinal vascular occlusion), eye pain, severe inflammation inside the eye (endophthalmitis), sensitivity to light, any vision changes, including sudden vision loss. seeing flashes of light with floaters (seeing spots or cobwebs), progressing to blurred vision or loss of sight	Tell your doctor immediately, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Nervous system disorders: signs of a stroke, such as weakness or numbness of limbs or face, difficulty speaking or swallowing Heart disorders: signs of a heart attack may include chest pain, which may spread to the neck and shoulders	Go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed here may also occur in some people. Some of these side effects (e.g. an increase in the pressure inside your eye) can only be found when your doctor does tests to check your progress.

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 Beovu contains

Active ingredient (main ingredient)	Pre-filled syringe contains 19.8 mg brolucizumab as the active ingredient. Vial contains 27.6 mg brolucizumab as the active ingredient.
Other ingredients (inactive ingredients)	sodium citrate sucrose polysorbate 80 water for injections
Potential allergens	This medicine contains sorbates.

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

What Beovu looks like

Pre-filled syringe (Aust R 313681)

Beovu is a solution for injection supplied in a glass pre-filled syringe. The pre-filled syringe contains 0.165 mL of a clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution.

Beovu is supplied as packs containing one single use sterile pre-filled syringe in a sealed tray.

Vial (Aust R 313680)*

Beovu is a solution for injection supplied in a glass vial.

The vial contains 0.230 mL of a clear to slightly opalescent, colourless to slightly brownish-yellow aqueous solution.

Beovu is supplied as packs containing one single use glass vial and one filter needle for withdrawal of the vial contents.

*Not all presentations may be marketed.

Who distributes Beovu

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1-800-671-203
Web site: www.novartis.com.au

This leaflet was prepared in March 2024.

® Registered trademark.

(beo190624c based on PI beo190624i)

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Beovu

Active ingredient

Brolucizumab

Schedule

1 Name of Medicine

Brolucizumab (rbe).

2 Qualitative and Quantitative Composition

One mL solution for injection contains 120 mg of brolucizumab*.
* Brolucizumab is a humanised monoclonal single-chain Fv (scFv) antibody fragment with a molecular weight of ~26 kDa, produced in Escherichia coli cells by recombinant DNA technology.

Beovu 120 mg/mL solution for injection in pre-filled syringe.

Each pre-filled syringe contains 19.8 mg brolucizumab in 0.165 mL solution. This provides a usable amount to deliver a single dose of 0.05 mL containing 6 mg of brolucizumab.

Beovu 120 mg/mL solution for injection in vial.

Each vial contains 27.6 mg brolucizumab in 0.230 mL solution. This provides a usable amount to deliver a single dose of 0.05 mL containing 6 mg of brolucizumab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Sterile, clear to slightly opalescent, colourless to slightly brownish-yellow and preservative-free aqueous solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Beovu is indicated for the treatment of:
Neovascular (wet) age-related macular degeneration (AMD);
Diabetic macular oedema (DME).

4.2 Dose and Method of Administration

Beovu must be administered by a qualified ophthalmologist experienced in administering intravitreal injections.

Dosage.

Wet AMD.

The recommended dose is 6 mg brolucizumab (0.05 mL solution) administered by intravitreal injection every 4 weeks (monthly) for the first 3 doses. Thereafter, the physician may individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. A disease activity assessment is suggested 16 weeks (4 months) after treatment start. In patients with disease activity, treatment every 8 weeks (2 months) should be considered. In patients without disease activity, treatment up to every 12 weeks (3 months) should be considered.
Following the first three loading doses, the interval between two doses should not be less than every 8 weeks (2 months) (see Section 4.4 Special Warnings and Precautions for Use).

Diabetic macular oedema (DME).

The recommended dose is 6 mg brolucizumab (0.05 mL solution) administered by intravitreal injection every 6 weeks for the first 5 doses. Thereafter, the physician may individualise treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. In patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered. After 12 months of treatment, in patients without disease activity, treatment intervals up to 16 weeks (4 months) could be considered.
Following the first five loading doses, the interval between 2 doses should not be less than every 8 weeks (2 months) (see Section 4.4 Special Warnings and Precautions for Use).
If visual and anatomical outcomes indicate that the patient is not benefiting from continued treatment, Beovu should be discontinued.

