Vabysmo

Clear to opalescent, colourless to brownish-yellow solution, with a pH of 5.5 and an osmolality of 270-370 mOsm/kg.
One mL of solution contains 120 mg of faricimab.
Each vial contains 28.8 mg faricimab in 0.24 mL solution. This provides a usable amount to deliver a single dose of 0.05 mL solution containing 6 mg of faricimab.
Faricimab is a humanised antibody produced in mammalian Chinese Hamster Ovary (CHO) cell culture by recombinant DNA technology.
Excipients with known effect: Each 0.05 mL solution contains 0.02 mg polysorbate and 0.07 mg sodium.
Excipients/Inactive Ingredients: L-histidine, Acetic acid 30% (for pH adjustment), L-methionine, Polysorbate 20, Sodium chloride, D-sucrose, Water for injections.

Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents. ATC code: S01LA09.
Pharmacology: Pharmacodynamics: Mechanism of action: Faricimab is a humanised bispecific immunoglobulin G1 (IgG1) antibody that acts through inhibition of two distinct pathways by neutralisation of both angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A).
Ang-2 causes vascular instability by promoting endothelial destabilisation, pericyte loss, and pathological angiogenesis, thus potentiating vascular leakage and inflammation. It also sensitises blood vessels to the activity of VEGF-A resulting in further vascular destabilisation. Ang-2 and VEGF-A synergistically increase vascular permeability and stimulate neovascularisation.
By dual inhibition of Ang-2 and VEGF-A, faricimab reduces vascular permeability and inflammation, inhibits pathological angiogenesis and restores vascular stability.
Pharmacodynamic effects: A suppression from baseline of median ocular free Ang-2 and free VEGF-A concentrations was observed from day 7 onwards in the six Phase III studies described hereafter.
nAMD: In TENAYA and LUCERNE, objective, pre-specified visual and anatomic criteria, as well as treating physician clinical assessment, were used to guide treatment decisions at the disease activity assessment time points (week 20 and week 24).
The mean central subfield thickness (CST) reduction from baseline at the primary endpoint visits (averaged at weeks 40-48) was comparable to those observed with aflibercept, with -137 µm and - 137 µm in patients treated with faricimab dosed up to every 16 weeks (Q16W) as compared to - 129 µm and -131 µm with aflibercept, in TENAYA and LUCERNE, respectively. These mean CST reductions were maintained through year 2.
At week 48, in both studies there was a comparable effect of faricimab and aflibercept on the reduction of intraretinal fluid (IRF), subretinal fluid (SRF), and PED. These effects in IRF, SRF, and PED were maintained at year 2. There were also comparable changes in total CNV lesion area and reductions in CNV leakage area from baseline for patients in the faricimab and aflibercept treatment arms.
DME: In YOSEMITE and RHINE, anatomic parameters related to macular oedema were part of the disease activity assessments guiding treatment decisions.
The mean CST reduction from baseline at the primary endpoint visits (averaged at weeks 48-56) was numerically greater than those observed with aflibercept, with -207 μm and -197 μm in patients treated with faricimab Q8W and faricimab up to Q16W adjustable dosing as compared to -170 μm in aflibercept Q8W patients in YOSEMITE; results were 196 μm, 188 μm and 170 μm, respectively in RHINE. Consistent reductions in CST were observed through Year 2.
Greater proportions of patients in both faricimab arms achieved absence of IRF and absence of DME (defined as reaching CST below 325 μm) over time through year 2 as compared to aflibercept in both studies.
RVO: In Phase III studies in patients with branch retinal vein occlusion (BRVO; BALATON) and central/hemiretinal vein occlusion (C/HRVO; COMINO), reductions in mean CST were observed from baseline to week 24 with faricimab Q4W and were comparable to those seen with aflibercept Q4W. The mean CST reduction from baseline to week 24 was 311.4 μm for faricimab Q4W versus 304.4 μm for aflibercept Q4W, in BALATON, and 461.6 μm versus 448.8 μm in COMINO for faricimab and aflibercept, respectively. CST reductions were maintained through week 72 when patients moved to a faricimab up to Q16W adjustable dosing regimen.
Comparable proportions of patients in both faricimab Q4W and aflibercept Q4W arms achieved absence of IRF, absence of SRF, and absence of macular edema (defined as reaching CST below 325 µm) over time through week 24, in both studies. These results were maintained through week 72 when patients moved to a faricimab up to Q16W adjustable dosing regimen.
Clinical efficacy and safety: nAMD: The safety and efficacy of faricimab were assessed in two randomised, multi-centre, double-masked, active comparator-controlled, 2-year non-inferiority studies in patients with nAMD, TENAYA and LUCERNE. A total of 1,329 patients were enrolled, with 1,135 (85%) patients completing the studies through week 112. A total of 1,326 patients received at least one dose (664 with faricimab). Patient ages ranged from 50 to 99 years with a mean [standard deviation; SD] of 75.9 [8.6] years.
In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms: Faricimab 6 mg up to Q16W after four initial monthly doses; Aflibercept 2 mg Q8W after three initial monthly doses.
After the first four monthly doses (weeks 0, 4, 8, and 12) patients randomised to the faricimab arm received Q16W, every 12 weeks (Q12W) or Q8W dosing based on an assessment of disease activity at weeks 20 and 24. Disease activity was assessed using objective pre-specified visual (BCVA) and anatomic (CST) criteria, as well as treating physician clinical assessment of the presence of macular haemorrhage or nAMD disease activity requiring treatment (week 24 only). Patients remained on these fixed dosing intervals until week 60 without supplemental therapy. From week 60 onwards, patients in the faricimab arm moved to an adjustable dosing regimen, where their treatment interval could be modified by up to 4 week interval extensions (up to Q16W) or reduced by up to 8 week intervals (up to Q8W) based on an automated objective assessment of pre-specified visual (BCVA) and anatomic (CST and macular haemorrhage) disease activity criteria. Patients in the aflibercept arm remained on Q8W dosing throughout the study period. Both studies were 112 weeks in duration.
Results: Both studies showed efficacy in the primary endpoint, defined as the mean change from baseline in BCVA when averaged over the week 40, 44, and 48 visits and measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (Table 1 and Table 2). In both studies, faricimab up to Q16W treated patients had a non-inferior mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1, and these vision gains were maintained through week 112. Improvements from baseline BCVA at week 112 are shown in Figure 1.
The proportion of patients on each of the different treatment intervals at week 112 in TENAYA and LUCERNE, respectively was: Q16W: 59% and 67%; Q12W: 15% and 14%; Q8W: 26% and 19%. (See Tables 1 and 2 and Figure 1.)

