Consumer medicine information

Vabysmo

Faricimab

BRAND INFORMATION

Brand name

Vabysmo

Active ingredient

Faricimab

Schedule

SUMMARY CMI

VABYSMO^®

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 being given VABYSMO?

VABYSMO contains the active ingredient faricimab. VABYSMO is used to treat the following eye disorders:

neovascular (wet) age-related macular degeneration (nAMD).
diabetic macular oedema (DMO)
macular oedema secondary to retinal vein occlusion.

For more information, see Section 1. Why am I being given VABYSMO? in the full CMI.

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

You must not be given VABYSMO if you have ever had an allergic reaction to faricimab or any of the ingredients listed at the end of this CMI.

You must not be given VABYSMO if you have an infection in or around your eye, or inflammation in your eye.

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 VABYSMO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VABYSMO 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 is VABYSMO given?

VABYSMO must be injected into your eye every month initially. Thereafter, the frequency of the ongoing injections will be determined by your doctor.

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

5. What should I know while I am being given VABYSMO?

Things you should do	Tell your doctor if you experience any problems during the treatment. Women who could become pregnant should use effective contraception during treatment and for at least 3 months after the last injection of VABYSMO.
Driving or using machines	You may not see as well after you are given VABYSMO and after the associated eye examinations. This is temporary. Do not drive or use machines until your eyesight has returned to normal.
Looking after your medicine	It is unlikely that you will have to store VABYSMO at home. If you have to store it, keep it in the refrigerator at 2°C to 8°C (do not freeze) in the outer carton.

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

6. Are there any side effects?

Common side effects may include eye pain, watery eyes, moving spots (floaters) or shadows in your vision

Serious side effects may include gradual or sudden decrease or changes in your vision, sudden onset of eye pain, a higher number of spots in the front of the eye (floaters), increased sensitivity to light, red tint to your vision, blood or redness of your eye, small marks or scratches on the eye surface with pain or tenderness when you touch the eye, gritty feeling in the eye.

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

VABYSMO^®

Active ingredient(s): faricimab

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I being given VABYSMO?

VABYSMO contains the active ingredient faricimab.

Faricimab belongs to a group of medicines called antineovascularisation agents.

VABYSMO is injected into the eye by your doctor to treat adults with the following eye disorders:

neovascular (wet) age-related macular degeneration (nAMD).
diabetic macular oedema (DMO)
macular oedema secondary to retinal vein occlusion (RVO).

These conditions affect the macula, the central part of the retina (the light-sensitive layer at the back of the eye) that is responsible for sharp, detailed vision.

nAMD is caused when tiny, abnormal blood vessels grow in the retina. The abnormal vessels leak blood or fluid in the macula and can form scars that cause vision to get worse and may result in permanent blind spots.

DMO is caused by leaky blood vessels that cause swelling of the macula.

RVO is a blockage of the blood vessels (veins) in the retina. Due to the increased pressure within these blood vessels, there is leakage of fluid into the retina, causing swelling of the macula (macular oedema).

How VABYSMO works

VABYSMO specifically recognises and blocks the activity of proteins known as angiopoietin-2 and vascular endothelial growth factor A. When these proteins are present in higher levels than normal, they can cause the growth of abnormal blood vessels and damage to the normal vessels, with leakage into the retina. This causes swelling of the retina or damage to the layers of the retina, which can negatively affect vision. By attaching to these proteins, VABYSMO can block their actions and may improve disease and/or slow down worsening of the disease, thereby maintaining your vision.

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

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

Warnings

Do not use VABYSMO if:

you are allergic to faricimab, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
Some symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
If you have or suspect you have an infection in or around your eye.
If you have inflammation in or around your eye (may be indicated by pain and/or redness)

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition
have glaucoma (an eye condition usually caused by high pressure in the eye)
have a history of seeing flashes of light or floaters (dark floating spots) or if you have a sudden increase in the size and number of floaters
have had eye surgery in the last four weeks or if eye surgery is planned in the next four weeks.
have ever had any eye diseases or eye treatments
have had a stroke or experienced any signs of a stroke, such as weakness or paralysis of limbs or face, difficulty speaking

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

VABYSMO should not be used during pregnancy unless the potential benefit outweighs the potential risk to your unborn child.
Check with your doctor if you are pregnant or intend to become pregnant.
Should you become pregnant during treatment with VABYSMO, tell your doctor.
Women who are able to become pregnant should use effective contraception during treatment and for at least 3 months after your last injection of VABYSMO.
Talk to your doctor if you are breastfeeding or intend to breastfeed. VABYSMO is not recommended during breastfeeding because it is not known whether VABYSMO passes into human 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.

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

4. How is VABYSMO given?

How much VABYSMO is given

The recommended dose is 6 mg (0.05 mL) of VABYSMO, injected into your eye.
The frequency of injections will be determined by your doctor based on the condition of your eye.

nAMD and DMO:

You will be treated with one injection every month for the first 4 months.
Thereafter, you may receive injections into your eye up to every 4 months.

RVO:

You will be treated with one injection every month for a minimum of 3 months.

Thereafter, you may receive injections less frequently.

How you will be given VABYSMO

VABYSMO is injected into your eye (intravitreal injections) by a doctor experienced in giving eye injections.

How long will you be given VABYSMO

VABYSMO is intended as a long-term treatment. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If you miss a dose of VABYSMO

If you miss a dose, schedule a new appointment with your doctor as soon as possible. Do not wait until the next planned dose.

Before stopping treatment with VABYSMO

If you are considering stopping treatment with VABYSMO, discuss this with your doctor.
Stopping treatment may increase your risk of vision loss and your vision may worsen.
Discuss suitable alternatives with your doctor, to determine the best treatment for you.

If you are given too much VABYSMO

Your doctor will ensure you are given the correct amount of VABYSMO. If you think that you have been given too much VABYSMO, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, 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 being given VABYSMO?

Things you should do

If you experience any problems during the treatment, tell your doctor.

