4.1. Therapeutic indications

Vabysmo is indicated for the treatment of adult patients with:

• neovascular (wet) age-related macular degeneration (nAMD) (see section 5.1),

• visual impairment due to diabetic macular oedema (DMO) (see section 5.1)

• visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO).

4.2. Posology and method of administration

Vabysmo must be administered by a qualified healthcare professional trained in intravitreal injections. Each pre-filled syringe should only be used for the treatment of a single eye.

Posology

nAMD, DMO and Macular oedema secondary to retinal vein occlusion (RVO)

The recommended dose is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks (monthly); 3 or more consecutive, monthly injections might be needed.

Thereafter, treatment may be individualised using a treat -and-extend approach. Based on the physician's judgement of the 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 shorter than 21 days and longer than 16 weeks have not been studied.

For patients on an intravitreal anti-VEGF therapy who are switching to Vabysmo, the treatment regimen may differ from that recommended for treatment-naïve patients. When switching a patient from an intravitreal anti-VEGF therapy to Vabysmo, the length of any subsequent treatment interval is at the discretion of the physician based on the patient's anatomic and/or visual outcomes.

Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion but there is no requirement for monthly monitoring between injections.

Duration of treatment

Vabysmo is intended for long-term treatment.

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 for assessment at the next available visit and continue dosing depending on physician's discretion.

Special populations

Elderly (≥ 65 years)

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

Renal impairment

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

Hepatic impairment

No specific studies in patients with hepatic impairment have been conducted with Vabysmo. No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Vabysmo in children and adolescents have not been established. No data are available.

Method of administration

Single-use pre-filled syringe for intravitreal use only.

Vabysmo should be inspected visually for particulate matter and discolouration prior to administration, and if present, the pre-filled syringe should not be used.

The intravitreal 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). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.8). 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 pre-filled syringe contains more than the recommended dose of 6 mg faricimab (equivalent to 0.05 mL solution for injection). Each pre-filled syringe contains 21 mg faricimab in 0.175 mL solution. The excess volume must be expelled before injecting the recommended dose. To expel air and excess medicinal product, slowly depress the plunger until the lower edge of the rubber stopper's dome is aligned with the 0.05 mL dose mark (see section 6.6).

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.

After injection, any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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. Sterile equipment should be available in case paracentesis is required.

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.

For instructions on handling of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Ocular or periocular infections.

Active intraocular inflammation.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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 (see section 4.8). 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.

Intraocular pressure increases

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal injection, including those with Vabysmo (see section 4.8). Sustained (present at 2 or more consecutive visits) IOP increases > 21 mm Hg have also been reported. 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 must be monitored and managed appropriately.

Vabysmo has not been studied in patients with poorly controlled glaucoma. Special precaution is needed in patients with poorly controlled glaucoma.

Systemic effects

Arterial thromboembolic events (ATE's): Systemic adverse events including arterial thromboembolic events have been reported following intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors, including Vabysmo, and there is a theoretical risk that these may be related to VEGF inhibition. This is similar to that reported in the other clinical trials with anti-VEGF inhibitors in patients.

There is limited data on the safety of Vabysmo in patients with history of stroke or transient ischemic attack or myocardial infarction.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with Vabysmo (see section 4.8). Patients should be instructed to inform their physician of 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 or other therapies (e.g., photodynamic therapy) for the treatment of nAMD,DMO and RVO in the same eye. Vabysmo should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).

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; 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

In nAMD clinical trials, there is limited data on patients with a total lesion size > 9 disc areas on fundus fluorescein angiography. There is only limited experience in the treatment of DMO patients with HbA1c over 10%, patients with high-risk proliferative diabetic retinopathy (DR), or nAMD,DMO and RVO patients with active systemic infections. There is also no experience of treatment with Vabysmo in diabetic or RVO patients with uncontrolled hypertension. This lack of information should be considered by the physician 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”.

Educational materials

Prescribers should be familiar with the patient guide prepared to ensure awareness of signs and symptoms of Intraocular inflammation and endophthalmitis and should provide this to the patient/caregiver explaining these events.