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In both TENAYA and LUCERNE, improvements from baseline in BCVA and CST at week 60 were comparable across the two treatment arms and consistent with those seen at week 48.
At week 60, 46% of patients in both TENAYA and LUCERNE were on a Q16W interval. Of these, 69% of patients in both studies maintained Q16W through week 112 without interval reduction.
At week 60, 80% and 78% of patients in TENAYA and LUCERNE, respectively, were on a ≥Q12W interval (Q16W or Q12W). Of these, 67% and 75% of patients, respectively, maintained a ≥Q12W interval through week 112 without an interval reduction below Q12W.
At week 60, 33% of patients in both TENAYA and LUCERNE were on a Q12W interval. Of these, 3.2% and 0% of patients in TENAYA and LUCERNE, respectively, maintained Q12W through week 112.
At week 60, 20% and 22% of patients in TENAYA and LUCERNE, respectively, were on a Q8W interval. Of these, 34% and 30% of patients in TENAYA and LUCERNE, respectively, maintained Q8W therapy through week 112.
Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, lesion type, lesion size) in each study, and in the pooled analysis, were consistent with the results in the overall populations.
Across studies, faricimab up to Q16W showed improvement in pre-specified efficacy endpoint of mean change from baseline to week 48 in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score that was comparable to aflibercept Q8W, and exceeded the threshold of 4 points. The magnitude of these changes corresponds to a 15-letter gain in BCVA.
The incidence of ocular adverse events in the study eye was 53.9% and 52.1% and non-ocular adverse events was 73.3% and 74.3%, through week 112 in the faricimab and aflibercept arms, respectively (see Precautions and Adverse Reactions).
DME: The safety and efficacy of faricimab were assessed in two randomised, multi-centre, double-masked, active comparator-controlled 2-year non-inferiority studies (YOSEMITE and RHINE) in patients with DME. A total of 1,891 patients were enrolled in the two studies with 1,622 (86%) patients completing the studies through week 100. A total of 1,887 patients were treated with at least one dose through week 56 (1,262 with faricimab). Patient ages ranged from 24 to 91 with a mean [SD] of 62.2 [9.9] years. The overall population included both anti-VEGF naïve patients (78%) and patients who had been previously treated with a VEGF inhibitor prior to study participation (22%). In both studies, patients were randomised in a 1:1:1 ratio to one of the three treatment regimens: Faricimab 6 mg Q8W after the first 6 monthly doses; Faricimab 6 mg up to Q16W adjustable dosing administered in 4, 8, 12 or 16-week intervals after the first 4 monthly doses; Aflibercept 2 mg Q8W after the first 5 monthly doses.
In the Q16W adjustable dosing arm, the dosing followed a standardised treat-and-extend approach. The interval could be increased in 4-week increments or decreased in 4- or 8-week increments based on anatomic and/or visual outcomes, using data obtained only at study drug dosing visits.
Results: Both studies showed efficacy in the primary endpoint, defined as the mean change from baseline in BCVA at year 1 (average of the week 48, 52, and 56 visits), measured by the ETDRS Letter Score. In both studies, faricimab up to Q16W treated patients had a non-inferior mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1, and these vision gains were maintained through year 2.
After 4 initial monthly doses, the patients in the faricimab up to Q16W adjustable dosing arm could have received between the minimum of 6 and the maximum of 21 total injections through week 96. At week 52, 74% and 71% of patients in the faricimab up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in YOSEMITE and RHINE, respectively (53% and 51% on Q16W, 21% and 20% on Q12W). Of these patients, 75% and 84% maintained ≥Q12W dosing without an interval reduction below Q12W through week 96; of the patients on Q16W at week 52, 70% and 82% of patients maintained Q16W dosing without an interval reduction through week 96 in YOSEMITE and RHINE, respectively. At week 96, 78% of patients in the faricimab up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in both studies (60% and 64% on Q16W, 18% and 14% on Q12W). 4% and 6% of patients were extended to Q8W and stayed on ≤Q8W dosing intervals through week 96; 3% and 5% received only Q4W dosing in YOSEMITE and RHINE through week 96, respectively.
Detailed results from the analyses of YOSEMITE and RHINE studies are listed in Table 3, Table 4, and Figure 2 as follows. (See Tables 3 and 4 and Figure 2.)