Call your doctor straight away or go to the emergency department if you:

develop sudden vision loss or change in vision
develop signs of a possible eye infection or inflammation, such as worsening redness of the eye or blood in and around the eye, eye pain, increased eye discomfort, blurred or decreased vision, an increased number of floaters (small particles) in your vision, increased sensitivity to light

Remind any doctor or dentist you visit that you are using VABYSMO.

Things you should not do:

Do not stop treatment with VABYSMO unless your doctor tells you to.
Stopping treatment may increase your risk of vision loss and your vision may worsen.

It is important for you to know that:

there is no information about injecting VABYSMO into both eyes at the same time. Use in this way may lead to an increased risk of experiencing side effects.
injections with VABYSMO may cause a temporary increase in eye pressure (intraocular pressure) in some patients within 60 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 chance of a tear or detachment of one of the layers at the back of the eye, in which case VABYSMO must be given with caution.
There is a risk of blood clots blocking blood vessels, which may lead to a heart attack or stroke with intravitreal injections of VABYSMO. However, this is a theoretical risk. Go to your nearest emergency room immediately if you experience signs of a stroke, such as weakness or paralysis of limbs or face or difficulty speaking.

Monitoring and care during your treatment with VABYSMO

Your doctor will monitor your condition throughout your treatment with VABYSMO to allow for prompt medical assistance if necessary. Follow your doctor's instructions for how to care for the treated eye. These instructions include but are not limited to the following:

Driving or using machines

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

You may not see as well after VABYSMO is injected into your eye and after the eye examinations associated with VABYSMO. Do not drive or use machines until your eyesight has returned to normal.

Looking after your medicine

It is unlikely that you will have to store VABYSMO at home. If you have to store it:

Store VABYSMO in the refrigerator at 2°C to 8°C in the original carton to protect from light.
Prior to use, the unopened vial or pre-filled syringe may be kept at 20°C to 25°C for up to 24 hours.
Do not freeze. Do not shake.
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 or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
Eye-related: eye pain pain while receiving the injection burning, stinging, itching, redness, irritation of the eye blurred, cloudy or decreased sharpness of vision increased production of tears or watery eyes a sensation that something is in your eye moving spots (floaters) or shadows in your vision small or distorted pupil	Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects

Serious side effects

What to do

Eye related:

redness or blood in and around the eye
bleeding into the eye causing a red tint to your vision
increase in eye pressure – symptoms include severe headache, eye pain, nausea and vomiting, blurred vision, eye redness
small marks or scratches on the eye surface with pain or tenderness when you touch the eye, gritty feeling in the eye
inflammation of the gel-like substance at the back of the eye – symptoms include hazy vision or a marked increase in floaters (moving spots)
sudden onset of the following: eye pain, increased discomfort, worsening eye redness, a higher number of floaters in your vision, or increased sensitivity to light – these are signs of a possible eye infection or inflammation
decrease or change in your vision which can be sudden or gradual, including blurred or dim vision, difficulty with vision at night, fading – these are signs of cataract or other serious eye disorders
sudden, brief flashes of light which is more likely to occur when you move your eye, heavy feeling in the eye

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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 affects 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 VABYSMO contains

Active ingredient (main ingredient)	faricimab
Other ingredients (inactive ingredients)	Histidine Acetic acid Methionine Polysorbate 20 Sodium chloride Sucrose Water for injections

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

What VABYSMO looks like

VABYSMO is a solution for injection for intravitreal use. VABYSMO solution is a clear to slightly milky, colourless to pale brown liquid, supplied in a glass vial or pre-filled syringe.

Vial (AUST R 369935)

Each VABYSMO carton contains one glass vial and one sterile 5 µm blunt transfer filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm).

Pre-filled syringe (AUST R 449965)

Each carton contains one glass pre-filled syringe and one sterile injection filter needle (30-gauge x ½ inch, 0.30 mm x 12.7 mm, Extra Thin Wall).

Who distributes VABYSMO

VABYSMO is distributed in Australia by:

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

This leaflet was prepared in September 2024.

Published by MIMS November 2024

BRAND INFORMATION

Brand name

Vabysmo

Active ingredient

Faricimab

Schedule

1 Name of Medicine

Faricimab.

2 Qualitative and Quantitative Composition

Each vial of 0.24 mL contains 28.8 mg of faricimab at a concentration of 120 mg/mL. Each prefilled syringe of 0.175 mL contains 21 mg of faricimab at a concentration of 120 mg/mL. This provides a usable amount to deliver a single dose of 0.05 mL solution containing 6 mg of faricimab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection for intravitreal use.
Clear to opalescent, colourless to brownish-yellow liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Vabysmo is indicated for the treatment of:
neovascular (wet) age-related macular degeneration (nAMD);
diabetic macular oedema (DMO);
macular oedema secondary to retinal vein occlusion (RVO).

4.2 Dose and Method of Administration

For intravitreal injection only. Vabysmo must be administered by a qualified ophthalmologist experienced in intravitreal injections. Each vial or pre-filled syringe should only be used for the treatment of a single eye.

Dosage.

Neovascular (wet) age-related macular degeneration (nAMD).

The recommended dose for Vabysmo is 6 mg (0.05 mL) administered by intravitreal injection every 4 weeks for the first 4 doses. Thereafter, an assessment of disease activity based on anatomic and/or visual outcomes is recommended 20 - 24 weeks after treatment initiation so that treatment can be individualised ("treat-and-extend" approach). Based on these assessments, in patients without disease activity, administration of Vabysmo every 16 weeks should be considered. In patients with disease activity, treatment every 8 weeks or 12 weeks should be considered. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see Section 5.1). There is limited safety data on treatment intervals of 8 weeks or less between injections (see Section 4.4).
Monitoring between dosing visits should be scheduled based on the patient's status and at the ophthalmologist's discretion.

Diabetic macular oedema (DMO).