Special populations.

Hepatic impairment.

No dosage regimen adjustment is required in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dosage regimen adjustment is required in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Elderly patients (aged 65 years and over).

No dose adjustment is required in patients aged 65 years or above (see Section 5.2 Pharmacokinetic Properties).

Paediatric patients (below 18 years).

The safety and efficacy of Beovu in children and adolescents below 18 years of age have not been established.

Method of administration.

Beovu is for intravitreal use only.
As with all medicinal products for intravitreal use, the solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, Beovu must not be used and appropriate replacement procedures followed.
Do not use if the packaging, or its content is damaged or expired. Detailed instructions for use are provided in the pack in the 'How to Use' leaflet.
The injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Sterile paracentesis equipment should be available as a precautionary measure. The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see Section 4.3 Contraindications). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
The injection needle should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 mL is then delivered slowly; a different scleral site should be used for subsequent injections.
The safety and efficacy of Beovu administered in both eyes concurrently have not been studied.

Pre-filled syringe.

The pre-filled syringe is for single use only. Each pre-filled syringe should only be used for the treatment of a single eye. Discard any residue.
Since the volume contained in the pre-filled syringe (0.165 mL) is greater than the recommended dose (0.05 mL), a portion of the volume contained in the pre filled syringe must be discarded prior to administration.
Injecting the entire volume in the pre-filled syringe could result in overdose. To expel the air bubble along with excess medicinal product, the plunger should be slowly depressed until the edge below the dome of the rubber stopper is aligned with the 0.05 mL dose mark (equivalent to 50 microL, i.e. 6 mg brolucizumab).

Vial.

The vial is for single use only. Each vial should only be used for the treatment of a single eye. Discard any residue.
Since the volume contained in the vial (0.230 mL) is greater than the recommended dose (0.05 mL), a portion of the volume contained in the vial must be discarded prior to administration.
Injecting the entire volume in the vial could result in overdose. To expel the air bubble along with excess medicinal product, the air should be carefully expelled from the syringe and the dose adjusted to the 0.05 mL mark (equivalent to 50 microL, i.e. 6 mg brolucizumab).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).
Patients with active or suspected ocular or periocular infections.
Patients with active intraocular inflammation.

4.4 Special Warnings and Precautions for Use

Endophthalmitis, intraocular inflammation and retinal detachments.

Intravitreal injections, including those with Beovu, have been associated with endophthalmitis, intraocular inflammation, and retinal detachments (see Section 4.8 Adverse Effects (Undesirable Effects)). Proper aseptic injection techniques must always be used when administering Beovu. Patients should be instructed to report any symptoms suggestive of endophthalmitis, intraocular inflammation or retinal detachment without delay and should be managed appropriately (see Section 4.2 Dose and Method of Administration).
In a Phase IIIa clinical study (MERLIN), patients with nAMD who received Beovu every 4 weeks maintenance dosing experienced a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients who received Beovu every 8 or 12 week maintenance dosing in the pivotal phase III Clinical studies (HAWK and HARRIER) (see Section 4.8 Adverse Effects (Undesirable Effects)). The interval between two Beovu doses during maintenance treatment should not be less than 8 weeks (see Section 4.2 Dose and Method of Administration).

Retinal vasculitis and/or retinal vascular occlusion.

Retinal vasculitis and/or retinal vascular occlusion have been reported with the use of Beovu. These immune mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with Beovu in patients who develop these events. Patients treated with Beovu who experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored. Concomitant intraocular inflammation was reported, but not in all cases (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). Prior treatment was not reported for all cases but some patients had previous intravitreal VEGF inhibitor therapy. Patients should be monitored and instructed to report any change in vision without delay.

Intraocular pressure increases.

Transient increases in intraocular pressure have been seen within 30 minutes of injection, similar to those observed with intravitreal administration of other VEGF inhibitors (see Section 4.8 Adverse Effects (Undesirable Effects)). Sustained intraocular pressure increases have also been reported with Beovu. Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. Special precaution is needed in patients with poorly controlled glaucoma.

Arterial thromboembolic events.

There is a potential risk of arterial thromboembolic events (ATE) following intravitreal use of VEGF inhibitors. ATEs include for example ischaemic stroke or myocardial infarction.