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Efficacy results in patients who were anti-VEGF treatment naïve prior to study participation and in all the other evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, baseline visual acuity) in each study were consistent with the results in the overall populations.
Across studies, faricimab Q8W and up to Q16W adjustable dosing showed improvements in the pre-specified efficacy endpoint of mean change from baseline to week 52 in the NEI VFQ-25 composite score that was comparable to aflibercept Q8W and exceeded the threshold of 4 points. Faricimab Q8W and up to Q16W adjustable dosing also demonstrated clinically meaningful improvements in the pre-specified efficacy endpoint of change from baseline to week 52 in the NEI VFQ-25 near activities, distance activities, and driving scores, that were comparable to aflibercept Q8W. The magnitude of these changes corresponds to a 15-letter gain in BCVA. Comparable proportions of patients treated with faricimab Q8W, faricimab up to Q16W adjustable dosing, and aflibercept Q8W experienced a clinically meaningful improvement of ≥4-points from baseline to week 52 in the NEI VFQ-25 composite score, a pre-specified efficacy endpoint. These results were maintained at week 100.
An additional key efficacy outcome in DME studies was the change in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) from baseline to week 52. Of the 1,891 patients enrolled in Studies YOSEMITE and RHINE, 708 and 720 patients were evaluable for DR endpoints, respectively.
The ETDRS-DRSS scores ranged from 10 to 71 at baseline.
The majority of patients, approximately 60%, had moderate to severe non-proliferative DR (DRSS 43/47/53) at baseline.
The proportion of patients who achieved ≥2-step and ≥3-step improvement from baseline in ETDRS-DRSS at week 52 and at week 96 are shown in Table 5 and Table 6 as follows. (See Tables 5 and 6.)