The recommended dose for Vabysmo is 6 mg (0.05 mL) administered by intravitreal injection every 4 weeks for the first 4 doses. Thereafter, treatment may be individualised using a treat-and-extend approach following an assessment of the individual patient's anatomic and/or visual outcomes. Following the outcome of this assessment, the dosing interval may remain at every 4 weeks, or may be extended in 4 week increments up to every 16 weeks. If anatomic or visual outcomes change, the treatment interval should be adjusted accordingly (see Section 5.1).
Continued monitoring of disease activity and individualisation of dosing is recommended. Monitoring between the dosing visits should be scheduled based on the patient's status and at the ophthalmologist's clinical judgement.

Macular oedema secondary to retinal vein occlusion (RVO).

The recommended dose for Vabysmo is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks; 3 or more consecutive 4 weekly injections may be needed.
Thereafter, treatment may be individualised using a treat-and-extend approach following an assessment of the individual patient's anatomic and/or visual outcomes. The dosing interval may be extended, in increments of up to 4 weeks. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see Section 5.1). Treatment intervals longer than 16 weeks between injections have not been studied.
Monitoring between dosing visits should be scheduled based on the patient's status and at the ophthalmologist's clinical judgement.

Duration of treatment.

Vabysmo can be used for long-term treatment, if clinically indicated. If visual and/or anatomic outcomes indicate that the patient is not benefitting from continued treatment, Vabysmo should be discontinued.

Delayed or missed dose.

If a dose is delayed or missed, the patient should return to be assessed by the ophthalmologist at the next available visit and continue dosing depending on the ophthalmologist's discretion.

Dose modification.

No dose modifications of Vabysmo are recommended.

Special populations.

Paediatric use.

The safety and efficacy of Vabysmo in pediatric patients have not been established.

Geriatric use.

No dose adjustment is required in patients ≥ 65 years of age (see Section 5.2).

Renal impairment.

No dose adjustment is required in patients with renal impairment (see Section 5.2).

Hepatic impairment.

No dose adjustment is required in patients with hepatic impairment (see Section 5.2).

Method of administration.

Single-use vial for intravitreal use in one patient only. Discard any residue.
Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, sterile equipment for paracentesis should be available.
Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g. vision loss, eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Instructions for use and handling of Vabysmo.

Vabysmo should be inspected visually for particulate matter and discoloration prior to administration. Vabysmo is a clear to opalescent and colourless to brownish-yellow liquid solution. Do not use if particles, cloudiness or discolouration are visible.
Vabysmo vial. Allow the Vabysmo vial to reach room temperature (20°C to 25°C) before use. Keep the vial in the original carton to protect from light. The unopened Vabysmo vial may be stored at room temperature (25°C) for up to 24 hours.

Preparation of the intravitreal injection.

Use aseptic technique to carry out the preparation of the intravitreal injection.
To ensure all liquid settles at the bottom of the vial, place the vial upright on a flat surface (for about 1 minute) after removal from packaging. Gently tap the vial with your finger, as liquid may stick to the top of the vial.
Remove the flip-off cap from the vial and disinfect the vial septum.
Firmly attach the included 18 G x 1½ inch transfer filter needle onto a 1 mL luer lock syringe.
Push the transfer filter needle into the centre of the vial septum until the needle is completely inserted into the vial. Tilt the vial slightly so that the needle touches the bottom edge of the vial.
Hold the vial slightly inclined and slowly withdraw all the liquid from the vial. The bevel of the transfer filter needle must be kept submerged in the liquid, to avoid introduction of air.
Ensure that the plunger rod is drawn sufficiently back when emptying the vial, in order to completely empty the transfer filter needle.
Disconnect the transfer filter needle from the syringe and appropriately dispose of it. Do not use the transfer filter needle for the intravitreal injection.
Aseptically and firmly attach a 30 G x ½ inch injection needle onto the luer lock syringe.
Hold the syringe with the needle pointing up to check for air bubbles. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
Carefully expel the air from the syringe and needle and slowly depress the plunger to align the rubber stopper tip to the 0.05 mL dose mark.
Ensure that the injection is given immediately after preparation of the dose.
Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.
Dispose of any waste material or unused medicinal product.
Vabysmo pre-filled syringe. Allow the Vabysmo pre-filled syringe to reach room temperature (20°C to 25°C) before use. Keep the sealed tray in the original carton to protect from light. The unopened Vabysmo pre-filled syringe may be stored at room temperature (25°C) for up to 24 hours.

Preparation of the intravitreal injection.

Use aseptic technique to carry out the preparation of the intravitreal injection.
Peel the lid off the syringe tray and remove the pre-filled syringe.
Hold the syringe by the white collar; snap off the syringe cap. Do not twist off the cap.
Remove the filter needle from its packaging.
Firmly attach the injection filter needle onto the luer lock syringe.
Hold the syringe with the injection filter needle pointing up. Check the syringe for air bubbles.
If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
Hold the syringe at eye level and slowly push the plunger rod until the lower edge of the rubber stopper's dome is aligned with the 0.05 mL dose mark. This will expel the air and the excess solution and set the dose to 0.05 mL.
Ensure that the injection is given immediately after preparation of the dose.
Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL.
Do not recap or detach the injection filter needle from the syringe. Dispose of any waste material or unused medicinal product.

4.3 Contraindications

Vabysmo is contraindicated in patients with:
A known hypersensitivity to faricimab or any of the excipients listed in Section 6.1. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.
Ocular or periocular infections.
Active intraocular inflammation.

4.4 Special Warnings and Precautions for Use

Intravitreal injection-related reactions.

Intravitreal injections, including those with Vabysmo have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Proper aseptic injection techniques must always be used when administering Vabysmo. Patients should be instructed to report any symptoms, such as pain, loss of vision, photophobia, blurred vision, floaters, or redness, suggestive of endophthalmitis or any of the above-mentioned events without delay, to permit prompt and appropriate management.

Retinal vasculitis and/or retinal occlusive vasculitis.