Bilateral treatment.

The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied.

Immunogenicity.

As this is a therapeutic protein, there is a potential for immunogenicity with brolucizumab (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be instructed to inform their physician if they develop symptoms such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity to light (see Section 4.8 Adverse Effects (Undesirable Effects)).

Concomitant use of other anti-VEGF.

There are no data available on the concomitant use of Beovu with other anti-VEGF medicinal products in the same eye. Brolucizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).

Withholding treatment.

In intravitreal anti-VEGF treatments, the dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:
a decrease in best-corrected visual acuity (BCVA) of ≥ 30 letters compared with the last assessment of visual acuity;
a retinal break;
a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥ 50% of the total lesion area;
performed or planned intraocular surgery within the previous or next 28 days.

Retinal pigment epithelial tear.

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating brolucizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes.

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

Systemic effects following intravitreal use.

Systemic adverse events, including non-ocular haemorrhages and arterial thromboembolic events, have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with AMD with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients.

Sodium content.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium-free".

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies have been performed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproductive or fertility studies have been conducted. However, VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF inhibitors, there is a potential risk for reproduction, and to embryofetal development.
(Category D)
There are no adequate and well-controlled studies of Beovu administration in pregnant women. The potential risk of use of Beovu in pregnancy is unknown.
In an enhanced pre and postnatal development (ePPND) study, in pregnant cynomolgus monkeys, brolucizumab was administered to animals by intravitreal (IVT) injection to one eye at doses up to 6 mg once every 4 weeks until delivery. One additional injection was administered to a subset of animals 28 days post-partum. There was no effect on embryofetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring. This represents an exposure approximately 6-times the human exposure (based on serum C_max) at the proposed clinical dose of 6 mg. However, based on the anti-VEGF mechanism of action, brolucizumab must be regarded as potentially teratogenic and embryo-fetotoxic. Therefore, brolucizumab should not be used during pregnancy unless the expected benefit outweighs the potential risks to the fetus.
It is unknown whether brolucizumab is excreted in human milk. There are no data on the effects of brolucizumab on the breast-fed newborn/infant or on milk production. In an ePPND study, brolucizumab was not detected in the maternal milk or infant serum of cynomolgus monkeys. Because of the potential for adverse drug reactions in the breast-fed newborn/infant, breast-feeding is not recommended during treatment and for at least one month after the last dose when stopping treatment with Beovu.

Women of childbearing potential/contraception in females.

Females of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Beovu and for at least one month after the last dose when stopping treatment with Beovu.

4.7 Effects on Ability to Drive and Use Machines

Patients may experience temporary visual disturbances after an intravitreal injection with Beovu and the associated eye examination (see Section 4.8 Adverse Effects (Undesirable Effects)) and should therefore be advised not to drive or use machinery until visual function has recovered sufficiently.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Wet AMD population.

A total of 1,088 patients treated with brolucizumab constituted the safety population in the two Phase III studies (HAWK and HARRIER) with a cumulative 96 weeks' exposure to Beovu and 730 patients treated with the recommended dose of 6 mg (see Section 5.1 Pharmacodynamic Properties).
The most frequently reported adverse drug reactions (in > 5% of patients treated with Beovu) 6 mg were reduced visual acuity (7.3%), cataract (7.0%), conjunctival haemorrhage (6.3%) and vitreous floaters (5.1%).
Serious adverse drug reactions reported in < 1% of the patients treated with Beovu 6 mg were endophthalmitis, uveitis, blindness, retinal artery occlusion and retinal detachment.

DME population.

The safety of Beovu was studied in two, Phase III active controlled studies (KESTREL and KITE) conducted respectively in 368 patients with visual impairment due to DME treated with the recommended dose of brolucizumab 6 mg for 100 weeks.
The ocular and non-ocular events in the KESTREL and KITE studies were reported with a frequency and severity similar to those seen in the wet AMD trials. Retinal vascular occlusion was reported in four patients (1.1%) treated with Beovu and two patients (0.5%) treated with aflibercept 2 mg. Retinal vasculitis was reported in one patient (0.3%) treated with Beovu and no patients treated with aflibercept 2 mg. The adverse drug reactions of iridocyclitis and vitreous haemorrhage were observed at a higher frequency (category of common) in the pooled DME Phase III studies as compared to the pooled nAMD Phase III studies (category of uncommon). In addition, the adverse drug reaction retinal vascular occlusion was observed at a frequency category of common in the pooled DME Phase III studies.

