RANIVISIO 10mg / ml injectible solution medication leaflet

Ranivisio 10 mg/ml solution for injection

One ml contains 10 mg ranibizumab*. Each vial contains 2.3 mg of ranibizumab in 0.23 ml solution.

This provides a usable amount to deliver a single dose of 0.05 ml containing 0.5 mg ranibizumab toadult patients.

*Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells byrecombinant DNA technology.

This medicine contains 0.005 mg of polysorbate 20 in each administered dose of 0.05 ml which isequivalent to 0.10 mg/ml.

For the full list of excipients, see section 6.1.

Solution for injection

Clear, colourless to pale yellow aqueous solution.

Ranivisio is indicated in adults for:

* The treatment of neovascular (wet) age-related macular degeneration (AMD)

* The treatment of visual impairment due to diabetic macular oedema (DME)

* The treatment of proliferative diabetic retinopathy (PDR)

* The treatment of visual impairment due to macular oedema secondary to retinal vein occlusion(branch RVO or central RVO)

* The treatment of visual impairment due to choroidal neovascularisation (CNV)

Ranivisio must be administered by a qualified ophthalmologist experienced in intravitreal injections.

The recommended dose for Ranivisio in adults is 0.5 mg given as a single intravitreal injection. Thiscorresponds to an injection volume of 0.05 ml. The interval between two doses injected into the sameeye should be at least four weeks.

Treatment in adults is initiated with one injection per month until maximum visual acuity is achievedand/or there are no signs of disease activity i.e. no change in visual acuity and in other signs andsymptoms of the disease under continued treatment. In patients with wet AMD, DME, PDR and RVO,initially, three or more consecutive, monthly injections may be needed.

Thereafter, monitoring and treatment intervals should be determined by the physician and should bebased on disease activity, as assessed by visual acuity and/or anatomical parameters.

If, in the physician’s opinion, visual and anatomic parameters indicate that the patient is not benefitingfrom continued treatment, Ranivisio should be discontinued.

Monitoring for disease activity may include clinical examination, functional testing or imagingtechniques (e.g. optical coherence tomography or fluorescein angiography).

If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity isachieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwiseuntil signs of disease activity or visual impairment recur. The treatment interval should be extended byno more than two weeks at a time for wet AMD and may be extended by up to one month at a time for

DME. For PDR and RVO, treatment intervals may also be gradually extended, however there areinsufficient data to conclude on the length of these intervals. If disease activity recurs, the treatmentinterval should be shortened accordingly.

The treatment of visual impairment due to CNV should be determined individually per patient basedon disease activity. Some patients may only need one injection during the first 12 months; others mayneed more frequent treatment, including a monthly injection. For CNV secondary to pathologicmyopia (PM), many patients may only need one or two injections during the first year (seesection 5.1).

Ranibizumab and laser photocoagulation in DME and in macular oedema secondary to BRVO

There is some experience of ranibizumab administered concomitantly with laser photocoagulation (seesection 5.1). When given on the same day, Ranivisio should be administered at least 30 minutes afterlaser photocoagulation. Ranivisio can be administered in patients who have received previous laserphotocoagulation.

Ranibizumab and verteporfin photodynamic therapy in CNV secondary to PM

There is no experience of concomitant administration of ranibizumab and verteporfin.

Ranibizumab has not been studied in patients with hepatic impairment. However, no specialconsiderations are needed in this population.

Dose adjustment is not needed in patients with renal impairment (see section 5.2).

No dose adjustment is required in the elderly. There is limited experience in patients older than75 years with DME.

The safety and efficacy of ranibizumab in children and adolescents below 18 years of age have notbeen established. Available data in adolescent patients aged 12 to 17 years with visual impairment dueto CNV are described in section 5.1 but no recommendation on a posology can be made.

Single-use vial for intravitreal use only.

Since the volume contained in the vial (0.23 ml) is greater than the recommended dose (0.05 ml foradults), a portion of the volume contained in the vial must be discarded prior to administration.

Ranivisio should be inspected visually for particulate matter and discoloration prior to administration.

The injection procedure should be carried out under aseptic conditions, which includes the use ofsurgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent)and the availability of sterile paracentesis (if required). The patient’s medical history forhypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure(see section 4.4). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect theperiocular skin, eyelid and ocular surface should be administered prior to the injection, in accordancewith local practice.

In adults the injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreouscavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injectionvolume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

For instructions on preparation of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with active or suspected ocular or periocular infections.

Patients with active severe intraocular inflammation.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Intravitreous injections, including those with ranibizumab, have been associated with endophthalmitis,intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumaticcataract (see section 4.8). Proper aseptic injection techniques must always be used when administeringranibizumab. In addition, patients should be monitored during the week following the injection topermit early treatment if an infection occurs. Patients should be instructed to report any symptomssuggestive of endophthalmitis or any of the above-mentioned events without delay.