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Treatment effects in evaluable subgroups (e.g. by previous anti-VEGF treatment, age, gender, race, baseline HbA1c, and baseline visual acuity) in each study were generally consistent with the results in the overall population.
Treatment effects in subgroups by DR severity at baseline were different and showed the greatest ≥2-step DRSS improvements among patients with moderately severe and severe non-proliferative DR with approximately 90% of patients achieving improvements consistently across all treatment arms in both studies.
The incidence of ocular adverse events in the study eye was 49.7%, 49.2% and 45.4% and non-ocular adverse events was 73.0%, 74.2%, and 75.7% through week 100, in the faricimab Q8W, faricimab up to Q16W, and aflibercept Q8W arms, respectively (see Precautions and Adverse Reactions).
RVO: The safety and efficacy of faricimab were assessed in two randomised, multi-centre, double-masked, 72-week long studies in patients with macular oedema secondary to BRVO (BALATON) or CRVO/HRVO (COMINO). Active comparator-controlled data are available through month 6.
A total of 1 282 patients (553 in BALATON and 729 in COMINO) were enrolled in the two studies, with 1 276 patients treated with at least one dose through week 24 (641 with faricimab). Patient ages ranged from 28 to 93 with a mean [SD] of 64 [10.7] years, and 22 to 100 with a mean [SD] of 65 [13.2] years in BALATON and COMINO, respectively.
A total of 489 out of 553 patients randomised in BALATON completed the study at week 72; 263 patients initially randomised to faricimab ('prior faricimab') and 267 patients initially randomised to aflibercept ('prior aflibercept') received at least one dose of faricimab during the faricimab adjustable dosing phase.
A total of 656 out of 729 patients randomised in COMINO completed the study at week 72; 353 prior faricimab and 342 prior aflibercept patients received at least one dose of faricimab during the faricimab adjustable dosing phase.
In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms until week 24: Faricimab 6 mg Q4W for 6 consecutive monthly doses; Aflibercept 2 mg Q4W for 6 consecutive monthly doses.
After 6 initial monthly doses, patients initially randomised to the aflibercept 2 mg arm moved to faricimab 6 mg, and could have received faricimab 6 mg up to Q16W adjustable dosing, where the dosing interval could be increased in 4-week increments or decreased by 4-, 8- or 12-weeks based on an automated objective assessment of pre-specified visual and anatomic disease activity criteria.
Results: Both studies showed efficacy in the primary endpoint, defined as the change from baseline in BCVA at week 24, measured by the ETDRS Letter Score. In both studies, faricimab Q4W treated patients had a non-inferior mean change from baseline in BCVA, compared to patients treated with aflibercept Q4W, and these vision gains were maintained through week 72 when patients moved to a faricimab up to Q16W adjustable dosing regimen.
Between week 24 and week 68, 81.5% and 74.0% of the patients receiving faricimab up to Q16W adjustable dosing regimen achieved a ≥Q12W (Q16W or Q12W) dosing interval in BALATON and COMINO, respectively. Of these patients, 72.1% and 61.6% completed at least one cycle of Q12W and maintained ≥Q12W dosing without an interval reduction below Q12W through week 68 in BALATON and COMINO, respectively; 1.2% and 2.5% of the patients received only Q4W dosing through week 68 in BALATON and COMINO, respectively.
Across studies, at week 24 patients in the faricimab Q4W arm showed improvement in the pre-specified efficacy endpoint of change from baseline to week 24 in the NEI VFQ-25 composite score that was comparable to aflibercept Q4W. Faricimab Q4W also demonstrated improvement in the pre-specified efficacy endpoint of change from baseline to week 24 in the NEI VFQ-25 near activities and distance activities, that were comparable to aflibercept Q4W. These results were maintained through week 72 when all patients were on faricimab up to Q16W adjustable dosing regimen. (See Tables 7 and 8 and Figures 3 and 4.)