Tabulated list of adverse reactions.

The adverse reactions experienced following administration of Beovu in clinical studies are summarised in Table 1.
Adverse reactions (Table 1) are listed according to the MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Frequency categories for each adverse reaction are based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10,000 to < 1/1 000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from post-marketing experience with Beovu via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Eye disorders.

Retinal vascular occlusion, retinal vasculitis, scleritis.

Description of selected adverse drug reaction.

Arterial thromboembolic events. Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. The ATE rate in the two controlled 96-week neovascular AMD studies (HAWK and HARRIER) was 4.5% (33 of 730) in the pooled brolucizumab arms compared with 4.7% (34 of 729) in the pooled aflibercept arms.
Immunogenicity. As with all therapeutic proteins, there is a potential for an immune response in patients treated with Beovu. The immunogenicity of Beovu was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Beovu in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Beovu with the incidence of antibodies to other products may be misleading.
Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion. Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, has been reported with the use of Beovu (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). A higher number of intraocular inflammation events were observed among patients with treatment-emergent antibodies. After investigation, retinal vasculitis and/or retinal vascular occlusion were found to be immune mediated events. Intraocular inflammation, including retinal vasculitis and/or retinal vascular occlusion, may occur following the first intravitreal injection and at any time of treatment. These events were observed more frequently at the beginning of the treatment.
Intraocular inflammation incidence was approximately 4% in phase III clinical studies HAWK and HARRIER. In the phase III clinical studies KESTREL and KITE, the incidence of intraocular inflammation for brolucizumab 6 mg was approximately 3%. Based on clinical studies these events were more frequent in female patients treated with Beovu than male patients (e.g. 5.3% females vs. 3.2% males in HAWK and HARRIER) and in Japanese patients.
In patients developing these events, treatment with Beovu should be discontinued and the events should be promptly managed. Patients treated with Beovu with a medical history of intraocular inflammation and/or retinal vascular occlusion (within 12 months prior to the first brolucizumab injection) should be closely monitored, since they are at increased risk of developing retinal vasculitis and/or retinal vascular occlusion.
The interval between two Beovu doses during maintenance treatment should not be less than 8 weeks considering that a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion was reported in patients with nAMD who received Beovu every 4 week maintenance dosing in a clinical study compared to patients who received Beovu every 8 or 12 week maintenance dosing in the pivotal Phase III clinical studies.

Wet AMD.

The pre-treatment incidence of anti-brolucizumab antibodies was 35-52%. After dosing with Beovu for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23-25% of patients.

DME.

The pre-treatment incidence of anti-brolucizumab antibodies was 64%. After dosing with Beovu for 96 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 16 to 23% of patients.
In wet AMD and DME, among patients with treatment-emergent antibodies, a higher number of intraocular inflammation events were observed. Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, are immune mediated adverse events related to exposure to Beovu. This treatment emergent antibody response may develop following the first intravitreal injection (see Section 4.4 Special Warnings and Precautions for Use).

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

Overdosing with greater than recommended injection volume may increase intraocular pressure. In the event of overdose, intraocular pressure should therefore be monitored and, if deemed necessary by the treating physician, appropriate treatment should be initiated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA06.

Mechanism of action.

Increased levels of signalling through the vascular endothelial growth factor A (VEGF-A) pathway are associated with pathological ocular angiogenesis and retinal oedema in age-related macular degeneration. Brolucizumab binds with picomolar affinity to VEGF-A isoforms (e.g. VEGF₁₁₀, VEGF₁₂₁, and VEGF₁₆₅), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A binding to its receptors, brolucizumab suppresses endothelial cell proliferation, thereby reducing pathological neovascularisation and decreasing vascular permeability.

Pharmacodynamic effects.

Wet AMD.

