Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or
revisions underlined:
5.1 Endophthalmitis, Retinal Detachments, and Retinal Vasculitis
with or without Occlusion
![]()
Intravitreal
injections, including those with EYLEA, have been associated with
endophthalmitis and retinal detachments [see Adverse Reactions (6.1)] and, more rarely, retinal vasculitis with
or without occlusion [see Adverse Reactions
(6.2)]. Proper aseptic injection
technique must always be used when administering EYLEA. Patients and/or
caregivers should be instructed to report any signs and/or symptoms suggestive
of endophthalmitis, retinal detachment, or retinal vasculitis
without delay and should be managed appropriately [see Dosage
and Administration (2.4) and Patient Counseling Information (17)].
6
Adverse Reactions
Additions and/or
revisions underlined:
…
…
6.2 Postmarketing
Experience
New
subsection added:
The following adverse reactions have been identified
during postapproval use of aflibercept. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Eye disorders: retinal vasculitis and occlusive retinal
vasculitis related to intravitreal injection with aflibercept (reported at a rate
of 0.6 and 0.2 per 1 million injections, respectively, based on postmarketing
experience from November 2011 until November 2023).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
In
the days following EYLEA administration, patients are at risk of developing endophthalmitis,
retinal detachment, or retinal vasculitis with or without occlusion.
If the eye becomes red, sensitive to light, painful, or develops a change in
vision, advise patients and/or caregivers to seek immediate care from an
ophthalmologist [see Warnings and
Precautions (5.1)].
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Endophthalmitis and Retinal Detachments
Additions and/or revisions underlined:
Intravitreal injections, including those with EYLEA,
have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)]. Proper
aseptic injection technique must always be used when administering EYLEA.
Patients and/or caregivers should be instructed to report any signs
and/or symptoms suggestive of endophthalmitis or retinal detachment without
delay and should be managed appropriately [see
Dosage and Administration (2.4) and Patient Counseling Information (17)].
5.3 Extended Monitoring and Additional Treatment in ROP
Newly
added subsection:
Reactivation
of abnormal angiogenesis and tortuosity may occur following treatment with
EYLEA. Infants should be monitored closely after injection with EYLEA until
retinal vascularization has completed or until the examiner is assured that
reactivation of ROP will not occur. In infants with ROP, treatment with EYLEA
will necessitate extended periods of ROP monitoring and additional EYLEA
injections and/or laser treatments may be necessary.
6
Adverse Reactions
6.1 Clinical
Trials Experience
Extensive changes;
please refer to label for complete information
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Data
…
At
the lowest dose shown to produce adverse embryofetal effects in rabbits (0.1 mg
per kg), systemic exposure (AUC) of free aflibercept was approximately 6 times
higher than systemic exposure (AUC) observed in adult patients after a
single intravitreal dose of 2 mg.
8.3 Females and
Males of Reproductive Potential
Additions and/or revisions underlined:
…
Infertility
There are no data regarding the effects of EYLEA on
human fertility. Aflibercept adversely affected female and male reproductive
systems in cynomolgus monkeys when administered by intravenous injection at a
dose approximately 1500 times higher than the systemic level observed in
adult patients with an intravitreal dose of 2 mg. A No Observed Adverse
Effect Level (NOAEL) was not identified. These findings were reversible within
20 weeks after cessation of treatment [see
Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
Additions
and/or revisions underlined:
The safety and effectiveness of EYLEA have been demonstrated
in two clinical studies of pre- term infants with ROP.
These two studies randomized pre-term infants
between initial treatment with EYLEA or laser. Efficacy of each treatment is
supported by the demonstration of a clinical course which was better than would
have been expected without treatment [see
Dosage and Administration (2.9), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.6)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
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 and/or
caregivers to seek immediate care from an ophthalmologist [see Warnings and Precautions (5.1)].
Patients
may experience temporary visual disturbances after an intravitreal injection
with EYLEA and the associated eye examinations [see Adverse Reactions (6)]. Advise patients
not to drive or use machinery until visual function has recovered sufficiently.
In
infants with ROP, treatment with EYLEA will necessitate extended periods of ROP
monitoring.
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions
underlined:
A
total of 2980 patients treated with EYLEA constituted the safety
population in eight phase 3 studies. Among those, 2379 patients
were treated with the recommended dose of 2 mg.
Diabetic
Macular Edema (DME) and Diabetic Retinopathy (DR)
Following Table 3,
addition of the following:
Safety
data observed in 269 patients with nonproliferative diabetic retinopathy (NPDR)
through week 52 in the PANORAMA trial were consistent with those seen in the
phase 3 VIVID and VISTA trials (see Table 3 above).
Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Thromboembolic Events
(additions
underlined)
There is a potential 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). The incidence of reported thromboembolic events in wet
AMD studies during the first year was 1.8% (32 out of 1824) in the combined group
of patients treated with EYLEA compared with 1.5% (9 out of 595) in patients
treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824)
in the EYLEA group compared with 3.2% (19 out of 595) in the ranibizumab group.
…
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions
underlined)
…
Neovascular (Wet) Age-Related Macular Degeneration
(AMD)
The data described below reflect exposure to EYLEA in 1824
patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2
double-masked, controlled clinical studies (VIEW1 and VIEW2) for 24 months
(with active control in year 1).
Safety data observed in the EYLEA group in a 52-week,
double-masked, Phase 2 study were consistent with these results.
…
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
Adequate and
well-controlled studies with EYLEA have not been conducted in pregnant women.
Aflibercept produced adverse embryofetal effects in rabbits, including
external, visceral, and skeletal malformations. A fetal No Observed Adverse
Effect Level (NOAEL) was not identified. At the lowest dose shown to produce
adverse embryofetal effects, systemic exposures (based on AUC for free
aflibercept) were approximately 6 times higher than AUC values observed in
humans after a single intravitreal treatment at the recommended clinical dose.
Animal
reproduction studies are not always predictive of human response, and it is not
known whether EYLEA can cause fetal harm when administered to a pregnant woman.
Based on the anti-VEGF mechanism of action for aflibercept, treatment with
EYLEA may pose a risk to human embryofetal development…
All pregnancies
have a background risk of birth defect, loss, or other adverse outcomes. The
background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In two
embryofetal development studies, aflibercept produced adverse embryofetal effects when
administered every three days during organogenesis to pregnant rabbits at
intravenous doses greater than or equal to 3 mg per kg, or every six days during
organogenesis at subcutaneous doses greater than or equal to 0.1 mg per kg.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
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. Because many drugs are excreted in human milk, and
because the potential for absorption and harm to infant growth and development
exists, EYLEA is not recommended during breastfeeding.
The
developmental and health benefits of breastfeeding should be considered along
with the mother's clinical need for EYLEA and any potential adverse effects on
the breastfed child from EYLEA.
8.3 Females and Males of Reproductive Potential
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Contraception
Females of
reproductive potential are advised 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. Aflibercept adversely
affected female and male reproductive systems in cynomolgus monkeys when
administered by intravenous injection at a dose approximately 1500 times higher
than the systemic level observed humans with an intravitreal dose of 2 mg. A No
Observed Adverse Effect Level (NOAEL) was not identified. These findings were
reversible within 20 weeks after cessation of treatment.
Approved Drug Label (PDF)
4
Contraindications
4.3 Hypersensitivity
EYLEA is contraindicated in patients with known
hypersensitivity to aflibercept or any of the excipients in EYLEA.
Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe
anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.
6
Adverse Reactions
The following potentially serious adverse reactions are described
elsewhere in the labeling:
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