In adults transient increases in intraocular pressure (IOP) have been seen within 60 minutes ofinjection of ranibizumab. Sustained IOP increases have also been identified (see section 4.8). Bothintraocular pressure and the perfusion of the optic nerve head must be monitored and managedappropriately.

Patients should be informed of the symptoms of these potential adverse reactions and instructed toinform their physician if they develop signs such as eye pain or increased discomfort, worsening eyeredness, blurred or decreased vision, an increased number of small particles in their vision, orincreased sensitivity to light (see section 4.8).

Limited data on bilateral use of ranibizumab (including same-day administration) do not suggest anincreased risk of systemic adverse events compared with unilateral treatment.

There is a potential for immunogenicity with ranibizumab. Since there is a potential for an increasedsystemic exposure in subjects with DME, an increased risk for developing hypersensitivity in thispatient population cannot be excluded. Patients should also be instructed to report if an intraocularinflammation increases in severity, which may be a clinical sign attributable to intraocular antibodyformation.

Concomitant use of other anti-VEGF (vascular endothelial growth factor)

Ranibizumab should not be administered concurrently with other anti-VEGF medicinal products(systemic or ocular).

Withholding ranibizumab in adults

The dose should be withheld and treatment should not be resumed earlier than the next scheduledtreatment in the event of:

* a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the lastassessment of visual acuity;

* an intraocular pressure of ≥30 mmHg;

* a retinal break;

* 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.

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGFtherapy for wet AMD and potentially also other forms of CNV, include a large and/or high pigmentepithelial retinal detachment. When initiating ranibizumab therapy, caution should be used in patientswith these risk factors for retinal pigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes in adults

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or4 macular holes.

There is only limited experience in the treatment of subjects with DME due to type I diabetes.

Ranibizumab has not been studied in patients who have previously received intravitreal injections, inpatients with active systemic infections, or in patients with concurrent eye conditions such as retinaldetachment or macular hole. There is limited experience of treatment with ranibizumab in diabeticpatients with an HbA1c over 108 mmol/mol (12%) and no experience in patients with uncontrolledhypertension. This lack of information should be considered by the physician when treating suchpatients.

There are insufficient data to conclude on the effect of ranibizumab in patients with RVO presentingirreversible ischaemic visual function loss.

In patients with PM, there are limited data on the effect of ranibizumab in patients who havepreviously undergone unsuccessful verteporfin photodynamic therapy (vPDT) treatment. Also, while aconsistent effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficientdata to conclude on the effect of ranibizumab in PM subjects with extrafoveal lesions.

Systemic effects following intravitreal use

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events havebeen reported following intravitreal injection of VEGF inhibitors.

There are limited data on safety in the treatment of DME, macular oedema due to RVO and CNVsecondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should beexercised when treating such patients (see section 4.8).

Ranivisio contains polysorbate

Polysorbates may cause allergic reactions.

No interaction studies have been performed.

For the adjunctive use of verteporfin photodynamic therapy (PDT) and ranibizumab in wet AMD and

PM, see section 5.1.

For the adjunctive use of laser photocoagulation and ranibizumab in DME and BRVO, see sections 4.2and 5.1.

In clinical studies for the treatment of visual impairment due to DME, the outcome with regard tovisual acuity or central retinal subfield thickness (CSFT) in patients treated with ranibizumab was notaffected by concomitant treatment with thiazolidinediones.

Women of childbearing potential should use effective contraception during treatment.

For ranibizumab no clinical data on exposed pregnancies are available. Studies in cynomolgusmonkeys do not indicate direct or indirect harmful effects with respect to pregnancy orembryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is low afterocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentiallyteratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during pregnancyunless the expected benefit outweighs the potential risk to the foetus. For women who wish to becomepregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after thelast dose of ranibizumab before conceiving a child.

Based on very limited data, ranibizumab may be excreted in human milk at low levels. The effect ofranibizumab on a breast-fed newborn/infant is unknown. As a precautionary measure, breast-feeding isnot recommended during the use of ranibizumab.

There are no data available on fertility.

The treatment procedure may induce temporary visual disturbances, which may affect the ability todrive or use machines (see section 4.8). Patients who experience these signs must not drive or usemachines until these temporary visual disturbances subside.

The majority of adverse reactions reported following administration of ranibizumab are related to theintravitreal injection procedure.