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The incidence of ocular adverse events in the study eye was 20.1% and 24.6%, and non-ocular adverse events was 32.9% and 36.4%, through week 24 in the faricimab Q4W and aflibercept Q4W arms, respectively (see Adverse Reactions).
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with faricimab in all subsets of the paediatric population in nAMD, DME, and RVO (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Faricimab is administered intravitreally to exert local effects in the eye.
Absorption and distribution: Based on a population pharmacokinetic analysis (including nAMD and DME N=2,246), maximum free (unbound to VEGF-A and Ang-2) faricimab plasma concentrations (C_max) are estimated to occur approximately 2 days post-dose. Mean (±SD [standard deviation]) plasma C_max are estimated 0.23 (0.07) μg/mL and 0.22 (0.07) μg/mL respectively in nAMD and in DME patients. After repeated administrations, mean plasma free faricimab trough concentrations are predicted to be 0.002-0.003 μg/mL for Q8W dosing.
Faricimab exhibited dose-proportional pharmacokinetics (based on C_max and AUC) over the dose range 0.5 mg-6 mg. No accumulation of faricimab was apparent in the vitreous or in plasma following monthly dosing.
Maximum plasma free faricimab concentrations are predicted to be approximately 600 and 6000-fold lower than in aqueous and vitreous humour respectively. Therefore, systemic pharmacodynamic effects are unlikely, further supported by the absence of significant changes in free VEGF and Ang-2 concentration in plasma upon faricimab treatment in clinical studies.
Population pharmacokinetic analysis has shown an effect of age and body weight on ocular or systemic pharmacokinetics of faricimab respectively. Both effects were considered not clinically meaningful; no dose adjustment is needed.
Biotransformation and elimination: Faricimab is a protein-based therapeutic hence its metabolism and elimination have not been fully characterised. Faricimab is expected to be catabolised in lysosomes to small peptides and amino acids, which may be excreted renally, in a similar manner to the elimination of endogenous IgG.
The faricimab plasma concentration-time profile declined in parallel with the vitreous and aqueous concentration-time profiles. The estimated mean ocular half-life and apparent systemic half-life of faricimab is approximately 7.5 days.
Pharmacokinetic analysis of patients with nAMD, DME, and RVO (N=2977) has shown that the pharmacokinetics of faricimab are comparable in nAMD, DME, and RVO patients.
Special populations: Elderly: In the six Phase III clinical studies, approximately 58% (1496/2571) of patients randomised to treatment with faricimab were ≥65 years of age. Population pharmacokinetic analysis has shown an effect of age on ocular pharmacokinetics of faricimab. The effect was considered not clinically meaningful. No dose adjustment is required in patients 65 years and above (see Dosage & Administration).
Renal impairment: No specific studies in patients with renal impairment have been conducted with faricimab. Pharmacokinetic analysis of patients in all clinical studies of which 63% had renal impairment (mild 38%, moderate 23%, and severe 2%), revealed no differences with respect to systemic pharmacokinetics of faricimab after intravitreal administration of faricimab. No dose adjustment is required in patients with renal impairment (see Dosage & Administration).
Hepatic impairment: No specific studies in patients with hepatic impairment have been conducted with faricimab. However, no special considerations are needed in this population because metabolism occurs via proteolysis and does not depend on hepatic function. No dose adjustment is required in patients with hepatic impairment (see Dosage & Administration).
Other special populations: The systemic pharmacokinetics of faricimab are not influenced by race. Gender was not shown to have a clinically relevant influence on systemic pharmacokinetics of faricimab. No dose adjustment is needed.
Toxicology: Preclinical safety data: No studies have been conducted on the carcinogenic or mutagenic potential of faricimab.
In pregnant cynomolgus monkeys, intravenous injections of faricimab resulting in serum exposure (C_max) more than 500-times the maximum human exposure did not elicit developmental toxicity or teratogenicity, and had no effect on weight or structure of the placenta, although, based on its pharmacological effect faricimab should be regarded as potentially teratogenic and embryo-/foetotoxic.
Systemic exposure after ocular administration of faricimab is very low.

Vabysmo is indicated for the treatment of adult patients with: neovascular (wet) age-related macular degeneration (nAMD), visual impairment due to diabetic macular oedema (DME), visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO).