In the HAWK and HARRIER studies, related anatomical parameters were part of the disease activity assessments guiding treatment decisions. Reductions in central subfield thickness (CST) and in presence of intraretinal/subretinal fluid (IRF/SRF) or sub-retinal pigment epithelium (sub-RPE) fluid (pre-specified secondary endpoints) were observed in patients treated with Beovu as early as 4 weeks after treatment initiation and up to week 48 and week 96. Statistically significant greater reductions in CST and in presence of IRF/SRF relative to aflibercept were demonstrated at weeks 16 and 48.
In these studies, for patients treated with Beovu, reductions in CNV lesion size were observed as early as 12 weeks, and at weeks 48 and 96 after treatment initiation.
At week 16, the reduction in CST on Beovu was statistically significantly superior versus aflibercept in both studies (HAWK: -161 vs. -134 microns, p = 0.0008; HARRIER: -174 vs. -134 microns, p < 0.0001). This decrease from baseline in CST was also statistically significant at week 48 (HAWK: -173 vs. -144 microns, p = 0.0012; HARRIER: -194 vs. -144 microns, p < 0.0001), and maintained to the end of each study at week 96 (HAWK: -175 vs. -149 microns, p = 0.0115; HARRIER: -198 vs. -155 microns, p < 0.0001).
At week 16, the percentage of patients with IRF and/or SRF fluid was statistically significantly lower on Beovu versus aflibercept in both studies (HAWK: 34% vs.52%, p < 0.0001; HARRIER: 29% vs. 45%, p < 0.0001). This difference was also statistically significant at week 48 (HAWK: 31% vs. 45%, p = 0.0001; HARRIER: 26% vs. 44%, p < 0.0001), and maintained to the end of each study at week 96 (HAWK: 24% vs. 37%, p = 0.0002; HARRIER: 24% vs. 39%, p < 0.0001).
At week 16, the percentage of patients with sub-RPE fluid was statistically significantly lower on Beovu versus aflibercept in both studies (HAWK: 19% vs.27%, p = 0.0030; HARRIER: 16% vs. 24%, p = 0.0041). This difference was also statistically significant at week 48 (HAWK: 14% vs. 22%, p = 0.0035; HARRIER: 13% vs. 22%, p = 0.0007), and maintained to the end of each study at week 96 (HAWK: 11% vs. 15%, p = 0.1213; HARRIER: 17% vs. 22%, p = 0.0371).

DME.

In the KESTREL and KITE studies, related anatomical parameters were part of the disease activity assessments guiding treatment decisions. Reductions in central subfield thickness (CST) and in presence of intraretinal/subretinal fluid (IRF/SRF) were observed in patients treated with Beovu as early as 4 weeks after treatment initiation and up to week 52. These reductions were maintained up to week 100.

Clinical trials.

Treatment of wet AMD. The efficacy and safety of Beovu were assessed in two randomised, multicentre, double-masked, active-controlled Phase III studies (HAWK and HARRIER) in patients with neovascular (wet) AMD. A total of 1,817 patients were treated in these studies for two years (1,088 on Beovu and 729 on aflibercept). Patient ages ranged from 50 to 97 years, with a mean age of 76 years.
In HAWK, patients were randomised in a 1:1:1 ratio to the following dosing regimens:
brolucizumab 3 mg administered every 12 or 8 weeks after the first 3 monthly doses;
brolucizumab 6 mg administered every 12 or 8 weeks after the first 3 monthly doses;
aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses.
In HARRIER, patients were randomised in a 1:1 ratio to the following dosing regimens:
brolucizumab 6 mg administered every 12 or 8 weeks after the first 3 monthly doses;
aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses.
In both studies, after the first three monthly doses (weeks 0, 4 and 8), brolucizumab patients were treated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based on disease activity. Disease activity was assessed by a physician during the first 12-week interval (at weeks 16 and 20) and at each subsequent scheduled 12-weekly treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased CST and/or presence of IRF/SRF or sub-RPE fluid) at any of these visits were adjusted to an 8-weekly treatment interval.
The below criteria for disease activity were provided as guidance and the Investigator should have considered the guidance while also applying their own expert judgment when making q12w/q8w treatment decisions.
Disease activity guidance criteria at week 16:
decrease in BCVA of ≥ 5 letters compared with baseline;
decrease in BCVA of ≥ 3 letters and CSFT increase ≥ 75 micrometre compared with week 12;
decrease in BCVA of ≥ 5 letters due to nAMD disease activity compared with week 12;
new or worse IRF/intraretinal cysts compared with week 12.
Disease activity guidance criterion at weeks 20, 32, and 44:
decrease in BCVA of ≥ 5 letters due to nAMD disease activity compared with week 12.
Disease activity guidance criterion at weeks 56, 68, 80, and 92:
decrease in BCVA of ≥ 5 letters due to nAMD disease activity compared with week 48.

