Eylea

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  • Miscellaneous ocular agents
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Eylea Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Aflibercept 2mg/0.05mL; soln for oph intravitreal inj; preservative-free.

    Pharmacological Class

    Recombinant fusion protein (human VEGF inhibitor + human IgG1).

    See Also

    How Supplied

    Kit (Eylea, Eylea HD)—1 (single-use vial w. supplies); Single-use prefilled syringe (Eylea)—1; Single-use vial (Eylea HD)—1

    How Supplied

    Eylea is supplied as:

    • one blister pack containing one Eylea 2 mg/0.05 mL sterile, single-dose prefilled glass syringe.
    • a vial kit with the following components: one Eylea 2 mg/0.05 mL single-dose glass vial; one 19-gauge x 1½-inch, 5-micron, filter needle for withdrawal of the vial contents; one 30-gauge x ½-inch injection needle for intravitreal injection; and one 1-mL syringe for administration.

    Storage

    Refrigerate Eylea at 2°C to 8ºC (36°F to 46ºF). Do not freeze. Do not use beyond the date stamped on the carton and container label. Store in the original carton until time of use to protect from light. Do not open sealed blister tray until time of use.

    Manufacturer

    Regeneron

    Generic Availability

    NO

    Mechanism of Action

    Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

    Eylea Indications

    Indications

    Neovascular (wet) age-related macular degeneration (AMD). Macular edema following retinal vein occlusion (RVO). Diabetic macular edema (DME). Diabetic retinopathy (DR). Preterm infants with retinopathy of prematurity (ROP).

    Eylea Dosage and Administration

    Adult

    Give by intravitreal injection. AMD: 2mg (0.05mL) once every 4 weeks (~28 days, monthly) for the 1st 12 weeks (3 months), followed by 2mg (0.05mL) once every 8 weeks (2 months); some may need the monthly dosing after the 1st 3 months. May also treat with 1 dose every 12 weeks after one year of successful therapy (not as effective); assess regularly. RVO: 2mg (0.05mL) once every 4 weeks (~25 days, monthly). DME, DR: 2mg (0.05mL) once every 4 weeks (~28 days, monthly) for the 1st 5 injections, followed by 2mg (0.05mL) once every 8 weeks (2 months); some may need the monthly dosing after the 1st 5 months.

    Adult

    For ophthalmic intravitreal injection. Must only be administered by a qualified physician. 

     

    Neovascular (wet) age-related macular degeneration (AMD)

    • Administer Eylea 2 mg (0.05 mL or 50 microliters) via intravitreal injection every 4 weeks (approx. every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although Eylea may be dosed as frequently as 2 mg every 4 weeks (approx. every 25 days, monthly), additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Assess patients regularly. 

    Macular edema following retinal vein occlusion (RVO)

    • Administer Eylea 2 mg (0.05 mL or 50 microliters) via intravitreal injection once every 4 weeks (approx. every 25 days, monthly).

    Diabetic macular edema (DME) & Diabetic retinopathy (DR)

    • Administer Eylea 2 mg (0.05 mL or 50 microliters) via intravitreal injection every 4 weeks (approx. every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although Eylea may be dosed as frequently as 2 mg every 4 weeks (approx. every 25 days, monthly), additional efficacy was not demonstrated in most patients when Eylea was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

    Children

    AMD, RVO, DME, DR: not established. Give by intravitreal injection. ROP: 0.4mg (0.01mL) as a single injection per eligible eye; may be given bilaterally on the same day. May repeat injections in each eye. Separate treatment interval into the same eye by at least 10 days.

    Administration

    Using aseptic technique the intravitreal injection should be performed with a 30-gauge x ½-inch injection needle. Each vial should only be used to treat a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before administered to the other eye. Discard unused product.

    Nursing Considerations

    Using aseptic technique the intravitreal injection should be performed with a 30-gauge x ½-inch injection needle. Each vial should only be used to treat a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before administered to the other eye. Discard unused product. Advise patients to seek immediate care if eye becomes red, sensitive to light, painful, or a change in vision develops.

    Eylea Contraindications

    Contraindications

    Ocular or periocular infections. Active intraocular inflammation.

    Eylea Boxed Warnings

    Not Applicable

    Eylea Warnings/Precautions

    Warnings/Precautions

    Must only be administered by a qualified physician. Evaluate if endophthalmitis, retinal detachment, or retinal vascultis with or without occlusion occurs. Monitor intraocular pressure and perfusion of optic nerve head after injection. Potential risk for arterial thromboembolic events (eg, nonfatal stroke or MI, vascular death). In ROP (Eylea only): reactivation of abnormal angiogenesis and tortuosity may occur after treatment; monitor infants closely until retinal vascularization has completed or until assurance that reactivation will not occur; may need extended monitoring, additional Eylea inj and/or laser treatments. Pregnancy. Advise females of reproductive potential to use effective contraception prior to initial dose, during therapy, and for at least 3 months (Eylea) and for at least 4 months (Eylea HD) after last injection. Nursing mothers: not recommended.