Retinal vasculitis and/or retinal occlusive vasculitis have been reported with the use of Vabysmo in the post-marketing setting. Discontinue treatment with Vabysmo in patients who develop these events. Patients should be instructed to report any change in vision without delay (see Section 4.8).

Intraocular pressure increase.

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal injection, including those with Vabysmo. Vabysmo has not been studied in patients with poorly controlled glaucoma. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Vabysmo while the IOP is ≥ 30 mmHg). In all cases, both the IOP and perfusion of the optic nerve head and/or vision must be monitored and managed appropriately.

Systemic effects.

Systemic adverse events including arterial thromboembolic events, such as stroke and myocardial infarction, have been reported following intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors and there is a theoretical risk that these may be related to VEGF inhibition. There is limited safety data in patients with a prior history of stroke or transient ischaemic attack or myocardial infarction.

Immunogenicity.

As with all therapeutic proteins, there is the potential for immune response to Vabysmo. Patients should be instructed to report any signs or symptoms of intraocular inflammation such as vision loss, eye pain, increased sensitivity to light, floaters or worsening eye redness, which might be a clinical sign attributable to hypersensitivity (see Section 4.8).

Bilateral treatment.

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

Concomitant use of other anti-VEGF.

There are no data available on the concomitant use of Vabysmo with anti-VEGF medicinal products in the same eye.

Withholding treatment.

Treatment should be withheld in patients with:
Rhegmatogenous retinal detachment, stage 3 or 4 macular holes, retinal break; treatment should not be resumed until an adequate repair has been performed.
Treatment related decrease in Best Corrected Visual Acuity (BCVA) of ≥ 30 letters compared with the last assessment of visual acuity; treatment should not be resumed earlier than the next scheduled treatment.
Performed or planned intraocular surgery within the previous or next 28 days guided by the ophthalmologist's clinical judgement; treatment should not be resumed earlier than the next scheduled treatment.

Retinal pigment epithelial tear.

Retinal pigment epithelial (RPE) tear is a complication of pigment epithelial detachment (PED) in patients with nAMD. Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for nAMD include a large and/or high pigment epithelial detachment. When initiating Vabysmo therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

Populations with limited data.

There is only limited experience in the treatment of nAMD patients ≥ 85 years, and DMO patients with type I diabetes, patients with HbA1c over 10%, patients with high-risk proliferative diabetic retinopathy (DR), high blood pressure (≥ 140/90 mmHg) and vascular disease, sustained dosing intervals shorter than every 8 weeks (Q8W), or nAMD, DMO and RVO patients with active systemic infections. There is limited safety information on sustained dosing intervals of 8 weeks or less and these may be associated with a higher risk of ocular and systemic adverse reactions, including serious adverse reactions. There is also no experience of treatment with Vabysmo in diabetic and RVO patients with uncontrolled hypertension. This lack of information should be considered by the ophthalmologist when treating such patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug-drug interaction studies have been performed with Vabysmo.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproductive or fertility studies have been conducted. No effects on reproductive organs in male or female animal were observed in a 6-month cynomolgus monkey study at faricimab doses of up to 3 mg/eye (10 times the clinical exposures based on AUC). VEGF inhibition has been shown to affect follicular development, corpus luteum function and fertility. Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female reproductive capacity however the risk is considered low due to the low systemic exposure after ocular administration.

Women of childbearing potential.

Women of childbearing potential should use contraception during treatment with Vabysmo and for at least 3 months following the last dose of Vabysmo.
(Category D)
There is no data from the use of Vabysmo in pregnant women.
In an embryofetal development study in pregnant cynomolgus monkeys, faricimab given intravenously throughout the period of organogenesis did not adversely affect pregnancy or fetal development at doses up to 3 mg/kg IV (523 times the clinical exposures based on the C_max at the MRHD of a single 6 mg intravitreal dose).
VEGF inhibition has been shown to cause malformations, embryofetal resorption and decreased fetal weight. No dedicated studies addressing the effects of Ang-2 inhibition on pregnancy are available. Based on nonclinical information Ang-2 inhibition may lead to effects comparable to VEGF inhibition. Systemic exposures after ocular administration of Vabysmo is very low.
It is not known whether faricimab can cross the placenta or cause harm to the fetus when administered to pregnant women. Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female reproductive capacity, and to embryo-fetal development. Although the systemic exposure after ocular administration is very low, Vabysmo should not be used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus.
The safe use of Vabysmo during labour and delivery has not been established.
It is not known whether faricimab is excreted in human breast milk. Animal studies have not been conducted to assess the impact of faricimab on milk production or its presence in breast milk. Because many drugs are excreted in human milk with the potential for absorption and harm to infant growth and development exists, caution should be exercised when Vabysmo is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Vabysmo and any potential adverse effects on the breastfed child from Vabysmo.

4.7 Effects on Ability to Drive and Use Machines

Vabysmo may have a minor influence on the ability to drive and use machines due to possible temporary visual disturbances following the intravitreal injection and the associated eye examination. Patients should not drive or use machines until visual function has recovered sufficiently.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

A total of 4,489 patients constituted the safety population in the six Phase III clinical studies for two years (2,567 Vabysmo treated patients; 664 in nAMD, 1,262 in DMO and 641 in RVO).
The most serious adverse reactions were uveitis (0.5%), endophthalmitis (0.4%), vitritis (0.4%), retinal tear (0.2%), rhegmatogenous retinal detachment (0.1%) and traumatic cataract (< 0.1%).
The most frequently reported adverse reactions in patients treated with Vabysmo were cataract (9.7%), conjunctival haemorrhage (6.7%), vitreous detachment (4.2%), intraocular pressure increased (3.5%), vitreous floaters (3.5%), eye pain (2.5%) and retinal pigment epithelial tear (nAMD only) (2.9%).

Tabulated summary of adverse reactions from clinical trials.

The safety data described below includes all adverse reactions from the pooled data across six Phase III clinical studies in the indications nAMD, DMO and RVO, with a reasonable possibility of causality attribution to the injection procedure or medicinal product.
The adverse reactions are listed according to the MedDRA system organ class and ranked by frequency using 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). See Table 1.