This medicinal product must be administered by a qualified physician experienced in intravitreal injections.
Posology: Neovascular (wet) age-related macular degeneration (nAMD): The recommended dose is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks (monthly) for the first 3 doses.
Thereafter, an assessment of disease activity based on anatomic and/or visual outcomes is recommended 16 and/or 20 weeks after treatment initiation so that treatment can be individualised. In patients without disease activity, administration of faricimab every 16 weeks (4 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) or 12 weeks (3 months) should be considered. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see Pharmacology: Pharmacodynamics under Actions). There is limited safety data on treatment intervals of 8 weeks or less between injections (see Precautions). Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion, but there is no requirement for monthly monitoring between injections.
Visual impairment due to diabetic macular oedema (DME) and macular oedema secondary to retinal vein occlusion (RVO): The recommended dose is 6 mg (0.05 mL solution) administered by intravitreal injection every 4 weeks (monthly); 3 or more consecutive, monthly injections may be needed.
Thereafter, treatment is individualised using a treat -and-extend approach. Based on the physician's judgement of the patient's anatomic and/or visual outcomes, the dosing interval may be extended in increments of up to 4 weeks. If anatomic and/or visual outcomes change, the treatment interval should be adjusted accordingly, and interval reduction should be implemented if anatomic and/or visual outcomes deteriorate (see Pharmacology: Pharmacodynamics under Actions). Treatment intervals shorter than 4 weeks and longer than 4 months between injections have not been studied. Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion but there is no requirement for monthly monitoring between injections.
Duration of treatment: This medicinal product is intended for long-term treatment.
If visual and/or anatomic outcomes indicate that the patient is not benefitting from continued treatment, treatment should be discontinued.
Delayed or missed dose: If a dose is delayed or missed, the patient should return to be assessed by physician at the next available visit and continue dosing depending on physician's discretion.
Special populations: Elderly: No dose adjustment is required in patients aged 65 years or above (see Pharmacology: Pharmacokinetics under Actions). Safety data in nAMD and RVO patients ≥85 years is limited (see Precautions).
Renal impairment: No dose adjustment is required in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is required in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: There is no relevant use of this medicinal product in the paediatric population for the indications of nAMD, DME, and RVO.
Method of administration: For intravitreal use only. Each vial should only be used for the treatment of a single eye.
Vabysmo should be inspected visually for particulate matter and discoloration prior to administration, and if present, the vial should not be used.
The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, a sterile drape and a sterile eyelid speculum (or equivalent). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see Adverse Reactions). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
Vial: The injection needle (30-gauge x ½ inch, not included in the package) should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 mL is then delivered slowly; a different scleral site should be used for subsequent injections.
Post-injection monitoring: After injection, any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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. vision loss, eye pain, redness of the eye, photophobia, blurring of vision) without delay.
For instructions on handling of the medicinal product before administration, see Special precautions for disposal under Cautions for Usage.

Overdosing with greater than recommended injection volume may increase intraocular pressure. In the event of overdose, IOP should be monitored and, if deemed necessary by the treating physician, appropriate treatment should be initiated.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Active or suspected ocular or periocular infections.
Active intraocular inflammation.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.
Intravitreal injection-related reactions: Intravitreal injections, including those with faricimab, 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 Vabysmo. Patients should be instructed to report any symptoms, such as pain, loss of vision, photophobia, blurred vision, floaters, or redness, suggestive of endophthalmitis or any of the previously mentioned adverse reactions without delay, to permit prompt and appropriate management. Patients with increased frequency of injections may be at increased risk of procedural complications.
Intraocular pressure increases: Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of intravitreal injection, including those with faricimab (see Adverse Reactions). Special precaution is needed in patients with poorly controlled glaucoma (do not inject Vabysmo while the IOP is ≥30 mmHg). In all cases, both the IOP and perfusion of the optic nerve head must be monitored and managed appropriately.
Systemic effects: Systemic adverse events including arterial thromboembolic events have been reported following intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors and there is a theoretical risk that these may be related to VEGF inhibition. A low incidence rate of arterial thromboembolic events was observed in the faricimab clinical trials in patients with nAMD, DME, and RVO. There are limited data on the safety of faricimab treatment in DME patients with high blood pressure (≥140/90 mmHg) and vascular disease, and in nAMD and RVO patients ≥85 years of age.
Immunogenicity: As this is a therapeutic protein, there is a potential for immunogenicity with faricimab (see Adverse Reactions). Patients should be instructed to inform their physician of any signs or symptoms of intraocular inflammation such as vision loss, eye pain, increased sensitivity to light, floaters or worsening eye redness, which might be a clinical sign attributable to hypersensitivity against faricimab (see Adverse Reactions).
Bilateral treatment: The safety and efficacy of faricimab administered in both eyes concurrently have not been studied. Bilateral treatment could cause bilateral ocular adverse reactions and/or potentially lead to an increase in systemic exposure, which could increase the risk of systemic adverse reactions. Until data for bilateral use become available, this is a theoretical risk for faricimab.
Concomitant use of other anti-VEGF: There are no data available on the concomitant use of faricimab with anti-VEGF medicinal products in the same eye. Faricimab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).
Withholding treatment: Treatment should be withheld in patients with: Rhegmatogenous retinal detachment, stage 3 or 4 macular holes, retinal break (treatment should not be resumed until an adequate repair has been performed); Treatment related decrease in Best Corrected Visual Acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity (treatment should not be resumed earlier than the next scheduled treatment); An intraocular pressure of ≥30 mmHg; A subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area; Performed or planned intraocular surgery within the previous or next 28 days (treatment should not be resumed earlier than the next scheduled treatment).
Retinal pigment epithelial tear: Retinal pigment epithelial (RPE) tear is a complication of pigment epithelial detachment (PED) in patients with nAMD. Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for nAMD, include a large and/or high pigment epithelial detachment. When initiating faricimab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears. RPE tears are common in nAMD patients with PED, treated with intravitreal anti-VEGF agents including faricimab. There was a higher rate of RPE tear in the faricimab group (2.9%) compared to aflibercept group (1.5%). The majority of events occurred during the loading phase, and were mild to moderate, without impact on vision.
Populations with limited data: There is only limited experience in the treatment of nAMD and RVO patients ≥85 years, and DME patients with type I diabetes, patients with HbA1c over 10%, patients with high-risk proliferative diabetic retinopathy (DR), high blood pressure (≥140/90 mmHg) and vascular disease, sustained dosing intervals shorter than every 8 weeks (Q8W), or nAMD, DME, and RVO patients with active systemic infections. There is limited safety information on sustained dosing intervals of 8 weeks or less and these may be associated with a higher risk of ocular and systemic adverse reactions, including serious adverse reactions. There is also no experience of treatment with faricimab in diabetic or RVO patients with uncontrolled hypertension and patients with RVO who have failed previous therapy. This lack of information should be considered by the physician when treating such patients.
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium-free".
Polysorbate content: This medicinal product contains 0.02 mg of polysorbate per 0.05 mL dose. Patients with hypersensitivity to polysorbate should not take this medicine.
Effects on ability to drive and use machines: Vabysmo has a minor influence on the ability to drive and use machines. Temporary visual disturbances may occur following the intravitreal injection and the associated eye examination. Patients should not drive or use machines until visual function has recovered sufficiently.

