Yesafili

Sterile, clear, colourless to pale yellow, iso-osmotic solution, pH 6.2, preservative-free.
1 mL solution for injection contains 40 mg aflibercept*.
One vial contains an extractable volume of at least 0.1 mL, equivalent to at least 4 mg aflibercept. This provides a usable amount to deliver a single dose of 0.05 mL containing 2 mg aflibercept.
*Fusion protein consisting of portions of human VEGF (vascular endothelial growth factor) receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 and produced in Chinese hamster ovary (CHO) K1 cells by recombinant DNA technology.
Yesafili has been developed as Biosimilar Product to Eylea.
Yesafili is available in the following pack: One pack containing 1 vial and a 5-micron sterile filter needle (18 G ×1½-inch).
Excipients/Inactive Ingredients: Histidine, Histidine hydrochloride monohydrate, Polysorbate 20, Trehalose dihydrate, Water for injections.

Pharmacotherapeutic group: Ophthalmologicals/Antineovascularisation agents. ATC code: S01LA05.
Pharmacology: Pharmacodynamics: 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.
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.
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.
Clinical Studies: wet AMD: The safety and efficacy of aflibercept were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD (VIEW1 and VIEW2) with a total of 2412 patients treated and evaluable for efficacy (1817 with aflibercept). Patient ages ranged from 49 to 99 years with a mean of 76 years. In these clinical studies, approximately 89% (1616/1817) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 63% (1139/1817) were 75 years of age or older. In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) Aflibercept administered at 2 mg every 8 weeks following 3 initial monthly doses (aflibercept 2Q8); 2) Aflibercept administered at 2 mg every 4 weeks (aflibercept 2Q4); 3) Aflibercept administered at 0.5 mg every 4 weeks (aflibercept 0.5Q4); and 4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).
In the second year of the studies, patients continued to receive the initially randomised dose but on a modified dosing schedule guided by assessment of visual and anatomic outcomes with a protocol-defined maximum dosing interval of 12 weeks.
In both studies, the primary efficacy endpoint was the proportion of patients in the Per Protocol Set who maintained vision, i.e. losing fewer than 15 letters of visual acuity at week 52 from baseline.
In the VIEW1 study, at week 52, 95.1% of patients in the aflibercept 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In the VIEW2 study, at week 52, 95.6% of patients in the aflibercept 2Q8 group maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. In both studies aflibercept was shown to be non-inferior and clinically equivalent to the ranibizumab 0.5Q4 group.
Detailed results from the combined analysis of both studies are shown in Table 1 and Figure 1 as follows: See Table 1 and Figure 1.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In combined data analysis of VIEW1 and VIEW2, aflibercept demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).
In the second year of the studies, efficacy was generally maintained through the last assessment at week 96, and 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month.
Decreases in mean CNV area were evident in all dose groups in both studies.
Efficacy results in all evaluable subgroups (e.g., age, gender, race, baseline visual acuity, lesion type, lesion size) in each study and in the combined analysis were consistent with the results in the overall populations.
ALTAIR was a 96-week multicentre, randomised, open-label study in 247 Japanese patients with treatment naive wet AMD, designed to assess the efficacy and safety of aflibercept following two different adjustment intervals (2-weeks and 4-weeks) of a treat-and-extend dosing regimen.
All patients received monthly doses of aflibercept 2 mg for 3 months, followed by one injection after a further 2-month interval. At week 16, patients were randomised 1:1 into two treatment groups: 1) aflibercept treat-and-extend with 2-week adjustments and 2) aflibercept treat-and-extend with 4-week adjustments. Extension or shortening of the treatment interval was decided based on visual and/or anatomic criteria defined by protocol with a maximum treatment interval of 16 weeks for both groups.
The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondary efficacy endpoints were the proportion of patients who did not lose ≥15 letters and the proportion of patients who gained at least 15 letters of BCVA from baseline to week 52.