    Warnings/Precautions

    Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion

    • Must always use proper aseptic injection technique during administration. Instruct patients to report any symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and manage appropriately.

    Increase in Intraocular Pressure

    • Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with Eylea. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. 

    • Monitor intraocular pressure and the perfusion of the optic nerve head and manage appropriately.

    Extended Monitoring and Additional Treatment in ROP

    • Reactivation of abnormal angiogenesis and tortuosity may occur after treatment. 
    • Monitor infants closely after injection until retinal revascularization has completed or until the examiner is assured that reactivation of ROP will not occur.
    • In infants with ROP, treatment with Eylea requires extended periods of ROP monitoring and additional Eylea injections and/or laser treatments may be necessary.

    Thromboembolic Events  

    • Risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including Eylea. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). 

    • There were no reported thromboembolic events in the patients treated with Eylea in the first six months of the RVO studies.

    Pregnancy Considerations

    No adequate and well-controlled studies with Eylea have been conducted in pregnant women. Aflibercept produced adverse embryofetal effects in rabbits, including external, visceral, and skeletal malformations. Based on the anti-VEGF mechanism of action for aflibercept, treatment with Eylea may pose a risk to human embryofetal development.

    Only use Eylea during pregnancy if the potential benefit justifies the potential risk to the fetus. 

    Nursing Mother Considerations

    There is no information regarding the presence of aflibercept in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production/excretion. 

    Eylea is not recommended to use during breastfeeding due to the potential risk for absorption and harm to infant growth and development. 

    Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Eylea and any potential adverse effects on the breastfed child from Eylea.

    Pediatric Considerations

    The safety and effectiveness of Eylea in pediatric patients have not been established, except in preterm infants with ROP.

    Geriatric Considerations

    No significant differences in efficacy or safety were seen with increasing age in these studies.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Contraception: Advise to use effective contraception prior to the initial dose, during treatment, and for at least 3 months after the last intravitreal injection of Eylea. 

    • Infertility: There are no data regarding the effects of Eylea on human fertility.

    Eylea Pharmacokinetics

    Absorption

    Following intravitreal administration of 2 mg per eye of Eylea to patients with wet AMD, RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. 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.

    Distribution

    The volume of distribution of free aflibercept following intravenous administration of aflibercept has been determined to be ~6L.

    Metabolism

    Aflibercept is a therapeutic protein and no drug 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.

    Elimination

    The terminal elimination half-life (t1/2) of free aflibercept in plasma was ~5 to 6 days after intravenous administration of doses of 2 to 4 mg/kg aflibercept.

    Eylea Interactions

    Not Applicable

    Eylea Adverse Reactions

    Adverse Reactions

    Conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, increased intraocular pressure; hypersensitivity reactions.

    Eylea Clinical Trials

    Clinical Trials

    Neovascular (Wet) Age-Related Macular Degeneration (AMD)

    • The safety and efficacy of Eylea were assessed in two randomized, multi-center, double-masked, active-controlled studies (VIEW1 and VIEW2) in a total of 2412 patients with wet AMD. In each study, up to week 52, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) Eylea administered 2 mg every 8 weeks following 3 initial monthly doses (Eylea 2Q8); 2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); 3) Eylea 0.5 mg administered every 4 weeks (Eylea 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). The primary efficacy endpoint for both studies was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline.
    • In VIEW1, 94% and 95% of patients treated with Eylea 2Q8 and Eylea 2Q4, respectively, maintained vision compared with 94% of those treated with ranibizumab. The mean change in best corrected visual acuity (BVCA) as measured by early treatment diabetic retinopathy study (ETDRS) letter score from baseline was 7.9 for Eylea 2Q8 and 10.9 for Eylea 2Q4 compared with 8.1 for ranibizumab. The number of patients who gained at least 15 letters of vision from baseline were: 92 for Eylea 2Q8, 114 for Eylea 2Q4, and 94 for ranibizumab.
    • In VIEW2, 95% and 95% of patients treated with Eylea 2Q8 and Eylea 2Q4, respectively, maintained vision compared with 95% of those treated with ranibizumab. The mean change in BVCA as measured by ETDRS letter score from baseline was 8.9 for Eylea 2Q8 and 7.6 for Eylea 2Q4 compared with 9.4 for ranibizumab. The number of patients who gained at least 15 letters of vision from baseline were: 96 for Eylea 2Q8, 91 for Eylea 2Q4, and 99 for ranibizumab.
    • VIEW1 and VIEW2 studies were both 96 weeks in duration. However after 52 weeks patients no longer followed a fixed dosing schedule. Between week 52 and week 96, patients continued to receive the drug and dosage strength to which they were initially randomized on a modified 12 week dosing schedule (doses at least every 12 weeks and additional doses as needed). Therefore, during the second year of these studies there was no active control comparison arm.