4.5. Interaction with other medicinal products and other forms of interaction

No studies evaluating the drug interaction potential of Vabysmo have been performed.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Female patients of childbearing potential should use effective contraception during treatment with Vabysmo and for at least 3 months following the last intravitreal injection of Vabysmo.

Pregnancy

There are no or limited amount of data from the use of faricimab in pregnant women. Systemic exposure after ocular administration of Vabysmo is very low. Animal studies in pregnant cynomolgus monkeys did not indicate direct or indirect harmful effects with respect to reproductive toxicity including embryo-foetal development (see section 5.3).

As a precautionary measure it is preferable to avoid the use of Vabysmo during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breast-feeding

It is unknown whether faricimab is excreted in human milk. A risk to the breast-fed newborn/infant cannot be excluded. Vabysmo is not recommended during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Vabysmo therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No effects on reproductive organs or fertility were observed in a 6-month cynomolgus monkey study with faricimab (see section 5.3).

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. Undesirable effects

Summary of the safety profile

Based on Phase III studies, the most frequently reported adverse reactions were cataract (10%), conjunctival haemorrhage (7.%), vitreous detachment (4%), IOP increased (4%), vitreous floaters (4%), retinal pigment epithelial tear (nAMD only) (3%), and eye pain (3%).

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%) (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions reported in clinical studies or during post-marketing surveillance 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) or not known (frequency cannot be estimated from the available data). Due to the widely varying conditions between studies, the adverse reaction profiles and frequencies reported from the development studies of Vabysmo cannot be directly compared to those reported in other development programs. Within each frequency grouping, adverse drug reactions are presented in order of decreasing frequency.

Table 1: Frequencies of adverse reactions in phase III clinical studies

MedDRA System organ class

Vabysmo

(n=2567)

Aflibercept

(n=1922 )

Frequency category

Eye disorders

Cataract

9.7%

7.0%

Common

Conjunctival haemorrhage

6.7%

6.5%

Common

Vitreous detachment

4.2%

3.6%

Common

Increased intraocular pressure

3.5%

3.2%

Common

Vitreous floaters

3.5%

2.4%

Common

Eye pain

2.5%

2.9%

Common

Retinal pigment epithelial tear (nAMD only)

2.9%

1.5%

Common

Corneal abrasion

0.9%

0.7%

Uncommon

Eye irritation

0.8%

0.7%

Uncommon

Increased lacrimation

0.8%

0.9%

Uncommon

Ocular discomfort

0.7%

0.4%

Uncommon

Eye pruritus

0.7%

0.6%

Uncommon

Ocular hyperaemia

0.7%

0.5%

Uncommon

Blurred vision

0.7%

0.6%

Uncommon

Reduced visual acuity

0.6%

0.6%

Uncommon

Iritis

0.6%

0.4%

Uncommon

Uveitis

0.5%

0.2%

Uncommon

Endophthalmitis

0.4%

0.2%

Uncommon

Sensation of foreign body

0.4%

0.2%

Uncommon

Vitreous haemorrhage

0.4%

0.4%

Uncommon

Iridocyclitis

0.3%

0.1%

Uncommon

Vitritis

0.4%

0.2%

Uncommon

Conjunctival hyperaemia

0.2%

0.3%

Uncommon

Retinal tear

0.2%

0.3%

Uncommon

Procedural pain

0.2%

<0.1%

Uncommon

Rhegmatogenous retinal detachment

0.1%

<0.1%

Uncommon

Transiently reduced visual acuity

<0.1%

0.0%

Rare

Traumatic cataract

<0.1%

<0.1%

Rare

Retinal vasculitis*

-

-

Not known

Retinal occlusive vasculitis*

-

-

Not known

Terms marked with asterisk (*) are adverse reactions which have been identified based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Description of selected adverse reactions

Retinal Vasculitis and Retinal Occlusive Vasculitis

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 IVT therapies.

Product-class-related adverse reactions

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%,9.6% and 14.4% of patients with nAMD, DMO and RVO randomized to faricimab 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 (1.5%). The majority of events were mild to moderate, without impact to vision and occurred during the loading phase.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system; Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Overdosing with greater than recommended injection volume may increase intraocular pressure. In the event of overdose, IOP should be monitored and, if deemed necessary by the treating physician, appropriate treatment should be initiated.