4.1. Therapeutic indications

Yesafili is indicated for adults for the treatment of

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

• visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO) (see section 5.1),

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

• visual impairment due to myopic choroidal neovascularisation (myopic CNV) (see section 5.1).

4.2. Posology and method of administration

Yesafili is for intravitreal injection only.

Yesafili must only be administered by a qualified healthcare professional experienced in administering intravitreal injections.

Posology

wet AMD

The recommended dose for Yesafili is 2 mg aflibercept, equivalent to 0.05 mL.

Yesafili treatment is initiated with one injection per month for three consecutive doses. The treatment interval is then extended to two months.

Based on the physician's judgement of visual and/or anatomic outcomes, the treatment interval may be maintained at two months or further extended using a treat-and-extend dosing regimen, where injection intervals are increased in 2- or 4-weekly increments to maintain stable visual and/or anatomic outcomes.

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

There is no requirement for monitoring between injections. Based on the physician's judgement the schedule of monitoring visits may be more frequent than the injection visits.

Treatment intervals greater than four months or shorter than 4 weeks between injections have not been studied (see section 5.1).

Macular oedema secondary to RVO (branch RVO or central RVO)

The recommended dose for Yesafili is 2 mg aflibercept equivalent to 0.05 mL.

After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month.

If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Yesafili should be discontinued.

Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed.

Treatment may then be continued with a treat-and-extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

The monitoring and treatment schedule should be determined by the treating physician based on the individual patient's response.

Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).

Diabetic macular oedema

The recommended dose for Yesafili is 2 mg aflibercept equivalent to 0.05 mL.

Yesafili treatment is initiated with one injection per month for five consecutive doses, followed by one injection every two months.

Based on the physician's judgement of visual and/or anatomic outcomes, the treatment interval may be maintained at 2 months or individualized, such as with a treat-and-extend dosing regimen, where the treatment intervals are usually increased by 2-week increments to maintain stable visual and/or anatomic outcomes. There are limited data for treatment intervals longer than 4 months. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

Treatment intervals shorter than 4 weeks have not been studied (see section 5.1). The schedule for monitoring should be determined by the treating physician.

If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Yesafili should be discontinued.

Myopic choroidal neovascularisation

The recommended dose for Yesafili is a single intravitreal injection of 2 mg aflibercept equivalent to 0.05 mL.

Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease.

The schedule for monitoring should be determined by the treating physician.

The interval between two doses should not be shorter than one month.

Special populations

Hepatic and/or renal impairment

No specific studies in patients with hepatic and/or renal impairment have been conducted with Yesafili.

Available data do not suggest a need for a dose adjustment with Yesafili in these patients (see section 5.2).

Elderly population

No special considerations are needed. There is limited experience in patients older than 75 years with DME.

Paediatric population

The safety and efficacy of Yesafili have not been established in children and adolescents. There is no relevant use of Yesafili in the paediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV.

Method of administration

Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualified healthcare professional experienced in administering intravitreal injections. In general, adequate anaesthesia and asepsis, including topical broad spectrum microbicide (e.g. povidone iodine applied to the periocular skin, eyelid and ocular surface), have to be ensured. Surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) are recommended.

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. eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Each pre-filled syringe should only be used for the treatment of a single eye. Extraction of multiple doses from a pre-filled syringe may increase the risk of contamination and subsequent infection.

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL solution for injection). The extractable volume of the syringe is the amount that can be expelled from the syringe and is not to be used in total. For the Yesafili pre-filled syringe, the extractable volume is at least 0.09 mL. The excess volume must be expelled before injecting the recommended dose (see section 6.6).

Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubbles along with excess medicinal product, slowly depress the plunger to align the base of the plunger dome (not the tip of the dome) with the dosing line on the syringe (equivalent to 0.05 mL i.e. 2 mg aflibercept) (see sections 4.9 and 6.6).

The injection needle should be inserted 3.5-4.0 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; a different scleral site should be used for subsequent injections.

After injection any unused product must be discarded.

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

4.3. Contraindications

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

Active or suspected ocular or periocular infection.

Active severe intraocular inflammation.

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 aflibercept, 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 aflibercept. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs.

Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay.

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). The excess volume must be expelled prior to administration (see sections 4.2 and 6.6).

Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including those with aflibercept (see section 4.8). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Yesafili while the intraocular pressure is ≥ 30 mmHg). In all cases, both the intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately.

Immunogenicity

As this is a therapeutic protein, there is a potential for immunogenicity with Yesafili (see section 4.8). Patients should be instructed to report any signs or symptoms of intraocular inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign attributable to hypersensitivity.

Systemic effects

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 CRVO, BRVO, DME or myopic CNV with a history of stroke or transient ischaemic attacks or myocardial infarction within the last 6 months. Caution should be exercised when treating such patients.

Other

As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, DME and myopic CNV the following also applies:

• The safety and efficacy of aflibercept therapy administered to both eyes concurrently have not been systematically studied (see section 5.1). If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events.

• Concomitant use of other anti-VEGF (vascular endothelial growth factor)

There is no data available on the concomitant use of aflibercept with other anti-VEGF medicinal products (systemic or ocular).