Results.

The primary efficacy endpoint for the studies was the change from baseline in best corrected visual acuity (BCVA) to week 48, as measured by the early treatment diabetic retinopathy study (ETDRS) letter score, with the primary objective being to demonstrate non-inferiority of Beovu versus aflibercept. In both studies, Beovu (administered in an every 12 weeks or an every 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks). The visual acuity gains observed in the first year were maintained in the second year.
Detailed results of both studies are shown in Table 2 and in Figure 1.

These visual acuity gains were achieved with 56% and 51% of patients treated with Beovu 6 mg on a 12-weekly dosing interval at week 48, and with 45% and 39% of patients at week 96 in HAWK and HARRIER, respectively. Among patients identified as eligible for the 12-weekly regimen during the first 12-week interval, 85% and 82% remained on the 12-weekly dosing interval up to week 48. Of patients on the 12-weekly interval at week 48, 82% and 75% remained on the 12-weekly dosing interval up to week 96.
Treatment effects in evaluable subgroups (e.g. age, gender, race, baseline visual acuity, baseline retinal thickness, lesion type, lesion size, fluid status) in each study were generally consistent with the results in the overall populations.
Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF or sub-RPE. At week 16, when disease activity was first assessed for determining the treatment interval, statistically fewer patients showed disease activity on Beovu 6 mg compared to aflibercept 2 mg (24% vs 35% in HAWK, p = 0.0013; 23% vs 32% in HARRIER, p = 0.0021). Disease activity was assessed throughout the studies. Anatomical parameters of disease activity were decreased at week 48 and at week 96 for Beovu compared to aflibercept.
In both studies, Beovu demonstrated clinically meaningful increases from baseline in the pre-specified secondary efficacy endpoint of patient-reported outcomes, reported through the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in BCVA. Patient-reported outcome benefits were maintained in the second year.
No clinically meaningful differences were found between Beovu and aflibercept in changes from baseline to week 48 in NEI VFQ-25 total score and subscales (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision and peripheral vision).
Treatment of DME. The safety and efficacy of Beovu were assessed in two randomised, multicentre, double-masked, active controlled, Phase III studies (KESTREL and KITE) in patients with diabetic macular oedema (DME).
A total of 926 patients were treated in these studies for 2 years (558 on brolucizumab and 368 on aflibercept 2 mg). Patient ages ranged from 23 to 87 years with a mean of 63 years.
In KESTREL, patients were randomised in a 1:1:1 ratio to the following dosing regimens:
brolucizumab 6 mg administered once every 6 weeks for first 5 doses, followed by brolucizumab 6 mg every 12 or 8 weeks;
brolucizumab 3 mg administered once every 6 weeks for first 5 doses, followed by brolucizumab 3 mg every 12 or 8 weeks;
aflibercept 2 mg administered once every 4 weeks for first 5 doses, followed by aflibercept 2 mg every 8 weeks.
In KITE, patients were randomised in a 1:1 ratio to the following dosing regimens:
brolucizumab 6 mg administered once every 6 weeks for first 5 doses, followed by brolucizumab 6 mg every 12 or 8 weeks or 16 weeks from week 72 onwards;
aflibercept 2 mg administered once every 4 weeks for first 5 doses, followed by aflibercept 2 mg every 8 weeks.
In both studies, after the first five doses (weeks 0, 6, 12, 18 and 24), brolucizumab patients were treated every 12 weeks, with the option of adjusting to a dosing interval every 8 weeks based on disease activity. Disease activity was assessed by a physician during the first 12-week interval (at weeks 32 and 36) and at each subsequent scheduled treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased central subfield thickness) at any of these visits were adjusted to an every 8 weeks treatment interval. In year 2 of KITE, patients who showed no disease activity could be extended to an every 16 weeks treatment interval. The comparator aflibercept was administered every 8 weeks after the first 5 monthly doses.