Description of selected adverse drug reactions from clinical trials.

There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the Vabysmo clinical trials in patients with nAMD, DMO and RVO. Across indications no notable difference between the groups treated with Vabysmo and the comparator were observed.

Immunogenicity.

There is a potential for an immune response in patients treated with Vabysmo (see Section 4.4). After dosing with Vabysmo for up to 112 (nAMD), 100 (DMO) and 72 (RVO) weeks, treatment-emergent anti-faricimab antibodies were detected in approximately 13.8% and 9.6% and 14.4% of patients with nAMD, DMO and RVO randomised to Vabysmo, respectively. The clinical significance of anti-faricimab antibodies on safety is unclear at this time. The incidence of intraocular inflammation in anti-faricimab antibody positive patients was 12/98 (12.2%; nAMD), 15/128 (11.7%; DMO) and 9/95 (9.5%; RVO), and in anti-faricimab antibody negative patients was 8/562 (1.4%; nAMD), 5/1124 (0.4%; DMO) and 10/543 (1.8%; RVO). The incidence of serious ocular adverse reactions in anti-faricimab antibody positive patients was 6/98 (6.1%; nAMD), 14/128 (10.9%; DMO) and 7/95 (7.4%; RVO), and in anti-faricimab antibody negative patients was 23/562 (4.1%; nAMD), 45/1124 (4.0%; DMO) and 34/543 (6.3%; RVO). Anti-faricimab antibodies were not associated with an impact on clinical efficacy or systemic pharmacokinetics.

Retinal pigment epithelial tear.

Retinal pigment epithelial (RPE) tear is a complication of pigment epithelial detachment (PED) in patients with nAMD. RPE tears are common in nAMD patients with PED, treated with IVT anti-VEGF agents including faricimab. There was a higher rate of RPE tear in the faricimab group (2.9%) compared to aflibercept group (1.4%). The majority of events were mild to moderate, without impact to vision and occurred during the loading phase.

Post-marketing experience.

Rare cases of retinal vasculitis and/or retinal occlusive vasculitis have been spontaneously reported in the post-marketing setting. Retinal vasculitis and retinal occlusive vasculitis have also been reported in patients treated with intravitreal (IVT) therapies.

Eye disorders.

Retinal vasculitis, retinal occlusive vasculitis.

Reporting of suspected adverse reactions.

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

4.9 Overdose

Doses higher than the recommended dosing regimen have not been studied. Overdosing with greater than recommended injection volume may increase intraocular pressure.
In the event of an overdose, IOP should be monitored and, if deemed necessary by the treating ophthalmologist, 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, other ocular vascular disorder agents. ATC code: S01LA09.

Mechanism of action.

Faricimab is a humanised bispecific immunoglobulin G1 (IgG1) antibody that acts through inhibition of two distinct pathways by neutralisation of both Ang-2 and vascular endothelial growth factor A (VEGF-A).
Ang-2 causes vascular instability by promoting endothelial destabilisation, pericyte loss, and pathological angiogenesis, thus potentiating vascular leakage and inflammation. It also sensitises blood vessels to the activity of VEGF-A resulting in further vascular destabilisation. Ang-2 and VEGF-A synergistically increase vascular permeability and stimulate neovascularisation.
By dual inhibition of Ang-2 and VEGF-A, faricimab reduces vascular permeability and inflammation, inhibits pathological angiogenesis and restores vascular stability.

Pharmacodynamic effect.

A suppression from baseline of median ocular free Ang-2 and free VEGF-A concentrations was observed from day 7 onwards in the six Phase III studies. Systemic pharmacodynamic effects are unlikely, supported by the absence of significant changes in free VEGF and Ang-2 concentration in plasma upon faricimab treatment in clinical studies.

nAMD.

In Phase III studies in patients with nAMD (TENAYA, LUCERNE), objective, pre-specified visual and anatomic criteria, as well as the treating ophthalmologist's clinical assessment, were used to guide treatment decisions at the disease activity assessment time points (week 20 and week 24).
Reductions in mean central subfield thickness (CST) were observed from baseline through week 48 with Vabysmo, and were comparable to those observed with aflibercept. The mean CST reduction from baseline to the primary endpoint visits (averaged at weeks 40-48) was -137 micrometre and -137 micrometre for Vabysmo dosed up to every 16 weeks (Q16W) versus -129 micrometre and -131 micrometre with aflibercept, in TENAYA and LUCERNE, respectively. In year 2, the mean CST reduction from baseline to the average of weeks 104-112 was -146.5 micrometre and -150.3 micrometre for Vabysmo dosed up to Q16W versus -146.2 micrometre and -141.6 micrometre with aflibercept, in TENAYA and LUCERNE, respectively.
There was a comparable effect of Vabysmo and aflibercept on the reduction of intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). At the primary endpoint visits (min-max, weeks 40-48), the proportion of patients in TENAYA and LUCERNE, respectively, with absence of IRF was: 76%-82% and 78%-85% in Vabysmo vs. 74%-85% and 78%-84% in aflibercept; absence of SRF: 70%-79% and 66%-78% in Vabysmo vs. 66%-78% and 62%-76% in aflibercept; absence of PED: 3%-8% and 3%-6% in Vabysmo vs. 8%-10% and 7%-9% in aflibercept. These reductions in IRF, SRF, and PED were similar at year 2 (weeks 104-108).
At week 48, there was comparable change in total CNV lesion area from baseline across treatment arms (0.0 mm² and 0.4 mm² in Vabysmo vs. 0.4 mm² and 1.0 mm² in aflibercept, in TENAYA and LUCERNE, respectively). There was a comparable reduction in CNV leakage area from baseline across treatment arms (-3.8 mm² and -3.2 mm² in Vabysmo and -3.0 mm² and -2.2 mm² in aflibercept, in TENAYA and LUCERNE, respectively).

DMO.