At week 52, patients in the treat-and-extend arm with 2-week adjustments gained a mean of 9.0 letters from baseline as compared to 8.4 letters for those in the 4-week adjustment group [LS mean difference in letters (95% CI): -0.4 (-3.8,3.0), ANCOVA]. The proportion of patients who did not lose ≥15 letters in the two treatment arms was similar (96.7% in the 2-week and 95.9% in the 4-week adjustment groups). The proportion of patients who gained ≥15 letters at week 52 was 32.5% in the 2-week adjustment group and 30.9% in the 4-week adjustment group. The proportion of patients who extended their treatment interval to 12 weeks or beyond was 42.3% in the 2-week adjustment group and 49.6% in the 4-week adjustment group. Furthermore, in the 4-week adjustment group 40.7% of patients were extended to 16-week intervals. At the last visit up to week 52, 56.8% and 57.8% of patients in the 2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 12 weeks or beyond.
In the second year of the study, efficacy was generally maintained up to and including the last assessment at week 96, with a mean gain from baseline of 7.6 letters for the 2-week adjustment group and 6.1 letters for the 4-week adjustment group. The proportion of patients who extended their treatment interval to 12 weeks or beyond was 56.9% in the 2-week adjustment group and 60.2% in the 4-week adjustment group. At the last visit prior to week 96, 64.9% and 61.2% of patients in the 2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 12 weeks or beyond.
During the second year of treatment patients in both the 2-week and 4-week adjustment groups received an average of 3.6 and 3.7 injections, respectively. Over the 2-year treatment period patients received an average of 10.4 injections.
Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2.
ARIES was a 104-week multicentre, randomised, open-label, active-controlled study in 269 patients with treatment naive wet AMD, designed to assess the non-inferiority in terms of efficacy as well as the safety of a treat-and-extend dosing regimen initiated after 3 consecutive monthly doses followed by extension to a 2 monthly treatment interval vs. a treat-and-extend dosing regimen initiated after the first year of treatment.
The ARIES study also explored the percentage of patients that required more frequent treatment than every 8 weeks based on the investigator's decision. Out of the 269 patients 62 patients received more frequent dosing at least once during the course of the study. Such patients remained in the study and received treatment according to the investigator's best clinical judgement but not more frequently than every 4 weeks and their treatment intervals could be extended again afterwards. The average treatment interval after the decision to treat more frequently was 6.1 weeks. Week 104 BCVA was lower in patients requiring more intensive treatment at least once over the course of the study compared with patients who did not and the mean change in BCVA from baseline to end of the study was +2.3±15.6 letters. Among the patients treated more frequently, 85.5% maintained vision, i.e., lost less than 15 letters, and 19.4% gained 15 letters or more. The safety profile of patients treated more frequently than every 8 weeks was comparable to the safety data in VIEW 1 and VIEW 2.
Macular oedema secondary to CRVO: The safety and efficacy of aflibercept were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO (COPERNICUS and GALILEO) with a total of 358 patients treated and evaluable for efficacy (217 with aflibercept). Patient ages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4), or the control group receiving sham injections every 4 weeks for a total of 6 injections.
After 6 consecutive monthly injections, patients received treatment only if they met pre-specified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. From this timepoint all patients were treated if pre-specified criteria were met.
In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. A secondary efficacy variable was change in visual acuity at week 24 compared to baseline.
The difference between treatment groups was statistically significant in favour of aflibercept in both studies. The maximal improvement in visual acuity was achieved at month 3 with subsequent stabilisation of visual acuity and CRT until month 6. The statistically significant difference was maintained through week 52.
Detailed results from the analysis of both studies are shown in Table 2 and Figure 2 as follows. (See Table 2 and Figure 2.)

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Click on icon to see table/diagram/image