Results.

The primary efficacy endpoint for both studies was the change from baseline at week 52 in best corrected visual acuity (BCVA) as measured by the early treatment diabetic retinopathy study (ETDRS) letter score with the primary objective to demonstrate non-inferiority of Beovu versus aflibercept 2 mg. In both studies, Beovu (administered in an every 12 weeks or an every 8 weeks regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered every 8 weeks).
The results of KESTREL and KITE also demonstrated non-inferiority of Beovu versus aflibercept 2 mg for the key secondary endpoint (average change from baseline in BCVA over the period week 40 through week 52).
The median number of injections given over 24 months was 11 in patients treated with Beovu versus 15 in patients treated with aflibercept 2 mg.
Detailed results of both studies are shown in Table 3 and Figure 2.

These visual acuity gains were achieved with 55% and 50% of patients treated with Beovu on a 12-weekly dosing interval at week 52, and 44% and 37% of patients treated with Beovu on a 12-weekly or 12-weekly/16-weekly dosing interval at week 100 in KESTREL and KITE, respectively. Among patients identified as eligible for the 12-weekly dosing during the first 12-week interval, approximately 70% remained on at least the 12-weekly dosing interval at week 100 in both studies.
In KITE, 25% of patients were treated with Beovu on a 16-weekly dosing interval at week 100.
Treatment effects in evaluable subgroups (i.e. age, gender, baseline HbA1c, baseline visual acuity, baseline central subfield thickness, DME lesion type, duration of DME since diagnosis, retinal fluid status) in each study were generally consistent with the results in the overall population.
In KESTREL and KITE, disease activity (DA) was assessed throughout the studies by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF. At the first assessment at week 32, disease activity was observed in 20.1% and 24.2% of patients treated with Beovu (5 injections received) and 27.8% and 39.8% of patients treated with aflibercept 2 mg (6 injections received) in KESTREL and KITE, respectively.
In both studies, Beovu demonstrated a significant reduction from baseline in CST starting at week 4 and continuing up to week 52. In KITE, the average reduction from baseline over the period week 40 to week 52 with Beovu was statistically superior to that observed with aflibercept 2 mg. From week 40 to week 52 in both studies, the proportion of patients with IRF/SRF was lower in patients treated with Beovu (range 54% to 65%) compared to patients treated with aflibercept 2 mg (range 71% to 80%). The reduction in CST from baseline was maintained up to week 100. At week 100, the proportion of patients with IRF/SRF was lower in patients treated with Beovu (42% KESTREL and 41% KITE) compared to patients treated with aflibercept 2 mg (54% KESTREL and 57% KITE).
In both studies, Beovu demonstrated increases from baseline in the pre-specified secondary efficacy endpoint of patient reported outcomes, reported through the national eye institute visual function questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in best corrected visual acuity (BCVA).
No differences were found between Beovu and aflibercept 2 mg in changes from baseline to week 52 and to week 100 in NEI VFQ-25 total score and subscales (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision, and peripheral vision).
Diabetic retinopathy severity score (DRSS) was assessed in the KESTREL and KITE studies. At baseline, 98.1% of patients in both KESTREL and KITE had gradable DRSS scores. Based on the pooled analysis, 28.9% of patients treated with Beovu experienced a ≥ 2 step improvement from baseline to week 52 in the DRSS score compared to 24.9% of patients treated with aflibercept 2 mg. The estimated difference between Beovu and aflibercept 2 mg was 4.0% (95% CI: [-0.6, 8.6]). At week 100, the proportion of patients with a ≥ 2 step improvement from baseline to week 100 in the DRSS score was 32.8% with Beovu and 29.3% with aflibercept 2 mg in KESTREL and 35.8% with Beovu and 31.1% with aflibercept 2 mg in KITE.
Paediatric population. The safety and efficacy of Beovu in children and adolescents below 18 years of age have not been established (see Section 4.2 Dose and Method of Administration, Paediatric patients (below 18 years) for information on paediatric use).

5.2 Pharmacokinetic Properties

Beovu is administered directly into the vitreous to exert local effects in the eye.

Absorption/distribution.

After intravitreal administration of 6 mg brolucizumab per eye to patients with nAMD, the mean C_max of free brolucizumab in the plasma was 49.0 nanogram/mL (range: 8.97 to 548 nanogram/mL) and was attained in 1 day.

