aflibercept: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Eylea

4.1 Therapeutic indications

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe.

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.

Applies to: Eylea 40 mg/mL solution for injection in a vial.

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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).

4.2 Posology and method of administration

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe.

Eylea is for intravitreal injection only.

Eylea must only be administered by a qualified physician experienced in administering intravitreal injections.

Posology

wet AMD

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

Eylea 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 Eylea 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, Eylea 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 Eylea is 2 mg aflibercept equivalent to 0.05 mL.

Eylea 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, Eylea should be discontinued.

Myopic choroidal neovascularisation

The recommended dose for Eylea 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.

Retinopathy of prematurity (ROP)

The recommended dose for Eylea is a single intravitreal injection of 0.4 mg aflibercept equivalent to 0.01 mL.
Treatment of ROP is initiated with a single injection per eye and may be given bilaterally on the same day. In total, up to 2 injections per eye may be administered within 6 months of treatment initiation if there are signs of disease activity. The treatment interval between the 2 doses injected into the same eye should be at least 4 weeks.

Special populations

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

Available data do not suggest a need for a dose adjustment with Eylea 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 Eylea in children and adolescents below 18 years of age for indications other than ROP have not been established (see section 4.4). There is no relevant use of Eylea 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 physician 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, adult 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.

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.

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.

Adults
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 Eylea 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.

Paediatric population
For treatment of preterm infants, the PICLEO paediatric dosing device in combination with the pre- filled syringe must be used for administration of a single dose of 0.4 mg aflibercept (equivalent to 0.01 mL solution for injection) (see section 6.6).

The injection needle should be inserted into the eye 1.0 to 2.0 mm from the limbus with the needle pointing towards the optic nerve.

After injection any unused product must be discarded.

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

Applies to: Eylea 40 mg/mL solution for injection in a vial.

Eylea is for intravitreal injection only.

Eylea must only be administered by a qualified physician experienced in administering intravitreal injections.

Posology

wet AMD

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

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

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 Eylea 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, Eylea 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.

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 Eylea is 2 mg aflibercept equivalent to 0.05 mL.

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

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, Eylea should be discontinued.

Myopic choroidal neovascularisation

The recommended dose for Eylea 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 Eylea.

Available data do not suggest a need for a dose adjustment with Eylea 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 Eylea have not been established in children and adolescents. There is no relevant use of Eylea in the paediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV.

Method of administration

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 vial should only be used for the treatment of a single eye. Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection.

The vial contains more than the recommended dose of 2 mg aflibercept (equivalent to 0.05 mL solution for injection). The extractable volume of the vial is the amount that can be withdrawn from the vial and is not to be used in total. For the Eylea vial, the extractable volume is at least 0.1 mL. The excess volume must be expelled before injecting the recommended dose (see section 6.6).

Injecting the entire volume of the vial could result in overdose. To expel the air bubbles along with excess medicinal product, slowly depress the plunger so that the flat plunger edge aligns with the line that marks 0.05 mL on the syringe (equivalent to 0.05 mL i.e. 2 mg aflibercept) (see sections 4.9 and 6.6).

After injection any unused product must be discarded.

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

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Eylea must only be administered by a qualified physician experienced in intravitreal injections.

Posology

nAMD and DME

The recommended dose is 8 mg aflibercept, equivalent to 0.07 ml solution. The posology is the same for the nAMD and DME indications. The 8 mg dose requires use of Eylea 114.3 mg/ml.

For patients who are initiating treatment, Eylea is administered with 1 injection per month for 3 consecutive doses. Injection intervals may then be extended up to every 4 months based on the physician’s judgement of visual and/or anatomic outcomes. Subsequently, the treatment intervals may be further extended up to 6 months, such as with a treat-and-extend dosing regimen, while maintaining stable visual and/or anatomic outcomes (see section 5.1).

For patients who have previously been treated with Eylea 40 mg/ml or other anti-VEGF medicinal products and are switching to Eylea 114.3 mg/ml, the treatment regimen can differ from that used for treatment-naïve patients. Treatment intervals should be determined based on visual and/or anatomic outcomes (see section 5.1).
- In patients with stable visual and anatomic outcomes, previous treatment intervals can be maintained or extended after the first injection of Eylea 114.3 mg/ml, such as with a treat-and-extend dosing regimen.
- In patients with suboptimal visual and/or anatomic outcomes, treatment with Eylea 114.3 mg/ml may begin with 1 injection per month for up to 3 consecutive doses followed by adjustment of injection intervals, such as with a treat-and-extend dosing regimen.

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly based on the physician’s discretion. The interval between 2 injections should not be shorter than 1 month.
If visual and/or anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea 114.3 mg/ml should be discontinued.

Eylea at monthly doses of 8 mg has not been studied for more than 3 consecutive doses in the PULSAR (nAMD) and PHOTON (DME) studies. Available data support the administration of more than 3 consecutive monthly doses for certain patients, however the data are currently limited.
The frequency of monitoring visits should be based on the patient’s status and at the physician’s discretion. For events in which treatment should be withheld see section 4.4.

RVO

The recommended dose is 8 mg aflibercept, equivalent to 0.07 ml solution. The 8 mg dose requires use of Eylea 114.3 mg/ml.

For patients who are initiating treatment, Eylea is administered with 1 injection per month for 3 consecutive doses. Injection intervals may then be extended based on the physician’s judgement of visual and/or anatomic outcomes (see section 5.1).

In patients with suboptimal visual and/or anatomic outcomes, treatment with Eylea 114.3 mg/ml may begin with 1 injection per month for up to 3 consecutive doses followed by adjustment of injection intervals, such as with a treat-and-extend dosing regimen.

If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly based on the physician’s discretion (see section 5.1). The interval between 2 injections should not be shorter than1 month.
If visual and/or anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea 114.3 mg/ml should be discontinued.

The frequency of monitoring visits should be based on the patient’s status and at the physician’s discretion. For events in which treatment should be withheld see section 4.4.

Special populations

Renal or hepatic impairment
No specific studies in patients with renal or hepatic impairment have been conducted.
Available data do not suggest a need for a dose adjustment with Eylea in these patients (see section 5.2).

Elderly
Available data do not suggest a need for a dose adjustment with Eylea in these patients.

Paediatric population
The safety and efficacy of Eylea 114.3 mg/ml in children and adolescents below 18 years have not been established. There is no relevant use of Eylea 114.3 mg/ml in the paediatric population in the nAMD, DME and RVO indications.

Method of administration

Eylea is for intravitreal injection only.

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 0.07 ml is then delivered. A different scleral site should be used for subsequent injections.

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 vial or pre-filled syringe should only be used for the treatment of a single eye.
After injection, discard any unused product or waste material in accordance with local requirements.

