Eylea · 4.4 Special warnings and precautions for use · 2

HOS-096132 · has-adverse-reaction-information · PDF-Seite 39

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 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%). 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: 39 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 (frequency 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,

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HOS-096126 · has-adverse-reaction-information · PDF-Seite 8

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 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%). 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: 8 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 (frequency 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,

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HOS-096138 · has-adverse-reaction-information · PDF-Seite 69

Summary of the safety profile Serious adverse reactions were cataract (7.1%), intraocular pressure increased (3.8%), retinal haemorrhage (2.8%), vitreous haemorrhage (1.1%), cataract subcapsular (0.6%), retinal tear (0.5%), cataract nuclear (0.4%), and retinal detachment (0.4%). The most frequently observed adverse reactions in patients treated with Eylea 114.3 mg/ml were cataract (7.1%), visual acuity reduced (4.3%), conjunctival haemorrhage (4.0%), intraocular pressure increased (3.8%), vitreous detachment (3.5%), vitreous floaters (3.2%), and retinal haemorrhage (2.8%). The safety profile observed in the 4 clinical studies was similar in patients treated with Eylea 114.3 mg/ml (N=1 808) and Eylea 40 mg/ml (N=857), and in patients with nAMD, DME and RVO. Tabulated list of adverse reactions A total of 1 808 patients treated with Eylea 114.3 mg/ml up to 96 weeks constituted the safety population in 4 clinical phase II/III studies (CANDELA, PULSAR, PHOTON, QUASAR). The safety data described below include all adverse reactions with a reasonable possibility of causality to the injection procedure or medicinal product reported. 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 (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 69 Table 1: All treatment-emergent adverse reactions reported in patients with nAMD, DME or RVO treated with Eylea 114.3 mg/ml in phase II/III studies or during post-marketing surveillance System organ class Frequency Adverse reaction Immune system Common Hypersensitivity* disorders Eye disorders Common Cataract, Intraocular pressure increased, Vitreous floaters, Vitreous detachment, Vitreous haemorrhage, Retinal haemorrhage, Visual acuity reduced, Eye pain, Conjunctival haemorrhage, Punctate keratitis, Corneal abrasion Uncommon Retinal detachment, Retinal tear, Retinal pigment epithelial tear, Detachment of the retin

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HOS-096134 · has-contraindication-information · PDF-Seite 67

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Ocular or periocular infection. - Active severe intraocular inflammation.

HOS-096128 · has-contraindication-information · PDF-Seite 37

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.

HOS-096122 · has-contraindication-information · PDF-Seite 5

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.

HOS-096121 · has-indication-information · PDF-Seite 2

Eylea 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). EYLEA is indicated in preterm infants for the treatment of • retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+) or AP-ROP (aggressive posterior ROP) disease.

HOS-096133 · has-indication-information · PDF-Seite 64

Eylea is indicated in adults for the treatment of - neovascular (wet) age-related macular degeneration (nAMD) (see section 5.1) - visual impairment due to diabetic macular oedema (DME) (see section 5.1) - visual impairment due to macular oedema secondary to retinal vein occlusion (branch, central and hemiretinal RVO) (see section 5.1). 64

HOS-096127 · has-indication-information · PDF-Seite 34

Eylea 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).

HOS-096130 · has-interaction-information · PDF-Seite 38

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. 38

HOS-096124 · has-interaction-information · PDF-Seite 7

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. Paediatric population No interaction studies have been performed. 7

HOS-096136 · has-interaction-information · PDF-Seite 68

No interaction studies have been performed.

HOS-096131 · has-pregnancy-information · PDF-Seite 39

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, Eylea 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 Eylea. 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.

HOS-096125 · has-pregnancy-information · PDF-Seite 8

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, Eylea 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 Eylea. 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.

HOS-096137 · has-pregnancy-information · PDF-Seite 68

Women of childbearing potential Women of childbearing potential have to use effective contraception during treatment and for at least 4 months after the last intravitreal injection with Eylea 114.3 mg/ml. Pregnancy There are limited data on the use of aflibercept in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Eylea 114.3 mg/ml should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. 68 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 effect of aflibercept on a breast-fed newborn/infant is unknown. As a precautionary measure breast-feeding is not recommended during the use of Eylea 114.3 mg/ml. Fertility There are no fertility data in humans. Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility (see section 5.3).

HOS-096135 · has-warning-information · PDF-Seite 67

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 Eylea, have been associated with endophthalmitis, intraocular inflammation, retinal detachment, retinal tear and traumatic cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering Eylea. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay and should be managed appropriately. Intraocular pressure increased Transient increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection, including those with Eylea (see section 4.8). Both the intraocular pressure and perfusion of the optic nerve head must therefore be monitored and managed appropriately. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Eylea while the intraocular pressure is ≥ 30 mmHg). Immunogenicity As this is a therapeutic protein, there is a potential for immunogenicity with aflibercept (see section 5.1). 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 (see section 4.8). There are limited data on safety in the treatment of patients with nAMD, DME and RVO with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 6 months. Caution should be exercised when treating such patients. Bilateral treatment The safety and efficacy of bilateral treatment with Eylea 114.3 mg/ml per eye have not been 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 There are limited data available on the concomitant use of Eylea with other anti-VEGF medicinal products (systemic or ocular). 67 Withholding treatment

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HOS-096129 · has-warning-information · PDF-Seite 37

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 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. 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 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. Immunogenicity 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 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: 37  • The safety and efficacy of Eylea therapy administered to both eyes concurrently have not been

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HOS-096123 · has-warning-information · PDF-Seite 5

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. 5 Intravitreal injection-related reactions 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. Immunogenicity 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 effects Systemic adverse e

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