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Aflibercept-yszy is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept-yszy 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-yszy is produced in recombinant Chinese hamster ovary (CHO) cells.
OPUVIZ (aflibercept-yszy) injection is a sterile, clear, and colorless to pale yellow solution. OPUVIZ does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose glass vial designed to deliver 0.05 mL (50 microliters) of solution containing 2 mg of afliberceptyszy in dibasic sodium phosphate (0.008 mg), monobasic sodium phosphate (0.040 mg), polysorbate 20 (0.015 mg), sucrose (4 mg) and water for injection, with a pH of 6.2.
The following potentially serious adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.
A total of 2980 adult patients treated with aflibercept constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with aflibercept including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.
The data described below reflect exposure to aflibercept 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) [see Clinical Studies (14.1)].
Safety data observed in the aflibercept group in a 52-week, double-masked, Phase 2 study were consistent with these results.
Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies
|
Adverse Reactions |
Baseline to Week 52 |
Baseline to Week 96 |
||
|
Aflibercept |
Active Control (ranibizumab) |
Aflibercept |
Control (ranibizumab) |
|
|
Conjunctival hemorrhage |
25% |
28% |
27% |
30% |
|
Eye pain |
9% |
9% |
10% |
10% |
|
Cataract |
7% |
7% |
13% |
10% |
|
Vitreous detachment |
6% |
6% |
8% |
8% |
|
Vitreous floaters |
6% |
7% |
8% |
10% |
|
Intraocular pressure increased |
5% |
7% |
7% |
11% |
|
Ocular hyperemia |
4% |
8% |
5% |
10% |
|
Corneal epithelium defect |
4% |
5% |
5% |
6% |
|
Detachment of the retinal pigment epithelium |
3% |
3% |
5% |
5% |
|
Injection site pain |
3% |
3% |
3% |
4% |
|
Foreign body sensation in eyes |
3% |
4% |
4% |
4% |
|
Lacrimation increased |
3% |
1% |
4% |
2% |
|
Vision blurred |
2% |
2% |
4% |
3% |
|
Intraocular inflammation |
2% |
3% |
3% |
4% |
|
Retinal pigment epithelium tear |
2% |
1% |
2% |
2% |
|
Injection site hemorrhage |
1% |
2% |
2% |
2% |
|
Eyelid edema |
1% |
2% |
2% |
3% |
|
Corneal edema |
1% |
1% |
1% |
1% |
|
Retinal detachment |
<1% |
<1% |
1% |
1% |
Less common serious adverse reactions reported in <1% of the patients treated with aflibercept were hypersensitivity, retinal tear, and endophthalmitis.
The data described below reflect 6 months exposure to aflibercept with a monthly 2 mg dose in 218 patients following central retinal vein occlusion (CRVO) in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following branch retinal vein occlusion (BRVO) in one clinical study (VIBRANT) [see Clinical Studies (14.2), (14.3)].
Table 2: Most Common Adverse Reactions (≥1%) in RVO Studies
|
Adverse Reactions |
CRVO |
BRVO |
||
|
Aflibercept |
Control |
Aflibercept |
Control |
|
|
Eye pain |
13% |
5% |
4% |
5% |
|
Conjunctival hemorrhage |
12% |
11% |
20% |
4% |
|
Intraocular pressure increased |
8% |
6% |
2% |
0% |
|
Corneal epithelium defect |
5% |
4% |
2% |
0% |
|
Vitreous floaters |
5% |
1% |
1% |
0% |
|
Ocular hyperemia |
5% |
3% |
2% |
2% |
|
Foreign body sensation in eyes |
3% |
5% |
3% |
0% |
|
Vitreous detachment |
3% |
4% |
2% |
0% |
|
Lacrimation increased |
3% |
4% |
3% |
0% |
|
Injection site pain |
3% |
1% |
1% |
0% |
|
Vision blurred |
1% |
<1% |
1% |
1% |
|
Intraocular inflammation |
1% |
1% |
0% |
0% |
|
Cataract |
<1% |
1% |
5% |
0% |
|
Eyelid edema |
<1% |
1% |
1% |
0% |
Less common adverse reactions reported in <1% of the patients treated with aflibercept in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
The data described below reflect exposure to aflibercept in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100 [see Clinical Studies (14.4)].