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

4.3 Contraindications

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe. · Eylea 40 mg/mL solution for injection in a vial.

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.

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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

4.8 Undesirable effects

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe.

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:

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, 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, Retinal vasculitis Not known Scleritis****, Retinal occlusive vasculitis**** * 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 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.

Paediatric population
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 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.

Applies to: Eylea 40 mg/mL solution for injection in a vial.

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.

Tabulated list of adverse reactions

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 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, Retinal vasculitis Not known Scleritis****, Retinal occlusive vasculitis**** * 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

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 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 Eylea.

Reporting of suspected adverse reactions

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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.

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 disorders Common Hypersensitivity* 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 retinal pigment epithelium, Uveitis, Iritis, Iridocyclitis, Vitritis, Cataract cortical, Cataract nuclear, Cataract subcapsular, Corneal erosion, Vision blurred, Injection site pain, Foreign body sensation in eyes, Lacrimation increased, Injection site haemorrhage, Conjunctival hyperaemia, Lenticular opacities, Eyelid oedema, Ocular hyperaemia, Injection site irritation, Retinal degeneration, Corneal oedema Rare Blindness, Endophthalmitis, Eyelid irritation, Retinal vasculitis Not known Scleritis**, Retinal occlusive vasculitis** * Reports of hypersensitivity included rash, pruritus, urticaria.
**
From post-marketing reporting.

The following adverse reactions of Eylea 40 mg/ml are also considered expected with Eylea 114.3 mg/ml: abnormal sensation in eye, corneal epithelium defect, anterior chamber flare, traumatic cataract, hypopyon, severe anaphylactic/anaphylactoid reactions.

Description of selected adverse reactions

Product-class-related adverse reactions
Arterial thromboembolic events (ATEs) are adverse reactions potentially related to systemic VEGF inhibition. There is a theoretical risk of ATEs, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of ATEs was observed in the aflibercept clinical studies in patients with nAMD, DME and RVO. Across indications, no notable difference between the groups treated with Eylea 114.3 mg/ml and the comparator groups treated with Eylea 40 mg/ml were observed.

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe.

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.
Adult 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) 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 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:

• 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.
• Eylea 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.

Paediatric population
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.

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.
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.

Information about excipients
This medicinal 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.

Applies to: Eylea 40 mg/mL solution for injection in a vial.

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.

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 Eylea 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 Eylea 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 Eylea 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.
• Eylea 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.

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.

Information about excipients
This medicinal product contains
- less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ’sodium-free’
- 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.

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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).

Withholding treatment

Treatment should be withheld in the event of:
- a decrease in best corrected visual acuity (BCVA) of ≥ 30 letters compared with the last assessment of visual acuity
- a rhegmatogenous retinal detachment or stage 3 or 4 macular holes
- a retinal break
- a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥ 50 % of the total lesion area
- performed or planned intraocular surgery within the previous or next 28 days.

Retinal pigment epithelial tear

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

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 (see section 4.6).

Populations with limited data

There is only limited experience with Eylea treatment 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.

Information about excipients

This medicinal product contains 0.021 mg of polysorbate 20 in each 0.07 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

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe.

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.

Applies to: Eylea 40 mg/mL solution for injection in a vial.

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.

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe. · Eylea 40 mg/mL solution for injection in a vial.

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.

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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.

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).

4.7 Effects on ability to drive and use machines

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe. · Eylea 40 mg/mL solution for injection in a vial.

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.

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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

4.9 Overdose

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe. · Eylea 40 mg/mL solution for injection in a vial.

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).

5.
PHARMACOLOGICAL PROPERTIES

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

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 sections 4.4 and 6.6).

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe. · Eylea 40 mg/mL solution for injection in a vial.

Pharmacotherapeutic group: Ophthalmologicals / Antineovascularisation agents
ATC code: S01LA05

Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc portion of human IgG1.

Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.

Mechanism of action
Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases; VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can synergize with VEGF- A in these processes, and is also known to promote leucocyte infiltration and vascular inflammation.

Pharmacodynamic effects

wet AMD

Wet AMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or sub-/intra-retinal haemorrhage, resulting in loss of visual acuity.

In patients treated with Eylea (one injection per month for three consecutive months, followed by one injection every 2 months), central retinal thickness [CRT] decreased soon after treatment initiation, and the mean CNV lesion size was reduced, consistent with the results seen with ranibizumab 0.5 mg every month.

In the VIEW1 study there were mean decreases in CRT on optical coherence tomography (OCT) (-130 and -129 microns at week 52 for the Eylea 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively). Also at the 52 week time point, in the VIEW2 study there were mean decreases in CRT on OCT (-149 and -139 microns for the Eylea 2 mg every two months and ranibizumab 0.5 mg every month study groups, respectively). The reduction of CNV size and reduction in CRT were generally maintained in the second year of the studies.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Pharmacotherapeutic group: Ophthalmologicals / Antineovascularisation agents, ATC code: S01LA05

Aflibercept is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc portion of human IgG1.

Aflibercept is produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.

Mechanism of action

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF can act independently to activate the VEGFR-1 to promote an inflammatory response within the retina, and is known to increase in pathological states such as nAMD, diabetic retinopathy (DR), DME, and retinal vein occlusion (RVO).

Pharmacodynamic effects

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity than their natural receptors, and thereby can inhibit the binding and activation of these cognate VEGF receptors.
In animal studies, aflibercept can prevent pathological neovascularization and vascular leakage in a number of different models of ocular disease.

nAMD

nAMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal oedema and/or sub-/intra-retinal haemorrhage, resulting in loss of visual acuity.

The pharmacodynamic effects of aflibercept 114.3 mg/ml administered every 12 (8Q12) and every 16 (8Q16) weeks are described in comparison with aflibercept 40 mg/ml administered every 8 weeks (2Q8) for the nAMD indication. These effects are shown as the change in CNV size from baseline to week 12; change in total lesion area from baseline to weeks 48, 60, and 96; and change from baseline in central retinal thickness (CRT).

In the pooled group of patients treated with 8Q12 or 8Q16, reductions in CNV size (LS mean, based on a mixed model for repeated measurements [MMRM]) at week 12 were -1.63 mm2 compared to -1.17 mm2 for patients treated with 2Q8.

Pharmacodynamic effects were generally maintained through week 156.

Table 2: Pharmacodynamic parameter (full analysis set) in the PULSAR study
Efficacy outcomes
Week
Eylea 8Q12
(N = 335)
Eylea 8Q16
(N = 338)
Eylea 2Q8
(N = 336)
Change in total lesion area from baseline [mm2]
LS mean A
-0.55
-0.30
Arithmetic mean (SD), observed
-0.4 (2.9)
-0.2 (3.1)

5.2 Pharmacokinetic properties

Applies to: Eylea 40 mg/mL solution for injection in pre-filled syringe.