In GALILEO, 86.4% (n=89) of the aflibercept group and 79.4% (n=54) of the sham group had perfused CRVO at baseline. At week 24, this was 91.8% (n=89) in the aflibercept group and 85.5% (n=47) in the sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the aflibercept group and 84.0% (n=42) in the sham group.
In COPERNICUS, 67.5% (n=77) of the aflibercept group and 68.5% (n=50) of the sham group had perfused CRVO at baseline. At week 24, this was 87.4% (n=90) in the aflibercept group and 58.6% (n=34) in the sham group. These proportions were maintained at week 100 with 76.8% (n=76) in the aflibercept group and 78% (n=39) in the sham group. Patients in the sham group were eligible to receive aflibercept from week 24.
The beneficial effect of aflibercept treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g., age, gender, race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results in the overall populations.
In combined data analysis of GALILEO and COPERNICUS, aflibercept demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).
Macular oedema secondary to BRVO: The safety and efficacy of aflibercept were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) which included Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with aflibercept). Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg aflibercept administered every 8 weeks following 6 initial monthly injections or laser photocoagulation administered at baseline (laser control group). Patients in the laser control group could receive additional laser photocoagulation (called 'rescue laser treatment') beginning at week 12 with a minimum interval of 12 weeks. Based on pre-specified criteria, patients in the laser group could receive rescue treatment with aflibercept 2 mg from week 24, administered every 4 weeks for 3 months followed by every 8 weeks.
In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline and the aflibercept group was superior to laser control.
A secondary efficacy endpoint was change in visual acuity at week 24 compared to baseline, which was statistically significant in favour of aflibercept in the VIBRANT study. The course of visual improvement was rapid and peaked at 3 months with maintenance of the effect until month 12.
In the laser group 67 patients received rescue treatment with aflibercept beginning at week 24 (Active Control/ aflibercept 2 mg group), which resulted in improvement of visual acuity by about 5 letters from week 24 to 52.
Detailed results from the analysis of the VIBRANT study are shown in Table 3 and Figure 3 as follows. (See Table 3 and Figure 3.)

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Click on icon to see table/diagram/image

At baseline, the proportion of perfused patients in the aflibercept and laser groups was 60% and 68%, respectively. At week 24 these proportions were 80% and 67%, respectively. In the aflibercept group the proportion of perfused patients was maintained through week 52. In the laser group, where patients were eligible for rescue treatment with aflibercept from week 24, the proportion of perfused patients increased to 78% by week 52.
Diabetic macular oedema (DME): The safety and efficacy of aflibercept were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME (VIVID^DME and VISTA^DME). A total of 862 patients were treated and evaluable for efficacy, 576 with aflibercept. Patient ages ranged from 23 to 87 years with a mean of 63 years. In the DME studies, approximately 47% (268/576) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. The majority of patients in both studies had Type II diabetes.
In both studies, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) Aflibercept administered 2 mg every 8 weeks following 5 initial monthly injections (aflibercept 2Q8); 2) Aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); and 3) Macular laser photocoagulation (active control).
Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the aflibercept groups could receive laser and patients in the control group could receive aflibercept.
In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 and both aflibercept 2Q8 and aflibercept 2Q4 groups demonstrated statistical significance and were superior to the control group. This benefit was maintained through week 100.
Detailed results from the analysis of the VIVID^DME and VISTA^DME studies are shown in Table 4 and Figure 4 as follows. (See Table 4 and Figure 4.)