The most frequently reported ocular adverse reactions following injection of ranibizumab are: eye pain,ocular hyperaemia, increased intraocular pressure, vitritis, vitreous detachment, retinal haemorrhage,visual disturbance, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation ineyes, increased lacrimation, blepharitis, dry eye and eye pruritus.

The most frequently reported non-ocular adverse reactions are headache, nasopharyngitis and arthralgia.

Less frequently reported, but more serious, adverse reactions include endophthalmitis, blindness, retinaldetachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).

The adverse reactions experienced following administration of ranibizumab in clinical studies aresummarised in the table below.

Tabulated list of adverse reactions#

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<1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Very common Nasopharyngitis

Common Urinary tract infection*

Common Anaemia

Common Hypersensitivity

Common Anxiety

Very common Headache

Very common Vitritis, vitreous detachment, retinal haemorrhage, visualdisturbance, eye pain, vitreous floaters, conjunctivalhaemorrhage, eye irritation, foreign body sensation in eyes,lacrimation increased, blepharitis, dry eye, ocularhyperaemia, eye pruritus.

Common Retinal degeneration, retinal disorder, retinal detachment,retinal tear, detachment of the retinal pigment epithelium,retinal pigment epithelium tear, visual acuity reduced,vitreous haemorrhage, vitreous disorder, uveitis, iritis,iridocyclitis, cataract, cataract subcapsular, posterior capsuleopacification, punctuate keratitis, corneal abrasion, anteriorchamber flare, vision blurred, injection site haemorrhage, eyehaemorrhage, conjunctivitis, conjunctivitis allergic, eyedischarge, photopsia, photophobia, ocular discomfort, eyelidoedema, eyelid pain, conjunctival hyperaemia.

Uncommon Blindness, endophthalmitis, hypopyon, hyphaema,keratopathy, iris adhesion, corneal deposits, corneal oedema,corneal striae, injection site pain, injection site irritation,abnormal sensation in eye, eyelid irritation.

Common Cough

Common Nausea

Common Allergic reactions (rash, urticaria, pruritus, erythema)

Very common Arthralgia

Very common Intraocular pressure increased#

Adverse reactions were defined as adverse events (in at least 0.5 percentage points of patients) whichoccurred at a higher rate (at least 2 percentage points) in patients receiving treatment with ranibizumab0.5 mg than in those receiving control treatment (sham or verteporfin PDT).

* observed only in DME population

In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse eventpotentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightlyincreased in ranibizumab-treated patients. However, there was no consistent pattern among thedifferent haemorrhages. There is a theoretical risk of arterial thromboembolic events, including strokeand myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate ofarterial thromboembolic events was observed in the ranibizumab clinical studies in patients with

AMD, DME, PDR, RVO and CNV and there were no major differences between the groups treatedwith ranibizumab compared to control.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of accidental overdose have been reported from the clinical studies in wet AMD and post-marketing data. Adverse reactions associated with these reported cases were intraocular pressureincreased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If anoverdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by theattending physician.

Pharmacotherapeutic group: Ophthalmologicals, antineovascularisation agents, ATC code: S01LA04

Ranivisio is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency https://www.ema.europa.eu.

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against humanvascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms(e.g. VEGF110, VEGF121 and VEGF165), thereby preventing binding of VEGF-A to its receptors

VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferationand neovascularisation, as well as vascular leakage, all of which are thought to contribute to theprogression of the neovascular form of age-related macular degeneration, pathologic myopia and CNVor to visual impairment caused by either diabetic macular oedema or macular oedema secondary to

RVO in adults.

Treatment of wet AMD

In wet AMD, the clinical safety and efficacy of ranibizumab have been assessed in three randomised,double-masked, sham- or active-controlled studies of 24 months duration in patients with neovascular

AMD. A total of 1 323 patients (879 active and 444 control) were enrolled in these studies.

In study FVF2598g (MARINA), 716 patients with minimally classic or occult with no classic lesionswere randomised in a 1:1:1 ratio to receive monthly injections of ranibizumab 0.3 mg, ranibizumab0.5 mg or sham.

In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV lesions wererandomised in a 1:1:1 ratio to receive ranibizumab 0.3 mg monthly, ranibizumab 0.5 mg monthly orverteporfin PDT (at baseline and every 3 months thereafter if fluorescein angiography showedpersistence or recurrence of vascular leakage).

Key outcome measures are summarised in Table 1 and Figure 1.