Eylea is administered directly into the vitreous to exert local effects in the eye.

Absorption / Distribution
Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitreal administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF.

In a pharmacokinetic sub-study in 6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 microgram/mL (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and were undetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks.

The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times below the aflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% in animal models, in which blood pressure changes were observed after circulating levels of free aflibercept attained approximately 10 microgram/mL and returned to baseline when levels fell below approximately 1 microgram/mL. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100-fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF (2.91 microgram/mL) in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Eylea 40 mg/mL solution for injection in a vial.

A)
Difference is Eylea 2 mg Q4 weeks minus Laser Control
B)
Difference and 95% CI are calculated using Mantel-Haenszel weighting scheme adjusted for region (North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200) C) LS mean difference and 95% CI based on an ANCOVA model with treatment group, baseline BCVA category (> 20/200 and ≤ 20/200) and region (North America vs. Japan) as fixed effects, and baseline BCVA as covariate.
D)
From week 24 on the treatment interval in the Eylea treatment group was extended for all subjects from 4 weeks to 8 weeks through week 48.
E)
Beginning at week 24 subjects in the Laser Group could receive rescue treatment with Eylea, if they met at least one pre-specified eligibility criterion. At total of 67 subjects in this group received Eylea rescue treatment. The fixed regimen for Eylea rescue was three times Eylea 2 mg every 4 weeks followed by injections every 8 weeks.
F)
Nominal p-value

Figure 3: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in VIBRANT Study

At baseline, the proportion of perfused patients in the Eylea and laser groups was 60% and 68%, respectively. At week 24 these proportions were 80% and 67%, respectively. In the Eylea group the proportion of perfused patients was maintained through week 52. In the laser group, where patients were eligible for rescue treatment with Eylea from week 24, the proportion of perfused patients increased to 78% by week 52.

Diabetic macular oedema

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Eylea 114.3 mg/ml solution for injection / Eylea 114.3 mg/ml solution for injection in pre-filled syringe

Absorption / Distribution

Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitreal administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF.

Following unilateral intravitreal administration of 8 mg aflibercept, the mean (SD) Cmax of free aflibercept in plasma was 0.25 (0.21) mg/l, and the median time to maximal concentration in plasma was 1 day, in the nAMD and DME population combined. The accumulation of free aflibercept in plasma following 3 initial monthly doses was minimal. Subsequently, no further accumulation was observed. These data are also supported by population pharmacokinetic analyses.

These pharmacokinetic results were consistent with data obtained in patients with RVO.

8Q8/3-group
95.9%
≥Q8
40.5% Q20
23.8% Q16
21.9% Q12
9.7% Q8
4.1% Q4
86.2%
≥Q12
64.3%
≥Q16

Elimination

Aflibercept is a protein-based therapeutic and no metabolism studies have been conducted.

Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The median time to reach the last quantifiable concentration of free aflibercept in plasma for 8 mg administered intravitreally was 3 weeks.

Renal or hepatic impairment

No special studies in patients with renal or hepatic impairment have been conducted with Eylea 114.3 mg/ml.

The systemic exposures to aflibercept in patients with mild to severe renal impairment were similar to those with normal renal function. Limited available data in patients with mild hepatic impairment do not indicate an influence on systemic exposures to aflibercept compared to patients with normal hepatic function.

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Zaltrap

4.1 Therapeutic indications

ZALTRAP in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy is indicated in adults with metastatic colorectal cancer (MCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.

4.2 Posology and method of administration

ZALTRAP should be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

Posology
The recommended dose of ZALTRAP, administered as an intravenous infusion over 1 hour, is 4 mg / kg of body weight, followed by the FOLFIRI regimen. This is considered as one treatment cycle.

The FOLFIRI regimen to be used is irinotecan 180 mg/m2 intravenous infusion over 90 minutes and folinic acid (dl racemic) 400 mg/m² intravenous infusion over 2 hours at the same time on day 1 using

a Y-line, followed by 5-fluorouracil (5-FU) 400 mg / m² intravenous bolus, followed by 5-FU 2400 mg / m² continuous intravenous infusion over 46 hours.

The treatment cycle is repeated every 2 weeks.

ZALTRAP treatment should be continued until disease progression or unacceptable toxicity occurs.

Dose modification
ZALTRAP should be discontinued for (see section 4.4):
- Severe haemorrhage
- Gastrointestinal (GI) perforation
- Fistula formation
- Hypertension that is not adequately controlled with anti-hypertensive therapy or occurrence of hypertensive crisis or hypertensive encephalopathy
- Cardiac failure and ejection fraction decreased
- Arterial thromboembolic events (ATE)
- Grade 4 venous thromboembolic events (including pulmonary embolism)
- Nephrotic syndrome or thrombotic microangiopathy (TMA)
- Severe hypersensitivity reactions (including bronchospasm, dyspnoea, angioedema, and anaphylaxis) (see sections 4.3 and 4.4)
- Compromised wound healing requiring medical intervention
- Posterior reversible encephalopathy syndrome (PRES) (also known as reversible posterior leukoencephalopathy syndrome (RPLS))

ZALTRAP should be temporarily suspended for at least 4 weeks prior to elective surgery (see section 4.4).

ZALTRAP/FOLFIRI Treatment delay or dose modification
Neutropenia or thrombocytopenia
(see sections 4.4 and 4.8)
Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is ≥1.5 x 109/L or platelet count is ≥75 x 109 /L.
Febrile neutropenia or neutropenic sepsis
Irinotecan dose should be reduced by 15-20 % in subsequent cycles.

If recurrence, 5-FU bolus and infusion doses should additionally be reduced by 20 % in subsequent cycles.

If recurrence after irinotecan and 5-FU dose reductions, reduction of ZALTRAP dose to 2 mg/kg could be considered.

The use of granulocyte colony-stimulating factor (G-CSF) may be considered.
Mild to moderate hypersensitivity reactions to ZALTRAP (including flushing, rash, urticaria, and pruritus) (see section 4.4) The infusion should be temporarily suspended until the reaction resolves. Treatment with corticosteroids and/or antihistamines can be used as clinically indicated.

Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles.
Severe hypersensitivity reactions
(including bronchospasm, dyspnoea, angioedema, and anaphylaxis)
(see sections 4.3 and 4.4)
ZALTRAP/FOLFIRI should be discontinued and appropriate medical therapy should be administered.

ZALTRAP Treatment delay and dose modification

Hypertension
(see section 4.4)
ZALTRAP should be temporarily suspended until hypertension is controlled.

In case of recurrent medically significant or severe hypertension, despite optimal treatment, ZALTRAP should be suspended until the hypertension is controlled and the dose reduced to 2 mg / kg for subsequent cycles.