In Phase III studies in patients with DMO (YOSEMITE and RHINE), anatomic parameters related to macular oedema were part of the disease activity assessments guiding treatment decisions.
The reductions in mean CST from baseline were numerically greater in patients treated with Vabysmo every 8 weeks (Q8W) and Vabysmo up to Q16W adjustable dosing as compared to aflibercept Q8W from week 4 to week 100 in both YOSEMITE and RHINE. Greater proportions of patients in both Vabysmo arms achieved absence of IRF and absence of DMO (defined as reaching CST below 325 micrometre) as measured on Spectral Domain Optical Coherence Tomography (SD-OCT) over time in both studies, compared to the aflibercept arm. Comparable reductions in SRF were observed across both Vabysmo and aflibercept treatment arms over time in both studies.
The mean reduction of CST from baseline to the primary endpoint visits (averaged at weeks 48-56) was 207 micrometre and 197 micrometre in patients treated with Vabysmo Q8W and Vabysmo up to Q16W adjustable dosing as compared to 170 micrometre in aflibercept Q8W patients in YOSEMITE; results were 196 micrometre, 188 micrometre and 170 micrometre, respectively in RHINE. These mean CST reductions were maintained through year 2. The proportion of patients with absence of DMO at primary endpoint visits (min-max, weeks 48-56) were 77%-87% and 80%-82% in patients treated with Vabysmo Q8W and Vabysmo up to Q16W adjustable dosing, as compared to 64%-71% in aflibercept Q8W patients in YOSEMITE; results were 85%-90%, 83%-87%, and 71%-77%, respectively in RHINE. These results were maintained through year 2.
The proportions of patients with absence of IRF at primary endpoint visits (min-max, weeks 48-56) were 42%-48% and 34%-43% in patients treated with Vabysmo Q8W and Vabysmo up to Q16W adjustable dosing, as compared to 22%-25% in aflibercept Q8W patients in YOSEMITE; results were 39%-43%, 33%-41%, and 23%-29%, respectively in RHINE. These results were maintained through year 2.

RVO.

In Phase III studies in patients with branch retinal vein occlusion (BRVO; BALATON) and central/hemiretinal vein occlusion (C/HRVO; COMINO), reductions in mean CST were observed from baseline to week 24 with Vabysmo every 4 weeks (Q4W) and were comparable to those seen with aflibercept Q4W. The mean CST reduction from baseline to week 24 was 311.4 micrometre for Vabysmo versus 304.4 micrometre for aflibercept, and 461.6 micrometre for Vabysmo Q4W versus 448.8 micrometre for aflibercept Q4W, in BALATON and COMINO, respectively. CST reductions were maintained through week 72 when patients moved to a Vabysmo up to Q16W adjustable dosing regimen.
Comparable proportions of patients in both Vabysmo and aflibercept arms achieved absence of IRF, absence of SRF and absence of macular oedema (defined as reaching CST below 325 micrometre) over time through week 24, in both studies. These results were maintained through week 72 when patients moved to a Vabysmo up to Q16W adjustable dosing regimen.
In BALATON, at week 24, the proportion of patients with absence of macular oedema was 95.3% in patients treated with Vabysmo Q4W versus 93.9% in patients treated with aflibercept Q4W; the proportion of patients with absence of IRF was 72.5% in patients treated with Vabysmo Q4W versus 66% in patients treated with aflibercept Q4W. The proportion of patients with absence of SRF was 91.3% in patients in the Vabysmo Q4W arm, versus 90.3% in patients in the aflibercept Q4W arm.
In COMINO, at week 24, the proportion of patients with absence of macular oedema was 93.7% in patients treated with Vabysmo Q4W versus 92% in patients treated with aflibercept Q4W. The proportion of patients with absence of IRF was 76.2% in patients treated with Vabysmo Q4W versus 70.8% in patients treated with aflibercept Q4W; the proportion of patients with absence of SRF was 96.4% in patients treated with Vabysmo Q4W versus 93.4% in patients treated with aflibercept Q4W.

Clinical trials.

Treatment of nAMD.

The safety and efficacy of Vabysmo (faricimab) were assessed in two randomised, multi-centre, double-masked, active comparator-controlled studies in patients with nAMD, TENAYA (NCT03823287) and LUCERNE (NCT03823300). A total of 1,329 patients were enrolled in these studies, with 1,135 (85%) patients completing the studies through week 112. A total of 1,326 patients received at least one dose (664 with Vabysmo). Patient ages ranged from 50 to 99 with a mean of 75.9 years.
In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms:
Vabysmo 6 mg up to Q16W after four initial monthly doses;
Aflibercept 2 mg Q8W after three initial monthly doses.
After the first four monthly doses (weeks 0, 4, 8, and 12) patients randomised to the Vabysmo arm received Q16W, every 12 weeks (Q12W) or Q8W dosing based on an assessment of disease activity at weeks 20 and 24, using objective pre-specified visual and anatomic criteria as well as the treating ophthalmologist's clinical assessment. Patients remained on these fixed dosing intervals until week 60 without supplemental therapy. From week 60 onwards, patients in the Vabysmo arm moved to an adjustable dosing regimen, where the dosing interval could be increased in up to 4-week increments (up to Q16W) or could be decreased by up to 8-week increments (up to Q8W) based on an automated objective assessment of pre-specified visual and anatomic disease activity criteria. Patients in the aflibercept arm remained on Q8W dosing throughout the study period. Both studies were 112 weeks in duration.
The primary efficacy endpoint was the change from baseline in BCVA based on an average at weeks 40, 44, and 48, measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. In both studies, Vabysmo up to Q16W treated patients had a comparable mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1.
Meaningful vision gains from baseline were seen through week 112 in both treatment arms. Detailed results of both studies are shown in Table 2, Table 3, Figure 1, and Figure 2.
The proportion of patients on each of the different treatment intervals at week 48 in TENAYA and LUCERNE, respectively was: Q16W: 46%, 45%; Q12W: 34%, 33%; Q8W: 20%, 22%.
The proportion of patients on each of the different treatment intervals at week 112 in TENAYA and LUCERNE, respectively was: Q16W: 59%, 67%; Q12W: 15%, 14%; Q8W: 26%, 19%.
See Table 2, Table 3, Figure 1 and Figure 2.