Women of childbearing potential: Women of childbearing potential should use effective contraception during treatment and for at least 3 months following the last intravitreal injection of faricimab.
Pregnancy: There are no or limited amount of data from the use of faricimab in pregnant women. The systemic exposure to faricimab is low after ocular administration, but due to its mechanism of action (i.e. VEGF inhibition), faricimab must be regarded as potentially teratogenic and embryo-/foetotoxic (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Faricimab should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.
Breast-feeding: It is unknown whether faricimab is excreted in human milk. A risk to the breast-fed newborn/infant cannot be excluded. Vabysmo should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from faricimab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: No effects on reproductive organs or fertility were observed in a 6-month cynomolgus monkey study with faricimab (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The most frequently reported adverse reactions were cataract (10%), conjunctival haemorrhage (7%), vitreous detachment (4%), IOP increased (4%), vitreous floaters (4%), eye pain (3%), and retinal pigment epithelial tear (nAMD only) (3%).
The most serious adverse reactions were uveitis (0.5%), endophthalmitis (0.4%), vitritis (0.4%), retinal tear (0.2%), rhegmatogenous retinal detachment (0.1%), and traumatic cataract (<0.1%) (see Precautions).
Tabulated list of adverse reactions: The adverse reactions reported in clinical studies or during post-marketing surveillance are listed according to the MedDRA system organ class and ranked by frequency using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 9.)