Proteinuria
(see section 4.4)
ZALTRAP should be suspended when proteinuria
≥2 grams per 24 hours and resumed when proteinuria
< 2 grams per 24 hours.

If recurrence, the treatment should be suspended until <2 grams per 24 hours and then the dose reduces to 2 mg/kg.
FOLFIRI Dose modification when used in combination with ZALTRAP
Severe stomatitis and Palmar-Plantar
Erythrodysaesthesia syndrome
5-FU bolus should be reduced and the infusion dose reduced by 20 %.
Severe diarrhoea

Irinotecan dose should be reduced by 15-20 %.

If severe diarrhoea recurs on a subsequent cycle, the 5-FU bolus and infusion dose should also be reduced by 20 %.

If severe diarrhoea persists with both dose reductions,
FOLFIRI should be discontinued.

Treatment with anti-diarrhoeal medicinal products and rehydration can be used as needed.

For additional toxicities related to irinotecan, 5-FU, or folinic acid, refer to the current respective summary of product characteristics.

Special populations

Elderly
In the pivotal MCRC study, 28.2 % of patients were aged ≥ 65 and < 75 and 5.4 % of patients were aged ≥ 75. No dose adjustments of ZALTRAP is required in the elderly people.

Hepatic impairment
There have been no formal studies with ZALTRAP in patients with hepatic impairment (see section 5.2). Clinical data suggest that no change in aflibercept dose is required in patients with mild to moderate hepatic impairment. There are no data regarding the administration of aflibercept in patients with severe hepatic impairment.

Renal impairment
There have been no formal studies with ZALTRAP in patients with renal impairment (see section 5.2).
Clinical data suggest that no change in starting dose is required in patients with mild to moderate renal impairment. There are very limited data in patients with severe renal impairment; therefore, these patients should be treated with caution.

Paediatric population
There is no relevant use of ZALTRAP in the paediatric population for the indication of metastatic colorectal cancer.

Method of administration

ZALTRAP is to be administered only as an intravenous infusion over 1 hour. Due to hyperosmolality (1000 mOsmol/kg) of the ZALTRAP concentrate, undiluted ZALTRAP concentrate must not be administered as an intravenous push or bolus. ZALTRAP must not be administered as an intravitreal injection (see sections 4.3 and 4.4).

Each vial of concentrate for solution for infusion is for single use (single-dose) only.

Precautions to be taken before handling or administering the medicinal product
For instructions on dilution of the medicinal product before administration, and on infusion sets for administration, see section 6.6.

4.3 Contraindications

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

Ophthalmic / intravitreal use due to hyperosmotic properties of ZALTRAP (see section 4.4).

For contraindications related to FOLFIRI components (irinotecan, 5-FU, and folinic acid), refer to the current respective summary of product characteristics.

4.8 Undesirable effects

Summary of the safety profile
The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1,216 patients previously treated for metastatic colorectal cancer, of which 611 patients were treated with ZALTRAP 4 mg/kg every two weeks (one cycle) and 605 patients were treated with placebo/FOLFIRI in a phase III study. Patients received a median number of 9 cycles of the ZALTRAP/FOLFIRI regimen.

The most common adverse reactions (all grades, ≥ 20 % incidence) reported at least 2 % greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency were leucopenia, diarrhoea, neutropenia, proteinuria, increased aspartate aminotransferase (AST), stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase (ALT), hypertension, weight loss, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache (see Table 1).

The most common reported grades 3-4 reactions ( ≥5 % incidence) reported at least 2 % greater incidence for the ZALTRAP/FOLFIRI regimen as compared to the placebo/FOLFIRI regimen in order of decreasing frequency, were neutropenia, diarrhoea, hypertension, leucopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1).

The most frequent adverse reactions leading to permanent discontinuation in ≥ 1 % of patients treated with the ZALTRAP/FOLFIRI regimen were vascular disorders (3.8 %) including hypertension (2.3 %), infections (3.4 %), asthenia/fatigue (1.6 %, 2.1 %),diarrhoea (2.3 %), dehydration (1 %), stomatitis (1.1 %), neutropenia (1.1 %), proteinuria (1.5 %), and pulmonary embolism (1.1 %).

Tabulated summary of adverse reactions
Adverse reactions and laboratory abnormalities reported in patients treated with the ZALTRAP/FOLFIRI regimen compared to patients treated with the placebo/FOLFIRI regimen are listed in Table 1 according to MedDRA system organ class and frequency categories. Adverse reactions in Table 1 are defined as either any adverse clinical reaction or laboratory abnormality

having ≥ 2 % greater incidence (all grades) in the aflibercept treatment group in comparison to the placebo treatment group in the MCRC study including those that do not meet this threshold but were consistent with the anti-VEGF class and were seen in any study with aflibercept. Intensity of the adverse reactions is graded according to NCI CTC version 3.0 (grade ≥ 3 = G ≥ 3). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Frequencies are based on all grades and defined as: 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); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 1 - Adverse reactions reported in patients treated with the ZALTRAP/FOLFIRI regimen from the MCRC study

System Organ Class
Adverse Reaction
Frequency Category
All grades
Grades ≥3
Infections and infestations
Very common
Infection (1)
Infection (1)
Common
Neutropenic infection/sepsis (1)
Urinary tract infection
Nasopharyngitis
Neutropenic infection/sepsis (1)
Uncommon

Urinary tract infection
Blood and lymphatic system disorders
Very common
Leucopenia (2)
Neutropenia (1),(2)
Thrombocytopenia (2)
Leucopenia (2)
Neutropenia (2)

Common
Febrile neutropenia
Febrile neutropenia
Thrombocytopenia (2)
Immune system disorders
Common
Hypersensitivity (1)

Uncommon

Hypersensitivity (1)
Metabolism and nutrition disorders
Very common
Decreased appetite
Weight loss

Common
Dehydration (1)
Dehydration (1)
Decreased appetite
Weight loss
Cardiac disorders
Uncommon

Cardiac failure

Rare
Ejection fraction decreased

Nervous system disorders
Very common
Headache

Common

Headache
Uncommon
PRES (1),(4)
PRES (1),(4)
Vascular disorders
Very common
Hypertension (1)
Haemorrhage (1)
Hypertension

System Organ Class
Adverse Reaction
Frequency Category
All grades
Grades ≥3
Common
Arterial thromboembolism (1)
Venous thromboembolism (1)
Arterial thromboembolism (1)
Venous thromboembolism (1)
Haemorrhage (1)
Not known
Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders
Very common
Dyspnoea
Epistaxis
Dysphonia