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Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study and in the combined analysis were generally consistent with the results in the overall populations.
In the VIVID^DME and VISTA^DME studies, 36 (9%) and 197 (43%) patients received prior anti-VEGF therapy, respectively, with a 3-month or longer washout period. Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor were similar to those seen in patients who were VEGF inhibitor naïve.
Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if assessed necessary by the physician. In the VISTA^DME study, 217 (70.7%) of aflibercept patients received bilateral aflibercept injections until week 100; in the VIVID^DME study, 97 (35.8%) of aflibercept patients received a different anti-VEGF treatment in their fellow eye.
An independent comparative trial (DRCR.net Protocol T) utilised a flexible dosing regimen based on strict OCT and vision re-treatment criteria. In the aflibercept treatment group (n=224) at week 52, this treatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to the administered number of doses in the aflibercept 2Q8 group in VIVID^DME and VISTA^DME, while overall efficacy of the aflibercept treatment group in Protocol T was comparable to the aflibercept 2Q8 group in VIVID^DME and VISTA^DME. A 13.3 mean letter gain with 42% of patients gaining at least 15 letters in vision from baseline was observed in Protocol T. Safety outcomes demonstrated that overall incidences of ocular and non-ocular adverse events (including ATEs) were comparable across all treatment groups in each of the studies and between the studies.
VIOLET, a 100-week multicentre, randomised, open-label, active controlled study in patients with DME compared three different dosing regimens of aflibercept 2 mg for treatment of DME after at least one year of treatment at fixed intervals, where treatment was initiated with 5 consecutive monthly doses followed by dosing every 2 months. The study evaluated non-inferiority of aflibercept 2 mg dosed according to a treat-and-extend regimen (2T&E where injections intervals were kept at a minimum of 8 weeks and gradually extended based on clinical and anatomical outcomes) and aflibercept 2 mg dosed as needed (2PRN where patients were observed every 4 weeks and injected when needed based on clinical and anatomical outcomes), compared to aflibercept 2 mg dosed every 8 weeks (2Q8) for the second and third year of treatment.
The primary efficacy endpoint (change in BCVA from baseline to week 52) was 0.5±6.7 letters in the 2T&E group and 1.7±6.8 letters in the 2PRN group compared to 0.4±6.7 letters in the 2Q8 group, achieving statistical non-inferiority (p<0.0001 for both comparisons; NI margin 4 letters). The changes in BCVA from baseline to week 100 were consistent with the week 52 results: -0.1±9.1 letters in the 2T&E group and 1.8±9.0 letters in the 2PRN group compared to 0.1±7.2 letters in the 2Q8 group. The mean number of injections over 100 weeks were 12.3, 10.0 and 11.5 for 2Q8fix, 2T&E and 2PRN, respectively.
Ocular and systemic safety profiles in all 3 treatment groups were similar to those observed in the pivotal studies VIVID and VISTA.
In the 2T&E group, the increments and decrements for the injection intervals were at the investigator's discretion; increments of 2 weeks were recommended in the study.
Myopic choroidal neovascularisation (myopic CNV): The safety and efficacy of aflibercept were assessed in a randomised, multi-centre, double-masked, sham-controlled study in treatment-naïve, Asian patients with myopic CNV. A total of 121 patients were treated and evaluable for efficacy (90 with aflibercept). Patient ages ranged from 27 to 83 years with a mean of 58 years. In the myopic CNV study, approximately 36% (33/91) of the patients randomised to treatment with aflibercept were 65 years of age or older, and approximately 10% (9/91) were 75 years of age or older.
Patients were randomly assigned in a 3:1 ratio to receive either 2 mg aflibercept intravitreally or sham injections administered once at study start with additional injections given monthly in case of disease persistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patients initially randomised to sham were eligible to receive the first dose of aflibercept. Following this, patients in both groups continued to be eligible for additional injections in case of disease persistence or recurrence.
The difference between treatment groups was statistically significant in favour of aflibercept for the primary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion of patients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for both endpoints were maintained through week 48.
Detailed results from the analysis of the MYRROR study are shown in Table 5 and Figure 5 as follows. (See Table 5 and Figure 5.)

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STUDY MYL-1701P-3001: Study MYL-1701P-3001 was a multicenter, randomized, double masked, active controlled, comparative clinical study to demonstrate that no clinically meaningful differences exist between MYL-1701P and US-licensed Eylea regarding efficacy, safety, and immunogenicity in subjects with Diabetic Macular Edema (DME). Study MYL-1701P-3001 enrolled subjects with DME following type 1 or type 2 diabetes mellitus, with baseline CRT of ≥300 μm and BCVA at 4 m from 73 to 38 letters (ETDRS chart) equivalent to Snellen visual acuity of 20/40 to 20/200 in the study eye.
MYL-1701P (a proposed biosimilar to Eylea, reference aflibercept) or Eylea for intravitreal injection, administered at a dose of 2 mg (0.05 mL) every 4 weeks for a total of 5 injections, and then every 8 weeks (with optional doses to continue at every 4 weeks) through the remainder of the 52-week treatment period, with the last dose at 48 weeks.
A total of 355 subjects were randomized with 179 subjects to the MYL-1701P arm and 176 subjects to the Eylea arm. A total of 172 (96.1%) subjects in the MYL-1701P arm and 173 (98.3%) in the Eylea arm completed the study up through Week 8, and a total of 161 (89.9%) subjects in the MYL-1701P arm and 158 (89.8%) subjects in the Eylea arm completed Week 52.
The primary efficacy endpoint was the mean change from baseline in BCVA as assessed by ETDRS letter score, at Week 8. The primary analysis was performed on the ITT and PP analysis set (Table 6 and Table 7). The adjusted mean difference for mean change in BCVA from baseline through Week 8 for ITT and PP analysis set were 0.04 and -0.19 letters respectively, which corresponding to 95% CI of -1.40, 1.47 and -1.66, 1.27 respectively. Both ITT and PP analysis set results were well within the predefined equivalence margin of [-3, 3]. (See Table 6 and 7.)