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Description of selected adverse reactions: Retinal Vasculitis and Retinal Occlusive Vasculitis: Rare cases of retinal vasculitis and/or retinal occlusive vasculitis have been spontaneously reported in the post-marketing setting (see Precautions). Retinal vasculitis and retinal occlusive vasculitis have also been reported in patients treated with IVT therapies.
Product-class-related adverse reactions: 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 faricimab clinical trials in patients with nAMD, DME, and RVO (see Precautions). Across indications, no notable difference between the groups treated with faricimab and the comparator were observed.
Immunogenicity: There is a potential for an immune response in patients treated with faricimab (see Precautions). After dosing with faricimab for up to 112 (nAMD), 100 (DME), and 72 (RVO) weeks, treatment-emergent anti-faricimab antibodies were detected in approximately 13.8%, 9.6%, and 14.4% of patients with nAMD, DME, and RVO randomised to faricimab, respectively. The clinical significance of anti-faricimab antibodies on safety is unclear at this time. The incidence of intraocular inflammation in anti-faricimab antibody positive patients was 12/98 (12.2%; nAMD), 15/128 (11.7%; DME), and 9/95 (9.5%; RVO), and in anti-faricimab antibody negative patients was 8/562 (1.4%; nAMD), 5/1124 (0.4%; DME), and 10/543 (1.8%; RVO). The incidence of serious ocular adverse reactions in anti-faricimab antibody positive patients was 6/98 (6.1%; nAMD), 14/128 (10.9%; DME), and 7/95 (7.4%; RVO), and in anti-faricimab antibody negative patients was 23/562 (4.1%; nAMD), 45/1124 (4.0%; DME), and 34/543 (6.3%; RVO). Anti-faricimab antibodies were not associated with an impact on clinical efficacy or systemic pharmacokinetics.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

No interaction studies have been performed. Based on the biotransformation and elimination of faricimab (see Pharmacology: Pharmacokinetics under Actions), no interactions are expected. However, faricimab should not be administered concurrently with other systemic or ocular anti-VEGF medicinal products (see Precautions).

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: Do not shake.
Vabysmo should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, Vabysmo must not be used.
Vial: The vial contains more than the recommended dose of 6 mg. The fill volume of the vial (0.24 mL) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the vial results in overdose. The injection dose must be set to the 0.05 mL dose mark, i.e. 6 mg faricimab.
The contents of the vial and the transfer filter needle are sterile and for single use only. Do not use if the packaging, vial and/or transfer filter needle are damaged or expired. Detailed instructions for use are provided in Instructions for use of vial as follows.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructions for use of vial: Gather supplies: 1. Gather the following supplies: One Vabysmo vial (included); One sterile 5-micron blunt transfer filter needle 18-gauge x 1½ inch, 1.2 mm x 40 mm (included); One sterile 1 mL Luer lock syringe with a 0.05 mL dose mark (not included); One sterile injection needle 30-gauge x ½ inch (not included); Alcohol swab (not included). Note that a 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles.
2. To ensure all liquid settles at the bottom of the vial, place the vial upright on a flat surface (for about 1 minute) after removal from packaging. Gently tap the vial with the finger, as liquid may stick to the top of the vial.
3. Remove the flip-off cap from the vial and wipe the vial septum with an alcohol swab.
Transfer medicinal product from vial to syringe: 4. Aseptically and firmly attach the included 18-gauge x 1½ inch transfer filter needle onto a 1 mL Luer lock syringe.
5. Using aseptic technique, push the transfer filter needle into the center of the vial septum, push it all the way in, then tilt the vial slightly so that the needle touches the bottom edge of the vial.
6. Hold the vial slightly inclined and slowly withdraw all the liquid from the vial. Keep the bevel of the transfer filter needle submerged in the liquid, to avoid introduction of air.
Attach injection needle: 7. Ensure that the plunger rod is drawn sufficiently back when emptying the vial, in order to completely empty the transfer filter needle.
8. Disconnect the transfer filter needle from the syringe and dispose of it in accordance with local regulations. Do not use the transfer filter needle for the intravitreal injection.
9. Aseptically and firmly attach a 30-gauge x ½ inch injection needle onto the Luer lock syringe.
Dislodge air bubbles and adjust medicinal product dose: 10. Carefully remove the plastic needle shield from the needle by pulling it straight off.
11. To check for air bubbles, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with the finger until the bubbles rise to the top.
12. Carefully expel the air from the syringe and needle, and slowly depress the plunger to align the rubber stopper tip to the 0.05 mL dose mark. The syringe is ready for the injection. Ensure that the injection is given immediately after preparation of the dose.
13. Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel. Excess volume should be expelled prior to injection. The injection dose must be set to the 0.05 mL dose mark to avoid overdose. Any waste material or unused medicinal product should be disposed of in accordance with local regulations.

Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Prior to use, the unopened vial may be kept at room temperature, 20°C to 25°C, for up to 24 hours.
Ensure that the injection is given immediately after preparation of the dose.

Other Eye Preparations

S01LA09 - faricimab ; Belongs to the class antineovasculatisation agents. Used in the management of neovascular macular degeneration.

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