Common
Oropharyngeal pain
Rhinorrhoea

Uncommon

Dyspnoea
Epistaxis
Dysphonia
Oropharyngeal pain
Gastrointestinal disorders
Very common
Diarrhoea (1)
Stomatitis
Abdominal pain
Abdominal pain upper
Diarrhoea (1)
Stomatitis
Common
Rectal haemorrhage
Fistula (1)
Aphthous stomatitis
Haemorrhoids
Proctalgia
Toothache
Abdominal pain
Abdominal pain upper
Uncommon
GI perforation (1)
GI perforation (1)
Rectal haemorrhage
Fistula (1)
Aphthous stomatitis
Proctalgia
Hepatobiliary disorders
Very common
Increased AST (2)
Increased ALT (2)

Common

Increased AST (2)
Increased ALT (2)

Skin and subcutaneous tissue disorders
Very common
Palmar-Plantar Erythrodysaesthesia syndrome

Common
Skin hyperpigmentation
Palmar-Plantar Erythrodysaesthesia syndrome
Uncommon
Compromised wound healing (1)
Compromised wound healing (1)

System Organ Class
Adverse Reaction
Frequency Category
All grades
Grades ≥3
Musculoskeletal and connective tissue disorders
Uncommon
Osteonecrosis of the Jaw (ONJ)

Renal and urinary disorders
Very common
Proteinuria (1),(3)
Increased serum creatinine

Common

Proteinuria (1),(3)
Uncommon
Nephrotic syndrome (1)
Thrombotic microangiopathy (1)
Nephrotic syndrome (1)
Thrombotic microangiopathy (1)
General disorders and administration site conditions
Very common
Asthenic conditions
Asthenic conditions
Note: Adverse reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 (1) See “Description of selected adverse reactions” in this section (2) Based on laboratory values (percentages done on patients with laboratory assessments) (3) Compilation of clinical and laboratory data (4) Not reported in MCRC study; however, PRES was reported in patients from other studies treated with aflibercept as monotherapy and in combination with chemotherapies other than FOLFIRI

In the pivotal MCRC study, anaemia, nausea, vomiting, constipation, alopecia, increased alkaline phosphatase, and hyperbilirubinaemia occurred in ≥ 20 % of patients. These were comparable between groups, and the difference between groups did not exceed ≥ 2 % incidence for the ZALTRAP/FOLFIRI regimen.

Description of selected adverse reactions

Haemorrhage
Patients treated with ZALTRAP have an increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events. In the pivotal study of MCRC patients, episodes of bleeding/haemorrhage (all grades) was reported in 37.8 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 19.0 % of patients treated with the placebo/FOLFIRI regimen. The most common reported form of bleeding was minor (grade 1-2) epistaxis occurring in 27.7 % of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 3-4 haemorrhage including GI haemorrhage, haematuria, and post-procedural haemorrhage was reported in 2.9 % of patients receiving the ZALTRAP/FOLFIRI regimen compared with 1.7 % of patients receiving the placebo/FOLFIRI regimen. In other studies, severe intracranial haemorrhage and pulmonary haemorrhage/haemoptysis including fatal events have occurred in patients receiving ZALTRAP (see section 4.4).

Gastrointestinal perforation
GI perforation including fatal GI perforation has been reported in patients treated with ZALTRAP. In the pivotal study of MCRC patients, GI perforation (all grades) was reported in 3 of 611 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5 %) treated with the placebo/FOLFIRI regimen. Grade 3-4 GI perforation events occurred in all 3 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen and in 2 patients (0.3 %) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8 % for patients treated with ZALTRAP and 0.3 % for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8 % of patients treated with ZALTRAP and 0.2 % of patients treated with placebo (see section 4.4).

Fistula formation
Fistula formation involving GI and non-GI sites has occurred in patients treated with ZALTRAP. In the pivotal study of MCRC patients, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5 %) treated with the ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5 %) treated with the placebo/FOLFIRI regimen.
Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3 %) and in 1 placebo-treated patient (0.2 %). Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of fistula (all grades) was 1.1 % for patients treated with ZALTRAP and 0.2 % for patients treated with placebo. Grade 3-4 fistula occurred in 0.2 % of patients treated with ZALTRAP and 0.1 % of patients treated with placebo (see section 4.4).

Hypertension
In the pivotal study of MCRC patients, hypertension (all grades) has been reported in 41.2 % of patients treated with ZALTRAP/FOLFIRI and 10.7 % of patients treated with placebo/FOLFIRI. An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients receiving the ZALTRAP/FOLFIRI regimen.
Grade 3 hypertension (requiring adjustment in existing anti-hypertensive therapy or treatment with more than one medicinal product) was reported in 1.5 % of patients treated with the placebo/FOLFIRI regimen and 19.1 % of patients treated with the ZALTRAP/FOLFIRI regimen. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2 %) treated with the ZALTRAP/FOLFIRI regimen.
Among those patients treated with the ZALTRAP/FOLFIRI regimen developing grade 3-4 hypertension, 54 % had onset during the first two cycles of treatment (see section 4.4).

Thrombotic and embolic events
Arterial thromboembolic events
In the pivotal study of MCRC patients, ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) were reported in 2.6 % of patients treated with the ZALTRAP/FOLFIRI regimen and 1.5 % of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 events occurred in 11 patients (1.8 %) treated with the ZALTRAP/FOLFIRI regimen and 3 patients (0.5 %) treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of ATE (all grades) was 2.3 % for patients treated with ZALTRAP and 1.7 % for patients treated with placebo. Grade 3-4 ATE occurred in 1.7 % of patients treated with ZALTRAP and 1.0 % of patients treated with placebo (see section 4.4).

Venous thromboembolic events
VTE include deep venous thrombosis and pulmonary embolism. In the pivotal study of MCRC patients, all grades VTE occurred in 9.3 % of patients treated with the ZALTRAP/FOLFIRI regimen and 7.3 % of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 VTE occurred in 7.9 % of patients treated with the ZALTRAP/FOLFIRI regimen and in 6.3 % of patients treated with the placebo/FOLFIRI regimen. Pulmonary embolism occurred in 4.6 % of patients treated with the ZALTRAP/FOLFIRI regimen and 3.5 % of patients treated with the placebo/FOLFIRI regimen.
Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of VTE (all grades) was 7.1 % for patients treated with ZALTRAP and 7.1 % for patients treated with placebo.

Proteinuria
In the pivotal study of MCRC patients, proteinuria (compiled from clinical and laboratory data) was reported in 62.2 % patients treated with the ZALTRAP/FOLFIRI regimen compared to 40.7 % patients treated with the placebo/FOLFIRI regimen. Grade 3-4 proteinuria occurred in 7.9 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.2 % of patients treated with the placebo/FOLFIRI regimen. Nephrotic syndrome occurred in 2 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen compared to none of the patients treated with the placebo/FOLFIRI regimen. One patient treated with the ZALTRAP/FOLFIRI regimen presenting with proteinuria and

hypertension was diagnosed with thrombotic microangiopathy (TMA). Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of nephrotic syndrome was 0.5 % of patients treated with ZALTRAP and 0.1 % of patients treated with placebo (see section 4.4).