Excretion.

Brolucizumab is a monoclonal antibody fragment and no drug metabolism studies have been conducted. As a single-chain antibody fragment, free brolucizumab is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF, passive renal elimination and metabolism via proteolysis.
After intravitreal injections, brolucizumab was eliminated with an apparent systemic half-life of 4.3 ± 1.9 days. Concentrations were generally near or below the quantitation limit (< 0.5 nanogram/mL) approximately 4 weeks after dosing in most patients. Beovu did not accumulate in the serum when administered intravitreally every 4 weeks.

Special populations.

Elderly (aged 65 years and over).

In the HAWK and HARRIER clinical studies, approximately 90% (978/1,088) of patients randomised to treatment with Beovu were ≥ 65 years of age and approximately 60% (648/1,088) were ≥ 75 years of age. In the KESTREL and KITE clinical studies, approximately 45% (164/368) of patients randomised to treatment with Beovu were ≥ 65 years of age and approximately 10% (37/368) were ≥ 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

Race/ethnicity.

There were no ethnic differences in systemic pharmacokinetics following intravitreal injection in a study with 24 Caucasian and 26 Japanese patients.

Renal impairment.

Mild to severe renal impairment should have no impact on the overall systemic exposure to brolucizumab, because the systemic concentration of brolucizumab is driven by the distribution from the eye rather than the elimination rate and because the systemic exposure of free brolucizumab is low.
The systemic clearance of brolucizumab was evaluated in nAMD patients who had both serum brolucizumab pharmacokinetic and creatinine clearance data available. Subjects with mild (50-79 mL/min [n = 13]) renal impairment had mean systemic clearance rates of brolucizumab which were within 15% of the mean clearance rate for subjects with normal renal function (≥ 80 mL/min [n = 25]). Patients with moderate (30-49 mL/min [n = 3]) renal impairment had mean systemic clearance rates of brolucizumab which were lower than patients with normal renal function but the number of patients was too low to make definitive conclusions. No patients with severe (< 30 mL/min) renal impairment were studied.

Hepatic impairment.

Brolucizumab has not been studied in patients with hepatic impairment. Mild to severe hepatic impairment should have no impact on the overall systemic exposure to brolucizumab, because metabolism occurs via proteolysis and does not depend on hepatic function.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been conducted on the mutagenic or clastogenic potential of brolucizumab. Considering the monoclonal antibody nature, brolucizumab is not expected to interact directly with DNA or other chromosomal material.

Carcinogenicity.

No studies have been conducted on the carcinogenic potential of brolucizumab.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium citrate, sucrose, polysorbate 80 and water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Pre-filled syringe.

Store in a refrigerator (2°C - 8°C).
Do not freeze.
Prior to use, the unopened blister may be kept at room temperature (25°C) for up to 24 hours.
Keep the pre-filled syringe in its sealed blister and in the outer carton in order to protect from light.
Refer to pre-filled syringe for expiry date.
Beovu must be kept out of the reach and sight of children.

Vial.

Store in a refrigerator (2°C - 8°C).
Do not freeze.
Prior to use, the unopened vial may be kept at room temperature (25°C) for up to 24 hours.
Keep the vial in the outer carton in order to protect from light.
Refer to vial for expiry date.
Beovu must be kept out of the reach and sight of children.

6.5 Nature and Contents of Container

Pre-filled syringe.

0.165 mL sterile solution in a pre-filled syringe consisting of a 0.5 mL long clear, colourless Type 1 glass syringe, rubber plunger stopper, an OVS tamper-evident closure system containing a rubber tip cap and a purple finger grip. The external surface of the pre-filled syringe is sterile and it is packed in a transparent rigid blister.
Pack size of 1 pre-filled syringe.

Vial.

0.230 mL sterile solution in a clear Type 1 glass vial with a coated rubber stopper sealed with an aluminium cap with a purple plastic flip-off disk.
Pack size of 1 vial and 1 blunt filter needle (18G x 1½", 1.2 mm x 40 mm, 5 micrometre) in a soft blister.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Brolucizumab is a humanised monoclonal single-chain Fv (scFv) antibody fragment.

CAS number.

1531589-13-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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