In both TENAYA and LUCERNE, improvements from baseline in BCVA and CST at week 60 were comparable across the two treatment arms and consistent with those seen at week 48.
Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, lesion type, lesion size) in each study, and in the pooled analysis, were consistent with the results in the overall populations.
In both studies, Vabysmo up to Q16W demonstrated clinically meaningful improvements from baseline to week 48 in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score that was comparable to aflibercept Q8W. Patients in Vabysmo arms in TENAYA and LUCERNE achieved a ≥ 4 point improvement from baseline in the NEI VFQ-25 composite score at week 48. At week 112, the mean improvement from baseline for patients receiving Vabysmo was 1.36 in TENAYA and 3.78 in LUCERNE.

Treatment of DMO.

The safety and efficacy of Vabysmo were assessed in two randomised, multi-centre, double-masked, active comparator-controlled 2-year studies (YOSEMITE and RHINE) in patients with DMO. A total of 1,891 patients were enrolled in the two studies with 1622 (85.8%) patients completing the studies through week 100. A total of 1,887 were treated with at least one dose through week 56 (1,262 with Vabysmo). Patient ages ranged from 24 to 91 with a mean of 62.2 years. The overall population included both anti-VEGF naive patients (78%) and patients who had been previously treated with a VEGF inhibitor prior to study participation (22%). In both studies, patients were randomised in a 1:1:1 ratio to one of the three treatment regimens:
Vabysmo 6 mg Q8W after the first 6 monthly doses.
Vabysmo 6 mg up to Q16W adjustable dosing administered in 4, 8, 12 or 16 week intervals after the first 4 monthly doses.
Aflibercept 2 mg Q8W after the first 5 monthly doses.
In the Q16W adjustable dosing arm, the dosing followed a standardised treat-and-extend approach. The interval could be increased in 4-week increments or decreased in 4- or 8-week increments based on anatomic and/or visual outcomes, using data obtained only at study drug dosing visits.
Both studies demonstrated efficacy in the primary endpoint, defined as the change from baseline in BCVA at year 1 (average of the week 48, 52, and 56 visits) as measured by the ETDRS Letter Score. In both studies, Vabysmo up to Q16W treated patients had a comparable mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1, and these vision gains were maintained through year 2. Detailed results of both studies are shown in Table 3, Table 4, Figure 3, and Figure 4.
After 4 initial monthly doses, the patients in the Vabysmo up to Q16W adjustable dosing arm could have received between the minimum of 6 and the maximum of 21 total injections through week 96. At week 52, 74% and 71% of patients in the Vabysmo up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in YOSEMITE and RHINE, respectively (53% and 51% on Q16W, 21% and 20% on Q12W). Of these patients, 75% and 84% maintained ≥ Q12W dosing without an interval reduction below Q12W through week 96; of the patients on Q16W at week 52, 70% and 82% of patients maintained Q16W dosing without an interval reduction through week 96 in YOSEMITE and RHINE, respectively. At week 96, 78% of patients in the Vabysmo up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in both studies (60% and 65% on Q16W, 18% and 14% on Q12W). 4% and 6% of patients were extended to Q8W and stayed on ≤ Q8W dosing intervals through week 96; 3% and 5% received only Q4W dosing in YOSEMITE and RHINE through to week 96, respectively.
Detailed results from the analyses of YOSEMITE and RHINE studies are listed in Table 4, Table 5 and Figures 3 and 4.

Efficacy results in patients who were anti-VEGF treatment naive prior to study participation and in all the other evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, baseline visual acuity) in each study were consistent with the results in the overall populations.
Across studies, Vabysmo Q8W and up to Q16W adjustable dosing showed clinically meaningful improvements in the pre-specified efficacy endpoint of mean change from baseline to week 52 in the NEI VFQ-25 composite score that were comparable to aflibercept Q8W and exceeded the threshold of 4 points. Vabysmo Q8W and up to Q16W adjustable dosing also demonstrated clinically meaningful improvements in the pre-specified efficacy endpoint of change from baseline to week 52 in the NEI VFQ-25 near activities, distance activities, and driving scores, that were comparable to aflibercept Q8W. The magnitude of these changes corresponds to a 15-letter gain in BCVA. Comparable proportions of patients treated with Vabysmo Q8W, Vabysmo up to Q16W adjustable dosing, and aflibercept Q8W experienced a clinically meaningful improvement of ≥ 4 points from baseline to week 52 in the NEI VFQ-25 composite score, a pre-specified efficacy endpoint. These results were maintained at week 100.
An additional key efficacy outcome in DMO studies was the change in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) from baseline to week 52. Of the 1,891 patients enrolled in Studies YOSEMITE and RHINE, 708 and 720 patients were evaluable for DR endpoints, respectively.
The ETDRS-DRSS scores ranged from 10 to 71 at baseline.
The majority of patients, approximately 60%, had moderate to severe non-proliferative DR (DRSS 43/47/53) at baseline.
At week 52, the proportion of patients improving by ≥ 2 steps on the ETDRS-DRSS was 43% to 46% across the Vabysmo Q8W and Vabysmo adjustable up to Q16W arms in both studies, compared to 36% and 47% in aflibercept Q8W arms of YOSEMITE and RHINE, respectively. The results at week 96 were 43% to 54% across the Vabysmo Q8W and Vabysmo adjustable up to Q16W arms in both studies, compared to 42% and 44% in aflibercept Q8W arms of YOSEMITE and RHINE, respectively.
Comparable results across the treatment arms were observed in both studies in the proportions of patients improving by ≥ 3 steps on the ETDRS-DRSS from baseline at week 52, and these results were maintained at week 96.
The results from the ≥ 2-step and ≥ 3-step ETDRS-DRSS improvement analyses from baseline at week 52 and at week 96 are shown in Tables 6 and 7.