Neutropenia and neutropenic complications
In the pivotal study of MCRC patients, neutropenia (all grades) has been reported in 67.8 % of patients treated with ZALTRAP/FOLFIRI and 56.3 % of patients treated with placebo/FOLFIRI.
Grade 3-4 neutropenia was observed in 36.7 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 29.5 % patients treated with the placebo/FOLFIRI regimen. The most common grade 3-4 neutropenic complication was the occurrence of febrile neutropenia in 4.3 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.7 % of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 neutropenic infection/sepsis occurred in 1.5 % of patients treated with the ZALTRAP/FOLFIRI regimen and 1.2 % of patients treated with the placebo/FOLFIRI regimen (see section 4.4).

Infections
Infections occurred at a higher frequency in patients receiving the ZALTRAP/FOLFIRI regimen (46.2 %, all grades; 12.3 %, grade 3-4) than in patients receiving the placebo/FOLFIRI regimen (32.7%, all grades; 6.9 %, grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

Diarrhoea and dehydration
In the pivotal study of MCRC patients, diarrhoea (all grades) has been observed in 69.2 % of patients treated with ZALTRAP/FOLFIRI and 56.5 % of patients treated with placebo/FOLFIRI. Dehydration (all grades) has been observed in 9.0 % of patients treated with ZALTRAP/FOLFIRI and 3.0 % of patients treated with placebo/FOLFIRI. Grade 3-4 diarrhoea was reported in 19.3 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 7.8 % of patients treated with the placebo/FOLFIRI regimen. Grade 3-4 dehydration was reported in 4.3 % of patients treated with the ZALTRAP/FOLFIRI regimen compared to 1.3 % of patients treated with the placebo/FOLFIRI regimen (see section 4.4).

Hypersensitivity reactions
In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in 0.3 % of patients treated with the ZALTRAP/FOLFIRI regimen and 0.5 % of patients treated with the placebo/FOLFIRI regimen (see section 4.4).

Compromised wound healing
Treatment with ZALTRAP is associated with potential for compromised wound healing (wound dehiscence, anastomotic leakage). In the pivotal study for MCRC, compromised wound healing was reported in 3 patients (0.5 %) treated with the ZALTRAP/FOLFIRI regimen and 5 patients (0.8 %) treated with the placebo/FOLFIRI regimen. Grade 3 compromised wound healing was reported in 2 patients (0.3 %) treated with the ZALTRAP/FOLFIRI regimen and in none of the patients treated with the placebo/FOLFIRI regimen. Across the three Phase III placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of compromised wound healing (all grades) was 0.5 % for patients treated with ZALTRAP and 0.4 % for patients treated with placebo. Grade 3-4 compromised wound healing occurred in 0.2 % of patients treated with ZALTRAP and none of patients treated with placebo (see section 4.4).

Posterior reversible encephalopathy syndrome (PRES)
PRES was not reported in the pivotal Phase III study of MCRC patients. In other studies, PRES was reported in patients treated with monotherapy ZALTRAP (0.5 %) and in combination with other chemotherapies (see section 4.4).

Additional adverse reactions and laboratory abnormalities reported with a ≥5 % difference (all grades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen The following adverse reactions and laboratory abnormalities were reported with a ≥ 5 % difference (all grades) in patients treated with the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen (in order of decreasing frequency): leucopenia (78.3 % versus 72.4 % all grades; 15.6 % versus 12.2 % Grades 3-4), increased AST (57.5 % versus 50.2 % all grades; 3.1 % versus 1.7% Grades 3-4), stomatitis (50.1 % versus 32.9 % all grades; 12.8 % versus 4.6 % Grades 3-4), fatigue (47.8 % versus 39.0 % all grades; 12.6 % versus 7.8 % Grade 3-4), thrombocytopenia (47.4 % versus 33.8 % all grades; 3.3 % versus 1.7 % Grades 3-4), increased ALT (47.3 % versus 37.1 % all grades; 2.7 % versus 2.2 % Grades 3-4), decreased appetite (31.9 % versus 23.8 % all grades; 3.4 % versus 1.8 % Grade 3-4), weight loss (31.9 % versus 14.4 % all grades; 2.6 % versus 0.8 % Grades 3-4), dysphonia (25.4 % versus 3.3 % all grades; 0.5 % versus 0 Grades 3-4), headache (22.3 % versus 8.8 % all grades; 1.6 % versus 0.3 % Grades 3-4), asthenia (18.3 % versus 13.2 % all grades; 5.1% versus 3.0 % Grades 3-4), Palmar- Plantar Erythrodysaesthesia syndrome (11.0 % versus 4.3 % all grades; 2.8 % versus 0.5 % Grades 3-4), and skin hyperpigmentation (8.2 % versus 2.8 % all grades; 0 versus 0 Grades 3-4).

Paediatric population
The safety in paediatric patients has not been established.

Other special populations
Elderly
Of the 611 patients treated with the ZALTRAP/FOLFIRI regimen in the pivotal study of MCRC patients, 172 (28.2 %) were aged ≥ 65 and < 75 and 33 (5.4 %) were age ≥ 75. Elderly (≥ 65 years of age) may be more likely to experience adverse reactions. The incidence of diarrhoea, dizziness, asthenia, weight decrease, and dehydration was increased by ≥5% in elderly compared to younger patients. Elderly people should be closely monitored for the development of diarrhoea and potential dehydration (see section 4.4).

Renal impairment
In patients receiving ZALTRAP, the adverse reactions in patients with mild renal impairment at baseline in three Phase III placebo-controlled clinical studies (N = 352) were comparable with those of patients without renal impairment (N = 642). A limited number of patients having moderate/severe renal impairment at baseline (N = 49) were treated with ZALTRAP. In these patients, non-renal events were generally comparable between patients with renal impairment and those without renal impairment, except a > 10 % higher incidence in dehydration (all grades) was noted (see section 4.4).

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

Overall across all clinical oncology studies, similar incidence of low titre anti-drug antibody (ADA) responses (post baseline) in the ADA assay were observed in both patients treated with placebo and ZALTRAP (3.3 % and 3.8 %, respectively). High-titre antibody responses to aflibercept were not detected in any patients. Seventeen (17) patients treated with ZALTRAP (1.6 %) and two (2) placebo-treated patients (0.2 %) were also positive in the neutralising antibody assay. In the pivotal study of MCRC patients, positive responses in the ADA assay were observed at higher levels in patients treated with the placebo/FOLFIRI regimen [18/526 (3.4 %)] than with the ZALTRAP/FOLFIRI regimen [8/521 (1.5 %)]. Positive results in the neutralising antibody assay in the MCRC pivotal study were also higher in patients treated with the placebo/FOLFIRI regimen [2/526 (0.38 % )] than with the ZALTRAP/FOLFIRI regimen [1/521 (0.19 %)]. There was no observed impact on the pharmacokinetic profile of aflibercept in patients who were positive in the immunogenicity assays.