Table 3: Most Common Adverse Reactions (≥1%) in DME Studies
|
Adverse Reactions |
Baseline to Week 52 |
Baseline to Week 100 |
||
|
Aflibercept |
Control |
Aflibercept |
Control |
|
|
Conjunctival hemorrhage |
28% |
17% |
31% |
21% |
|
Eye pain |
9% |
6% |
11% |
9% |
|
Cataract |
8% |
9% |
19% |
17% |
|
Vitreous floaters |
6% |
3% |
8% |
6% |
|
Corneal epithelium defect |
5% |
3% |
7% |
5% |
|
Intraocular pressure increased |
5% |
3% |
9% |
5% |
|
Ocular hyperemia |
5% |
6% |
5% |
6% |
|
Vitreous detachment |
3% |
3% |
8% |
6% |
|
Foreign body sensation in eyes |
3% |
3% |
3% |
3% |
|
Lacrimation increased |
3% |
2% |
4% |
2% |
|
Vision blurred |
2% |
2% |
3% |
4% |
|
Intraocular inflammation |
2% |
<1% |
3% |
1% |
|
Injection site pain |
2% |
<1% |
2% |
<1% |
|
Eyelid edema |
<1% |
1% |
2% |
1% |
Less common adverse reactions reported in <1% of the patients treated with aflibercept were hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage.
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).
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:
No information provided.
Included as part of the PRECAUTIONS section.
Intravitreal injections, including those with aflibercept products, 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 Aflibercept-yszy. 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 (2.7) and Patient Counseling Information (17)].
Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with aflibercept products [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors.
Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.7)].
There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including aflibercept products. 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 aflibercept 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 aflibercept group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with aflibercept compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with aflibercept compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with aflibercept in the first six months of the RVO studies.
No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept products. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) for free aflibercept that was approximately 1500 times higher than the systemic exposure observed in adult patients after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.
Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.
Aflibercept-yszy is contraindicated in patients with ocular or periocular infections.
Aflibercept-yszy is contraindicated in patients with active intraocular inflammation.
Aflibercept-yszy is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in Aflibercept-yszy. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.
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 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. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.
Aflibercept products act as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.
In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions during the first year.
Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions [see Clinical Studies (14.2, 14.3)].
Reductions in mean retinal thickness were observed in VIVID and VISTA at weeks 52 and 100 compared to baseline. Anatomic data were not used to influence aflibercept treatment decisions [see Clinical Studies (14.4)].
Aflibercept is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of aflibercept, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).
Absorption/Distribution
Following intravitreal administration of 2 mg per eye of aflibercept 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.
The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L.
Metabolism/Elimination
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. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept.
Renal Impairment
Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a RVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, RVO, or DME patients.
Other
No dosage modification is required based on gender or in the elderly.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of aflibercept or of other aflibercept products.
In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to aflibercept was approximately 1% to 3% across treatment groups. After dosing with aflibercept for 24-100 weeks, antibodies to aflibercept were detected in a similar percentage range of patients.
There were no differences in efficacy or safety between patients with or without immunoreactivity.
Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in adult patients after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies [see Clinical Studies (14)].
In the days following Aflibercept-yszy 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)].
Patients may experience temporary visual disturbances after an intravitreal injection with Aflibercept-yszy and the associated eye examinations [see Adverse Reactions (6)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.
Aflibercept-yszy
Manufactured by:
Samsung Bioepis Co., Ltd.
76, Songdogyoyuk-ro,
Yeonsu-gu, Incheon, 21987
Republic of Korea
US License No. 2046
