YESAFILI Solution for injection Ref.[51275] Active ingredients: Aflibercept

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 vial contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL). The excess volume must be discarded 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 antiVEGF 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:
  • a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity;
  • 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 medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium-free'

No interaction studies have been performed.

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

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

It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed child cannot be excluded.

Aflibercept is not recommended during breast-feeding. A decision must be made whether to discontinue breast-feeding or to abstain from aflibercept therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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.

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.

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). 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:

^* 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.

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 and 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 national reporting system listed in Appendix V.

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