     

    Macular Edema Following Central Retinal Vein Occlusion (CRVO)

    • The safety and efficacy of Eylea were assessed in two randomized, multicenter, double-masked, sham-controlled studies (COPERNICUS and GALILEO) in a total of 358 patients with macular edema following CRVO. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. The primary efficacy endpoint for both studies was the proportion of patients who gained at least 15 letters in BCVA compared to baseline.  
    • In COPERNICUS, 56% of patients treated with Eylea gained at least 15 letters in BCVA compared with 12% of patients in the control group (weighted difference, 44.8%; 95.1% CI, 32.9-56.6; P <.01). The mean change in BCVA as measured by ETDRS letter score from baseline was 17.3 for Eylea and -4.0 for the control group (difference in least squares [LS] mean, 21.7; 95.1% CI, 17.3-26.1; P <.01).
    • In GALILEO, 60% of patients treated with Eylea gained at least 15 letters in BCVA compared with 22% of patients in the control group (weighted difference, 38.3%; 95.1% CI, 24.4-52.1; P <.01). The mean change in BCVA as measured by ETDRS letter score from baseline was 18.0 for Eylea and 3.3 for the control group (difference in LS mean, 14.7; 95.1% CI, 10.7-18.7; P <.01).

     

    Macular Edema Following Branch Retinal Vein Occlusion (BRVO)  

    • The safety and efficacy of Eylea were assessed in the 24-week, randomized, multi-center, double-masked, controlled VIBRANT study in a total of 181 patients with macular edema following BRVO. Patients were randomly assigned in a 1:1 ratio to either 2 mg Eylea administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). The primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline.
    • Results showed that 52.7% of patients treated with Eylea gained at least 15 letters in BCVA from baseline compared with 26.7% of patients in the control group (weighted difference, 26.6%; 95% CI, 13.0-40.1; P <.01). The mean change in BCVA as measured by ETDRS letter score from baseline was 17.0 for Eylea and 6.9 for the control group (difference in LS mean, 10.5; 95% CI, 7.1-14.0; P <.01).

     

    Diabetic Macular Edema (DME)

    • The safety and efficacy of Eylea were assessed in two randomized, multi-center, double-masked, controlled studies (VIVID and VISTA) in a total of 862 patients with DME. In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) Eylea administered 2 mg every 8 weeks following 5 initial monthly injections (Eylea 2Q8); 2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed).
    • Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the Eylea groups could receive laser and patients in the laser group could receive Eylea. The primary efficacy endpoint for both studies was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score.
    • At week 52 for VIVID, the mean change in BCVA as measured by ETDRS letter score from baseline was 10.7 for Eylea 2Q8 (difference in LS mean, 9.1; 97.5% CI, 6.3-11.8; P <.01) and 10.5 for Eylea 2Q4 (difference in LS mean, 9.3; 97.5% CI, 6.5-12.0; P <.01) compared with 1.2 for the control group. Moreover, 33.3% and 32.4% of patients treated with Eylea 2Q8 and Eylea 2Q4 gained at least 15 letters in BCVA from baseline compared with 9.1% of those treated with control (both P <.01). 
    • At week 100 for VIVID, the mean change in BCVA as measured by ETDRS letter score from baseline was 9.4 for Eylea 2Q8 (difference in LS mean, 8.2; 97.5% CI, 5.2-11.3; P <.01) and 11.4 for Eylea 2Q4 (difference in LS mean, 10.7; 97.5% CI, 7.6-13.8; P <.01) compared with 0.7 for the control group. Moreover, 31.1% and 38.2% of patients treated with Eylea 2Q8 and Eylea 2Q4 gained at least 15 letters in BCVA from baseline compared with 12.1% of those treated with control (both P <.01). 
    • At week 52 for VISTA, the mean change in BCVA as measured by ETDRS letter score from baseline was 10.7 for Eylea 2Q8 (difference in LS mean, 10.5; 97.5% CI, 7.7-13.2; P <.01) and 12.5 for Eylea 2Q4 (difference in LS mean, 12.2; 97.5% CI, 9.4-15.0; P <.01) compared with 0.2 for the control group. Moreover, 31.1% and 41.6% of patients treated with Eylea 2Q8 and Eylea 2Q4 gained at least 15 letters in BCVA from baseline compared with 7.8% of those treated with control (both P <.01). 
    • At week 100 for VISTA, the mean change in BCVA as measured by ETDRS letter score from baseline was 11.1 for Eylea 2Q8 (difference in LS mean, 10.1; 97.5% CI, 7.0-13.3; P <.01) and 11.5 for Eylea 2Q4 (difference in LS mean, 10.6; 97.5% CI, 7.1-14.2; P <.01) compared with 0.9 for the control group. Moreover, 33.1% and 38.3% of patients treated with Eylea 2Q8 and Eylea 2Q4 gained at least 15 letters in BCVA from baseline compared with 13.0% of those treated with control (both P <.01). 
    • Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation.