Given the similar ADA assay results in patients treated with placebo or ZALTRAP, the actual incidence of immunogenicity with ZALTRAP based on these assays is likely to be overestimated.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medicinal products, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading.

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.

4.4 Special warnings and precautions for use

Haemorrhage
An increased risk of haemorrhage, including severe and sometimes fatal haemorrhagic events has been reported in patients treated with aflibercept (see section 4.8).

Patients should be monitored for signs and symptoms of GI bleeding and other severe bleeding.
Aflibercept should not be administered to patients with severe haemorrhage (see section 4.2).

Thrombocytopenia has been reported in patients treated with the ZALTRAP/FOLFIRI regimen.
Monitoring of complete blood count (CBC) with platelets is recommended at baseline, prior to initiation of each cycle of aflibercept, and as clinically necessary. Administration of the ZALTRAP/FOLFIRI should be delayed until platelet count is ≥75 x 109 / L (see section 4.2).

Gastrointestinal perforation
GI perforation including fatal GI perforation has been reported in patients treated with aflibercept (see section 4.8).

Patients should be monitored for signs and symptoms of GI perforation. Aflibercept treatment should be discontinued in patients who experience GI perforation (see section 4.2).

Fistula formation
Fistula formation involving GI and non-GI sites has occurred in patients treated with aflibercept (see section 4.8).

Aflibercept treatment should be discontinued in patients who develop fistula (see section 4.2).

Hypertension
An increased risk of grade 3-4 hypertension (including hypertension and one case of essential hypertension) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

Pre-existing hypertension must be adequately controlled before starting aflibercept. If hypertension cannot be adequately controlled, treatment with aflibercept should not be initiated. It is recommended to monitor blood pressure every two weeks, including before each administration or as clinically

indicated during treatment with aflibercept. In the event of hypertension on aflibercept treatment, blood pressure should be controlled with appropriate anti-hypertensive therapy and blood pressure should be monitored regularly. In case of recurrent medically significant or severe hypertension, despite optimal treatment, aflibercept should be suspended until the hypertension is controlled and the aflibercept dose should be reduced to 2 mg/kg for subsequent cycles. Aflibercept should be permanently discontinued if hypertension cannot be adequately managed with appropriate anti-hypertensive therapy or aflibercept dose reduction, or if hypertensive crisis or hypertensive encephalopathy occurs (see section 4.2).

Hypertension may exacerbate underlying cardiovascular disease. Caution should be exercised when treating patients with history of clinically significant cardiovascular disease such as coronary artery disease, or congestive heart failure with ZALTRAP. Patients with NYHA class III or IV congestive heart failure should not be treated with ZALTRAP.

Aneurysms and artery dissections
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating ZALTRAP, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Cardiac failure and ejection fraction decreased
Cardiac failure and ejection fraction decreased have been reported in patients treated with ZALTRAP.
Baseline and periodic evaluations of left ventricular function should be considered while the patient is receiving Zaltrap. Patients should be monitored for signs and symptoms of cardiac failure and ejection fraction decreased. Discontinue ZALTRAP in patients who experience cardiac failure and ejection fraction decreased.

Thrombotic and embolic events

Arterial thromboembolic events (ATE)
ATE (including transient ischaemic attack, cerebrovascular accident, angina pectoris, intracardiac thrombus, myocardial infarction, arterial embolism, and ischaemic colitis) have been observed in patients treated with aflibercept (see section 4.8).

Aflibercept treatment should be discontinued in patients who experience an ATE (see section 4.2).

Venous thromboembolic events (VTE)
VTE including deep vein thrombosis (DVT) and pulmonary embolism (infrequently fatal) have been reported in patients treated with aflibercept (see section 4.8).

ZALTRAP should be discontinued in patients with life-threatening (Grade 4) thromboembolic events (including pulmonary embolism) (see section 4.2). Patients with Grade 3 DVT should be treated with anticoagulation as clinically indicated, and aflibercept therapy should be continued. In the event of recurrence, despite appropriate anticoagulation, aflibercept treatment should be discontinued. Patients with thromboembolic events of Grade 3 or lower need to be closely monitored.

Proteinuria
Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) have been observed in patients treated with aflibercept (see section 4.8).

Proteinuria should be monitored by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria before each aflibercept administration.
Patients with a dipstick of ≥ 2+ for protein or a UPCR > 1 or a protein/creatinine ratio (PCR)> 100 mg/mmol should undergo a 24-hour urine collection.

Aflibercept administration should be suspended for ≥ 2 grams of proteinuria/24 hours and restarted when proteinuria is <2 grams/24 hours. If there is recurrence, the administration should be suspended

until <2 grams/24 hours and then the dose reduced to 2 mg/kg. Aflibercept treatment should be discontinued in patients who develop nephrotic syndrome or TMA (see section 4.2).

Neutropenia and neutropenic complications
A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

Monitoring of complete blood count (CBC) with differential count is recommended at baseline and prior to initiation of each cycle of aflibercept. Administration of ZALTRAP/FOLFIRI should be delayed until neutrophil count is ≥1.5 x 109 / L (see section 4.2). Therapeutic use of G-CSF at first occurrence of grade ≥ 3 neutropenia and secondary prophylaxis may be considered in patients who may be at increased risk for neutropenia complications.

Diarrhoea and dehydration
A higher incidence of severe diarrhoea has been observed in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

Dose modification of FOLFIRI regimen (see section 4.2), anti-diarrhoeal medicinal products, and rehydration as needed should be instituted.

Hypersensitivity reactions
In the pivotal study of MCRC patients, severe hypersensitivity reactions have been reported in patients treated with the ZALTRAP/FOLFIRI regimen (see section 4.8).

In the event of a severe hypersensitivity reaction (including bronchospasm, dyspnoea, angioedema, and anaphylaxis), aflibercept should be discontinued and appropriate medical measures should be administered (see section 4.2).

In the event of a mild to moderate hypersensitivity reaction to ZALTRAP (including flushing, rash, urticaria, and pruritus), aflibercept should be temporarily suspended until the reaction is resolved.
Treatment with corticosteroids and/or antihistamines can be initiated as clinically indicated.
Pre-treatment with corticosteroids and/or antihistamines may be considered in subsequent cycles (see section 4.2). Caution should be used when retreating patients with prior hypersensitivity reactions as recurrent hypersensitivity reactions have been observed in some patients despite prophylaxis, including corticosteroids.