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Pharmacokinetics: Aflibercept 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 C_max) 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 dose 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.
In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean C_max of free aflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/mL and individual values not exceeding 0.14 microgram/mL. Thereafter, plasma concentrations of free aflibercept declined to values below or close to the lower limit of quantitation generally within one week; undetectable concentrations were reached before the next administration after 4 weeks in all patients.
Elimination: As aflibercept is a protein-based therapeutic, no metabolism studies have been conducted.
Free aflibercept binds VEGF to form a stable, inert complex. As with other large proteins, both free and bound aflibercept are expected to be cleared by proteolytic catabolism.
Renal Impairment: No special studies in patients with renal impairment have been conducted with aflibercept.
Pharmacokinetic analysis of patients in the VIEW2 study, of which 40% had renal impairment (24% mild, 15% moderate, and 1% severe), revealed no differences with respect to plasma concentrations of active substance after intravitreal administration every 4 or 8 weeks.
Similar results were seen in patients with CRVO in the GALILEO study, in patients with DME in the VIVID^DME study, and in patients with myopic CNV in the MYRROR study.
Toxicology: Preclinical Safety Data: Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures considered substantially in excess of the maximum human exposure after intravitreal administration at the intended clinical dose indicating little relevance to clinical use.
Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at systemic exposures in excess of the maximum human exposure.
The systemic exposure based on C_max and AUC for free aflibercept were approximately 200- and 700-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold higher based on C_max and AUC, respectively.
No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.
An effect of aflibercept on intrauterine development was shown in embryo-foetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on C_max and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg.
Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at doses ranging from 3 to 30 mg/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. Based on C_max and AUC for free aflibercept observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4900-fold and 1500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible.

Yesafili is indicated for the treatment of: Neovascular (wet) age-related macular degeneration (wet AMD).
Visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO).
Visual impairment due to diabetic macular oedema (DME).
Visual impairment due to myopic choroidal neovascularisation (myopic CNV).

Yesafili is for intravitreal injection.
Yesafili must only be administered by a qualified physician experienced in administering intravitreal injections.
Dosage Regimen: Neovascular (wet) age-related macular degeneration (wet AMD): The recommended dose for Yesafili is 2 mg aflibercept, equivalent to 0.05 mL.
Yesafili 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 Pharmacology: Pharmacodynamics under Actions).
Macular oedema secondary to RVO (branch RVO or central RVO): The recommended dose for Yesafili 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, Yesafili 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 (DME): The recommended dose for Yesafili is 2 mg aflibercept equivalent to 0.05 mL.
Yesafili treatment is initiated with one injection per month for five consecutive doses, followed by one injection every two months. There is no requirement for monitoring between injections.
After the first 12 months of treatment with Yesafili and based on the physician's judgement of visual and/or anatomic outcomes, the treatment interval may be extended, 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 between injections have not been studied (see Pharmacology: Pharmacodynamics under Actions).
The schedule for monitoring should be determined by the treating physician and may be more frequent than the schedule of injections.
If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Yesafili should be discontinued.
Myopic choroidal neovascularisation (myopic CNV): The recommended dose for Yesafili 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.
Additional Information on Special Populations: Patients with Hepatic and/or renal impairment: No specific studies in patients with hepatic and/or renal impairment have been conducted with aflibercept.
Available data do not suggest a need for a dose adjustment with Yesafili in these patients.
Paediatric population: The safety and efficacy have not been established in children and adolescents. There is no relevant use of aflibercept in the paediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV.
Elderly population: No special considerations are needed for dosing as phase III clinical trials were conducted in this subpopulation (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). There is limited experience in patients older than 75 years with DME.
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.
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.
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 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 Yesafili vial, the extractable volume is at least 0.1 mL.
(The excess volume must be expelled before injecting the recommended dose) (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
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 Overdosage and Special Instructions for Use, Handling and Disposal under Cautions for Usage).
After injection any unused product must be discarded.
For handling of the medicinal product before administration, see Special Instructions for Use, Handling and Disposal under Cautions for Usage.