     

    Diabetic Retinopathy (DR)  

    Efficacy and safety data of Eylea in diabetic retinopathy (DR) are derived from the VIVID, VISTA, and PANORAMA studies.

    VIVID and VISTA

    • In the VIVID and VISTA studies, an efficacy outcome was the change in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (ETDRS-DRSS). The ETDRS-DRSS score was assessed at baseline and approximately every 6 months thereafter for the duration of the studies. At week 100, the proportion of patients improving by at least 2 steps on the ETDRS-DRSS was significantly greater in both Eylea treatment groups (2Q4 and 2Q8) when compared to the control group.
    • In VIVID, 32% (n=32/101) and 27% (n=27/97) of patients treated with Eylea 2Q8 and Eylea 2Q4, respectively, improved by at least 2 steps on the ETDRS-DRSS at week 100 from baseline compared with 7% (n=7/99) of those in the control group (both P <.01).
    • In VISTA, 38% (n=56/148) and 38% (n=58/153) of patients treated with Eylea 2Q8 and Eylea 2Q4, respectively, improved by at least 2 steps on the ETDRS-DRSS at week 100 from baseline compared with 16% (n=24/150) of those in the control group (both P <.01).

    PANORAMA

    • The randomized, multicenter, double-masked, controlled PANORAMA study assessed the safety and efficacy of Eylea in a total of 402 patients with moderately severe to severe nonproliferative diabetic retinopathy (NPDR) (ETDRS-DRSS of 47 or 53), without central-involved DME (CI-DME). Patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) 3 initial monthly Eylea 2 mg injections followed by one injection after 8 weeks and then one injection every 16 weeks (Eylea 2Q16); 2) 5 monthly Eylea 2 mg injections followed by one injection every 8 weeks (Eylea 2Q8); and 3) sham treatment.
    • The primary efficacy endpoint was the proportion of patients who improved by ≥2 steps on the DRSS from baseline to week 24 in the combined Eylea groups and at week 52 in the 2Q16 and 2Q8 groups individually versus sham. A key secondary endpoint was the proportion of patients developing the composite endpoint of proliferative diabetic retinopathy or anterior segment neovascularization through week 52.  
    • At week 24, results showed that 58% of patients in the combined Eylea groups achieved at least a 2-step improvement on ETDRS-DRSS from baseline compared with 6% of those in the control group (adjusted difference, 52%; 95% CI, 45-60; P <.01). 
    • At week 52, results showed that 65% and 80% of patients treated with Eylea 2Q16 (adjusted difference, 50%; 95% CI, 40-60; P <.01) and Eylea 2Q8 (adjusted difference, 65%; 95% CI, 56-74; P <.01), respectively, achieved at least a 2-step improvement on ETDRS-DRSS from baseline compared with 15% of those in the control group.

     

    Retinopathy of Prematurity (ROP)

    • Efficacy and safety data of Eylea in ROP are derived from the BUTTERFLEYE (N=113) and FIREFLEYE (N=120) studies.
    • Study participants had a maximum gestational age at birth of 32 weeks or a maximum birth weight of 1500g, had to weigh at least 800g on the day of treatment and had treatment-naïve ROP.
    • Patients were randomly assigned to receive 0.4mg of aflibercept via intravitreal injection or laser photocoagulation (the standard treatment for ROP). The primary endpoint was the proportion of patients with absence of active ROP and unfavorable structural outcomes at week 52 of chronological age. 
    • Findings from both trials showed that approximately 80% of patients who received aflibercept achieved an absence of active ROP and unfavorable structural outcomes at 52 weeks of age. However, the trials failed to meet the primary endpoint of noninferiority due to laser photocoagulation achieving comparable levels of efficacy, which were higher than previously seen in similar ROP trials.

    Eylea Note

    Not Applicable

    Eylea Patient Counseling

    Patient Counseling

    In the days following Eylea administration, patients are at risk of developing endophthalmitis or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an ophthalmologist.

    Patients may experience temporary visual disturbances after an intravitreal injection with Eylea and the associated eye examinations. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

    Cost Savings Program

    Eylea Patient Support & Education:

    https://eylea.us/s/patient-support

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