Compromised wound healing
Aflibercept impaired wound healing in animal models (see section 5.3).

Potential for compromised wound healing (wound dehiscence, anastomotic leakage) has been reported with aflibercept (see section 4.8).

Aflibercept should be suspended for at least 4 weeks prior to elective surgery.

It is recommended that aflibercept not be initiated for at least 4 weeks following major surgery and not until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, aflibercept may be initiated/restarted once the surgical wound is fully healed. Aflibercept should be discontinued in patients with compromised wound healing requiring medical intervention (see section 4.2).

Osteonecrosis of the jaw (ONJ)
Cases of ONJ have been reported in cancer patients treated with Zaltrap, several of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when Zaltrap and intravenous bisphosphonates are administered concurrently or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Zaltrap. Invasive dental procedures should, if possible, be avoided in patients treated with Zaltrap and who have previously received or are receiving intravenous bisphosphonates (see section 4.8).

Posterior reversible encephalopathy syndrome (PRES)
PRES was not reported in the pivotal phase III study of MCRC patients. In other studies, PRES was reported in patients treated with aflibercept as monotherapy and in combination with other chemotherapies (see section 4.8).

PRES may present with altered mental status, seizure, nausea, vomiting, headache, or visual disturbances. The diagnosis of PRES is confirmed by brain Magnetic Resonance Imaging (MRI).

Aflibercept should be discontinued in patients that develop PRES (see section 4.2).

Elderly
Elderly patients ≥65 years had an increased risk of diarrhoea, dizziness, asthenia, weight loss and dehydration. Careful monitoring is recommended in order to rapidly detect and treat signs and symptoms of diarrhoea and dehydration and to minimize potential risk (see section 4.8).

Renal impairment
There are very limited data available for patients with severe renal impairment treated with aflibercept.
No dose adjustment is required for aflibercept (see sections 4.2, 4.8 and 5.2).

Performance status and co-morbidities
Patients with ECOG performance status ≥ 2 or having significant co-morbidities may be at greater risk for a poor clinical outcome and should be carefully monitored for early clinical deterioration.

Off-label intravitreal use
ZALTRAP is a hyperosmotic solution, which is not formulated for compatibility with the intraocular environment. ZALTRAP must not be administered as an intravitreal injection (see section 4.3).

ZALTRAP contains sodium
This medicinal product contains up to 22 mg sodium per vial, equivalent to 1.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Population pharmacokinetics analysis and inter study comparisons did not reveal any pharmacokinetic drug-drug interaction between aflibercept and the FOLFIRI regimen.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in females
Women of childbearing potential should be advised to avoid becoming pregnant while on ZALTRAP, and should be informed of the potential hazard to the foetus. Women of childbearing potential treated with ZALTRAP must use effective contraception during treatment and for 3 months after the last dose of treatment.

Pregnancy
There are no data from the use of aflibercept in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). As angiogenesis is critical to foetal development, the inhibition

of angiogenesis following administration of ZALTRAP may result in adverse effects on pregnancy.
ZALTRAP should be used only if the potential benefit justifies the potential risk during pregnancy. If the patient becomes pregnant while taking ZALTRAP, she should be informed of the potential hazard to the foetus.

Breast-feeding
No studies have been conducted to assess the impact of ZALTRAP on milk production, its presence in breast milk or its effects on the breast-fed child.

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

Fertility
Male and female fertility are likely to be compromised during treatment with aflibercept based on studies in monkeys (see section 5.3).

4.7 Effects on ability to drive and use machines

ZALTRAP has no or negligible influence on the ability to drive and use machines. If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive or use machines (see section 4.8).

4.9 Overdose

There is no information on the safety of aflibercept given at doses exceeding 7 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. The most commonly observed adverse reactions at these doses were similar to those observed at the therapeutic dose.

There is no specific antidote to ZALTRAP overdose. Cases of overdose should be managed by appropriate supportive measures particularly with regard to monitoring and treatment of hypertension and proteinuria. The patient should remain under close medical supervision to monitor any adverse reactions (see section 4.8).

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX44

Mechanism of action
Vascular endothelial growth factor A and B (VEGF-A, VEGF-B), and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF-A acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF and VEGF-B bind only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF is also linked to pathological neovascularisation and recruitment of inflammatory cells into tumours.

Aflibercept, also known as VEGF TRAP in the scientific literature, is a recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1. Aflibercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-1 mammalian expression system. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15 % of the total molecular mass, resulting in a total molecular weight of 115 kDa.

Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native receptors, as well as the related ligands PlGF and VEGF-B. By acting as a ligand trap, aflibercept prevents binding of endogenous ligands to their cognate receptors and thereby blocks receptor mediated signaling.

Aflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby inhibiting the growth of new vessels that supply tumours with oxygen and nutrients.

Aflibercept binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for VEGF-A165 and 0.36 pM for VEGF-A121), to human PlGF (KD of 39 pM for PlGF-2), and to human VEGF-B (KD of 1.92 pM) to form a stable, inert complex which has no detectable biological activity.

Pharmacodynamic effects
Administration of aflibercept to mice bearing xenotransplant or allotransplant tumours inhibited the growth of various cancer types.

Clinical efficacy and safety

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

The pharmacokinetic properties described below have to a large extent been derived from a population pharmacokinetic analysis with data from 1,507 patients with various types of advanced malignancies.

Absorption

In preclinical tumour models, biologically active doses of aflibercept correlated with those necessary to produce circulating concentrations of free aflibercept in excess of VEGF-bound aflibercept.
Circulating concentrations of VEGF-bound aflibercept increase with the aflibercept dose until most available VEGF is bound. Further increases in the aflibercept dose resulted in dose-related increases in circulating free aflibercept concentrations but only small further increases in the VEGF-bound aflibercept concentration.

In patients, ZALTRAP is administered at the dose of 4 mg/kg intravenously every two weeks for which there is an excess of circulating free aflibercept compared to VEGF-bound aflibercept.

At the recommended dose regimen of 4 mg/kg every two weeks, concentration of free aflibercept were near steady-state levels by the second cycle of treatment with essentially no accumulation (accumulation ratio of 1.2 at steady-state compared to the first administration).

Distribution
The volume of distribution of free aflibercept at steady-state is approximately 8 litres.

Biotransformation
No metabolism studies have been conducted with aflibercept since it is a protein. Aflibercept is expected to degrade to small peptides and individual amino acids.

Elimination
Free aflibercept is primarily cleared by binding to endogenous VEGF to form a stable, inactive complex. As with other large proteins, both free and bound aflibercept, are expected to be cleared, more slowly, by other biological mechanisms, such as proteolytic catabolism.
At doses greater than 2 mg/kg, free aflibercept clearance was approximately 1.0L/day with a terminal half-life of 6 days.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.