Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bayer AG, 51368 Leverkusen, Germany
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.
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 injections, including those with Eylea, 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 Eylea. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs.
Adult patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay.
Patients with ROP should be observed by healthcare professionals for any signs suggestive of endophthalmitis (e.g. redness/irritation of the eye, ocular discharge, lid swelling, photophobia).
Parents and caregivers should also be instructed to observe and report any signs suggestive of endophthalmitis without delay.
The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL) for adult patients. The excess volume must be expelled prior to administration (see sections 4.2 and 6.6).
The pre-filled syringe contains more than the recommended dose of 0.4 mg (equivalent to 0.01 mL) for preterm infants (see section 6.6). The pre-filled syringe must be used in combination with the PICLEO paediatric dosing device to avoid a higher than recommended volume that could result in increased intraocular pressure (see sections 4.9 and 6.6).
Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including those with Eylea (see section 4.8). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Eylea 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.
As this is a therapeutic protein, there is a potential for immunogenicity with Eylea (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 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.
As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, DME and myopic CNV the following also applies:
The warnings and precautions for adults also apply to preterm infants with ROP. The long-term safety profile in preterm infants has not been established.
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. Eylea 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 Eylea 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 Eylea in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.
This medicine 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 Eylea has not been studied, therefore, a safety profile is not established.
No interaction studies have been performed.
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).
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, Eylea should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.
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 Eylea.
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 Eylea 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.
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 Eylea 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 Eylea) 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%).
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:
| System Organ Class | Very common | Common | Uncommon | Rare |
|---|---|---|---|---|
| Immune system disorders | Hypersensitivity*** | |||
| Eye disorders | Visual acuity reduced, Retinal haemorrhage, Conjunctival haemorrhage, Eye pain | 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 | 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 | Blindness, Cataract traumatic, Vitritis, Hypopyon |
* 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.
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 Eylea.
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 Eylea clinical trials in patients with AMD, DME, RVO, myopic CNV and ROP. 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 Eylea.
The safety of Eylea for the treatment of ROP was evaluated in a 6-month phase III study, which included 75 preterm infants treated with aflibercept 0.4 mg at baseline. The long-term safety profile in preterm infants has not been established.
Adverse reactions reported in more than one patient treated with aflibercept 0.4 mg were retinal detachment, retinal haemorrhage, conjunctival haemorrhage, injection site haemorrhage, intraocular pressure increased and eyelid oedema.
Adverse reactions established for adult indications are considered applicable to preterm infants with ROP, though not all were observed in the phase III study.
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.
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