• 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 aflibercept therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.

• Treatment should be withheld in patients with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.

• In the event of a retinal break the dose should be withheld and treatment should not be resumed until the break is adequately repaired.

• The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:

o a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity;

o a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area.

• The dose should be withheld within the previous or next 28 days in the event of a performed or planned intraocular surgery.

• Aflibercept should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus (see section 4.6).

• Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept (see section 4.6).

• There is limited experience with treatment of patients with ischaemic CRVO and BRVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, the treatment is not recommended.

Populations with limited data

There is only limited experience in the treatment of subjects with DME due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy.

Aflibercept has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with aflibercept in diabetic patients with uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.

In myopic CNV there is no experience with aflibercept in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.

Information about excipients

This medicine product contains

- less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium-free'.

- 0.003 mg of polysorbate 20 in each 0.01 ml dose or 0.015 mg of polysorbate 20 in each 0.05 ml dose which is equivalent to 0.3 mg/ml. Polysorbates may cause allergic reactions.

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

No interaction studies have been performed.

Adjunctive use of verteporfin photodynamic therapy (PDT) and Yesafili has not been studied, therefore, a safety profile is not established.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection of aflibercept (see section 4.4).

Pregnancy

There are no data on the use of aflibercept in pregnant women.

Studies in animals have shown embryo-foetal toxicity (see section 5.3).

Although the systemic exposure after ocular administration is very low, aflibercept should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breast-feeding

Based on very limited human data, aflibercept may be excreted in human milk at low levels. Aflibercept is a large protein molecule and the amount of medication absorbed by the infant is expected to be minimal. The effects of aflibercept on a breast-fed newborn/infant are unknown.

As a precautionary measure, breast-feeding is not recommended during the use of Yesafili.

Fertility

Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility (see section 5.3). Such effects are not expected after ocular administration with very low systemic exposure.

4.7. Effects on ability to drive and use machines

Injection with aflibercept has a minor influence on the ability to drive and use machines due to possible temporary visual disturbances associated either with the injection or the eye examination. Patients should not drive or use machines until their visual function has recovered sufficiently.

4.8. Undesirable effects

Summary of the safety profile

A total of 3,102 patients constituted the safety population in the eight phase III studies. Among those, 2,501 patients were treated with the recommended dose of 2 mg.

Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in less than 1 in 1,900 intravitreal injections with aflibercept and included blindness, endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, and intraocular pressure increased (see section 4.4).

The most frequently observed adverse reactions (in at least 5% of patients treated with aflibercept) were conjunctival haemorrhage (25%), retinal haemorrhage (11%), visual acuity reduced (11%), eye pain (10%), cataract (8%), intraocular pressure increased (8%), vitreous detachment (7%), and vitreous floaters (7%).

Tabulated list of adverse reactions

The safety data described below include all adverse reactions from the eight phase III studies in the indications wet AMD, CRVO, BRVO, DME and myopic CNV with a reasonable possibility of causality to the injection procedure or medicinal product.

The adverse reactions are listed by system organ class and 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) , not known (cannot be estimated from the available data).

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 1: All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications wet AMD, CRVO, BRVO, DME and myopic CNV) or during post-marketing surveillance

System Organ Class

Frequency

Adverse reaction

Immune system disorders

Uncommon

Hypersensitivity***

Eye disorders

Very common

Visual acuity reduced, Retinal haemorrhage, Conjunctival haemorrhage, Eye pain

Common

Retinal pigment epithelial tear*, Detachment of the retinal pigment epithelium, Retinal degeneration, Vitreous haemorrhage, Cataract, Cataract cortical, Cataract nuclear, Cataract subcapsular, Corneal erosion, Corneal abrasion, Intraocular pressure increased, Vision blurred, Vitreous floaters, Vitreous detachment, Injection site pain, Foreign body sensation in eyes, Lacrimation increased, Eyelid oedema, Injection site haemorrhage, Punctate keratitis, Conjunctival hyperaemia, Ocular hyperaemia

Uncommon

Endophthalmitis**, Retinal detachment, Retinal tear, Iritis, Uveitis, Iridocyclitis, Lenticular opacities, Corneal epithelium defect, Injection site irritation, Abnormal sensation in eye, Eyelid irritation, Anterior chamber flare, Corneal oedema

Rare

Blindness, Cataract traumatic, Vitritis, Hypopyon

Not known

Scleritis****

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.

** Culture positive and culture negative endophthalmitis

*** During the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases of severe anaphylactic/anaphylactoid reactions.

**** From post-marketing reporting.

Description of selected adverse reactions

In the wet AMD phase III studies, there was an increased incidence of conjunctival haemorrhage in patients receiving anti-thrombotic agents. This increased incidence was comparable between patients treated with ranibizumab and aflibercept.

Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. 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 Aflibercept clinical trials in patients with AMD, DME, RVO, myopic CNV. Across indications no notable difference between the groups treated with aflibercept and the respective comparator groups were observed.

As with all therapeutic proteins, there is a potential for immunogenicity with Yesafili.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In clinical trials, doses of up to 4 mg in monthly intervals have been used and isolated cases of overdoses with 8 mg occurred.

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdose, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated (see section 6.6).