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 Special Instructions for Use, Handling and Disposal under Cautions for Usage).

Hypersensitivity to the active substance or to any of the excipients.
Active or suspected ocular or periocular infection.
Active severe intraocular inflammation.

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 aflibercept, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see Adverse Reactions). Proper aseptic injection techniques must always be used when administering aflibercept. 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.
Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including those with aflibercept (see Adverse Reactions). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Yesafili 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 Yesafili (see Adverse Reactions).
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: The safety and efficacy of aflibercept therapy administered to both eyes concurrently have not been systematically studied (see Pharmacology: Pharmacodynamics under Actions). 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 aflibercept 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 aflibercept 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: A decrease in best-corrected visual acuity (BCVA) of 30% letters compared with the last assessment of visual acuity; 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.
Aflibercept should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus (see Use in Pregnancy & Lactation).
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.
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.
Aflibercept 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 aflibercept 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 aflibercept in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.
Ability to Drive and Use Machines: Injection with aflibercept 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.

Pregnancy: There are no data on the use of aflibercept in pregnant women.
Studies in animals have shown embryo-foetal toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Although the systemic exposure after ocular administration is very low, aflibercept should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.
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.
Lactation: It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed child cannot be excluded.
Aflibercept is not recommended during breast-feeding. A decision must be made whether to discontinue breast-feeding or to abstain from aflibercept therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: Results from animal studies with high systemic exposure indicate that aflibercept can impair male and female fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Such effects are not expected after ocular administration with very low systemic exposure.

Summary of the Safety Profile: A total of 3102 patients constituted the safety population in the eight phase III studies. Among those, 2501 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 1900 intravitreal injections with aflibercept and included blindness, endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, vitreous detachment, and intraocular pressure increased (see Precautions).
The most frequently observed adverse reactions (in at least 5% of patients treated with aflibercept) were conjunctival haemorrhage, retinal haemorrhage, visual acuity reduced, eye pain, cataract, intraocular pressure increased, vitreous detachment, and vitreous floaters.
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 <1/1000). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. (See Table 8.)

Click on icon to see table/diagram/image

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 aflibercept.
Arterial Thromboembolic Events: 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 aflibercept 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 Yesafili.

No interaction studies have been performed.
Adjunctive use of verteporfin photodynamic therapy (PDT) and aflibercept has not been studied, therefore, a safety profile is not established.

Incompatibilities: Yesafili must not be mixed with other medicinal products.
Special Instructions for Use, Handling and Disposal: Instructions for Use: 1. Remove the plastic cap and disinfect the outer part of the rubber stopper of the vial.
2. The 18 G × 1½-inch, 5-micron, filter needle is used for withdrawal of drug product from the vial.
Remove the 18 G × 1½-inch, 5-micron, filter needle and the 1 mL syringe from their packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip.
3. Push the filter needle into the centre of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.
4. Using aseptic technique withdraw all of the Yesafili vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid.
5. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
6. Remove the filter needle and properly dispose of it.
Note: Filter needle is not to be used for intravitreal injection.
7. Ensure the 30 G × ½-inch injection needle is used for the intravitreal injection.
Remove the 30 G × ½-inch injection needle from its packaging and using aseptic technique, firmly twist onto the Luer-lock syringe tip.
8. When ready to administer, remove the plastic needle shield from the needle.
Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with finger until the bubbles rise to the top.
9. Eliminate all bubbles and expel excess medicinal product by slowly depressing the plunger so that the flat plunger edge aligns with the line that marks 0.05 mL on the syringe.
10. The vial is for single use only. Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
The vial is for single use in one eye only.
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.
The solution should be inspected visually for any foreign particulate matter and/or discolouration or any variation in physical appearance prior to administration. In the event of either being observed, discard the medicinal product.

Store in a refrigerator (2°C-8°C). Do not freeze.
Store in the original package in order to protect from light.
The unopened vial may be stored outside the refrigerator below 25°C for up to 24 hours. After opening the vial, proceed under aseptic conditions.

Other Eye Preparations

S01LA05 - aflibercept ; Belongs to the class antineovasculatisation agents. Used in the management of neovascular macular degeneration.

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