Among patients who had no proliferative DR at baseline (Vabysmo Q8W n = 406, Vabysmo up to Q16W adjustable dosing n = 422 and aflibercept Q8W n = 400, in pooled YOSEMITE and RHINE), the proportions of patients who developed new proliferative DR diagnosis (defined by ETDRS-DRSS 61 or worse) from baseline to week 96 were comparable between the Vabysmo Q8W, Vabysmo up to Q16W adjustable dosing and aflibercept Q8W dosed patients in pooled YOSEMITE and RHINE studies. In a descriptive analysis in the ITT population, almost no patients required vitrectomy (0 to 4 per group) or Pan-retinal Photocoagulation (PRP) (1 to 2 per group) during the two year duration of the studies.
DR treatment effects in the subgroup of patients who were anti-VEGF naive prior to study participation were comparable to those observed in the overall DR evaluable population. Treatment effects in evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, and baseline visual acuity) in each study were generally consistent with the results in the overall population.
Treatment effects in subgroups by DR severity at baseline were different and showed the greatest ≥ 2-step DRSS improvements among patients with moderately severe and severe non-proliferative DR (Vabysmo Q8W n = 188, Vabysmo up to Q16 adjustable dosing n = 190 and aflibercept Q8W n = 170, in pooled YOSEMITE and RHINE) with approximately 90% of patients achieving improvements. These results were comparable across the study arms, and comparable in overall and anti-VEGF treatment-naive populations.

Treatment of macular oedema secondary to RVO.

The safety and efficacy of Vabysmo were assessed in two randomised, multi-centre, double-masked, 72-week long studies in patients with macular oedema secondary to BRVO (BALATON) or C/HRVO (COMINO). Active comparator-controlled data are available through month 6.
A total of 1,282 patients (553 in BALATON and 729 in COMINO) were enrolled in the two studies, with 1,276 patients treated with at least one dose through week 24 (641 with Vabysmo).
In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms:
Vabysmo 6 mg Q4W for six consecutive monthly doses.
Aflibercept 2 mg Q4W for six consecutive monthly doses.
After six initial monthly doses, patients initially randomised to the 2 mg aflibercept arm moved to the 6 mg Vabysmo arm and could receive 6 mg Vabysmo up to Q16W adjustable dosing regimen, where the dosing interval could be increased in 4-week increments up to Q16W or decreased by 4-, 8- or 12-weeks based on an automated objective assessment of pre-specified visual and anatomic disease activity criteria.
Both studies assessed and demonstrated efficacy using a primary endpoint of change from baseline in BCVA at week 24, measured by the ETDRS Letter Score. In both studies, Vabysmo Q4W treated patients had a non-inferior mean change from baseline in BCVA at week 24, compared to patients treated with aflibercept Q4W. These vision gains were maintained through week 72 when patients moved to a Vabysmo up to Q16W adjustable dosing regimen.
Between week 24 and week 68, 81.5% and 74.0% of the patients receiving Vabysmo 6 mg up to Q16W adjustable dosing regimen achieved a Q16W or Q12W dosing interval in BALATON and COMINO, respectively. Of these patients, 72.1% and 61.6% completed at least one cycle of Q12W, and maintained Q16W or Q12W dosing interval without an interval reduction below Q12W through week 68 in BALATON and COMINO, respectively; 1.2% and 2.5% of the patients received only Q4W dosing through week 68 in BALATON and COMINO, respectively.
Detailed results of both studies are shown in Table 8, Table 9, Figure 5 and Figure 6.

Vabysmo 6 mg up to Q16W adjustable dosing started at week 24 but not all patients received Vabysmo at week 24.

Immunogenicity.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to Vabysmo with the incidence of antibodies to other products may be misleading.

5.2 Pharmacokinetic Properties

Absorption.

Vabysmo is administered intravitreally (IVT) to exert local effects in the eye. There have been no clinical studies performed with other routes of administration.
Based on a population pharmacokinetic analysis (including nAMD and DMO N = 2,246), maximum free (unbound to VEGF-A and Ang-2) faricimab plasma concentrations (C_max) are estimated to occur approximately 2 days post-dose. Mean (± SD) plasma C_max are estimated 0.23 (0.07) microgram/mL and 0.22 (0.07) microgram/mL respectively in nAMD and in DMO/DR patients. After repeated administrations, mean plasma free faricimab trough concentrations are predicted to be 0.002-0.003 microgram/mL for Q8W dosing.
Faricimab exhibited dose-proportional pharmacokinetics (based on C_max and AUC) over the dose range 0.5 mg-6 mg. No accumulation of faricimab was apparent in the vitreous or in plasma following monthly dosing.
Pharmacokinetic analysis of patients with nAMD, DMO, and RVO (n = 2,977) has shown that the pharmacokinetics of faricimab are comparable in nAMD, DMO and RVO patients.

Distribution.

Maximum plasma free faricimab concentrations are predicted to be approximately 600 and 6000-fold lower than in aqueous and vitreous humour respectively and are below the binding affinity for VEGF-A and Ang-2. Therefore, systemic pharmacodynamic effects are unlikely, further supported by the absence of significant changes in free VEGF and Ang-2 concentration in plasma upon faricimab treatment in clinical studies.
Population pharmacokinetic analysis has shown an effect of age and body weight on ocular or systemic pharmacokinetics of faricimab respectively. Both effects were considered not clinically meaningful; no dose adjustment is needed.
In the clinical studies with faricimab, no significant suppression in free VEGF and Ang-2 was observed in plasma.

Metabolism.

The metabolism of faricimab has not been directly studied, as monoclonal antibodies are cleared principally by catabolism.

Elimination.

The faricimab plasma concentration-time profile declined in parallel with the vitreous and aqueous concentration-time profiles. The estimated mean ocular half-life and apparent systemic half-life of faricimab is approximately 7.5 days after IVT administration.