Table 1 Outcomes at Month 12 and Month 24 in study FVF2598g (MARINA) and FVF2587g(ANCHOR)

FVF2598g (MARINA) FVF2587g (ANCHOR)

Outcome measure Month Sham Ranibizumab Verteporfin Ranibizumab(n=238) 0.5 mg PDT 0.5 mg(n=240) (n=143) (n=140)

Loss of <15 letters in Month 12 62% 95% 64% 96%visual acuity (%)a(maintenance of

Month 24 53% 90% 66% 90%vision, primaryendpoint)

Gain of ≥15 letters in Month 12 5% 34% 6% 40%visual acuity (%)a

Month 24 4% 33% 6% 41%

Mean change in visual Month 12 -10.5 (16.6) +7.2 (14.4) -9.5 (16.4) +11.3 (14.6)acuity (letters) (SD)a

Month 24 -14.9 (18.7) +6.6 (16.5) -9.8 (17.6) +10.7 (16.5)a p<0.01

Figure 1 Mean change in visual acuity from baseline to Month 24 in study FVF2598g(MARINA) and study FVF2587g (ANCHOR)

Results from both trials indicated that continued ranibizumab treatment may also be of benefit inpatients who lost ≥15 letters of best-corrected visual acuity (BCVA) in the first year of treatment.

Statistically significant patient-reported visual functioning benefits were observed in both MARINAand ANCHOR with ranibizumab treatment over the control group as measured by the NEI VFQ-25.

In study FVF3192g (PIER), 184 patients with all forms of neovascular AMD were randomised in a1:1:1 ratio to receive ranibizumab 0.3 mg, ranibizumab 0.5 mg or sham injections once a month for3 consecutive doses, followed by a dose administered once every 3 months. From Month 14 of thestudy, sham-treated patients were allowed to receive ranibizumab and from Month 19, more frequenttreatments were possible. Patients treated with ranibizumab in PIER received a mean of 10 totaltreatments.

After an initial increase in visual acuity (following monthly dosing), on average, patients’ visual acuitydeclined with quarterly dosing, returning to baseline at Month 12 and this effect was maintained inmost ranibizumab-treated patients (82%) at Month 24. Limited data from sham subjects who laterreceived ranibizumab suggested that early initiation of treatment may be associated with betterpreservation of visual acuity.

Data from two studies (MONT BLANC, BPD952A2308 and DENALI, BPD952A2309) conductedpost approval confirmed the efficacy of ranibizumab but did not demonstrate additional effect of thecombined administration of verteporfin (Visudyne PDT) and ranibizumab compared to ranibizumabmonotherapy.

Treatment of visual impairment due to CNV secondary to PM

The clinical safety and efficacy of ranibizumab in patients with visual impairment due to CNV in PMhave been assessed based on the 12-month data of the double-masked, controlled pivotal study F2301(RADIANCE). In this study 277 patients were randomised in a 2:2:1 ratio to the following arms:

* Group I (ranibizumab 0.5 mg, dosing regimen driven by “stability” criteria defined as no changein BCVA compared to two preceding monthly evaluations).

* Group II (ranibizumab 0.5 mg, dosing regimen driven by “disease activity” criteria defined asvision impairment attributable to intra- or subretinal fluid or active leakage due to the CNV lesionas assessed by optical coherence tomography and/or fluorescence angiography).

* Group III (vPDT - patients were allowed to receive ranibizumab treatment as of Month 3).

In Group II, which is the recommended posology (see section 4.2), 50.9% of patients required 1 or2 injections, 34.5% required 3 to 5 injections and 14.7% required 6 to 12 injections over the 12-monthstudy period. 62.9% of Group II patients did not require injections in the second 6 months of the study.

The key outcomes from RADIANCE are summarised in Table 2 and Figure 2.

Table 2 Outcomes at Month 3 and 12 (RADIANCE)

Group I Group II Group

Ranibizumab Ranibizumab III0.5 mg 0.5 mg vPDTb“vision stability” “disease activity”(n=105) (n=116) (n=55)

Month 3

Mean average BCVA change from Month 1 +10.5 +10.6 +2.2to Month 3 compared to baselinea(letters)

Proportion of patients who gained:

≥15 letters, or reached ≥84 letters in BCVA 38.1% 43.1% 14.5%

Month 12

Number of injections up to Month 12:

Mean 4.6 3.5 N/A

Median 4.0 2.5 N/A

Mean average BCVA change from Month 1 +12.8 +12.5 N/Ato Month 12 compared to baseline (letters)

Proportion of patients who gained:

≥15 letters, or reached ≥84 letters in BCVA 53.3% 51.7% N/Aap<0.00001 comparison with vPDT controlb

Comparative control up to Month 3. Patients randomised to vPDT were allowed to receiveranibizumab treatment as of Month 3 (in Group III, 38 patients received ranibizumab as of Month 3)

Figure 2 Mean change from baseline BCVA over time to Month 12 (RADIANCE)

The improvement of vision was accompanied by a reduction in central retinal thickness.

Patient-reported benefits were observed with ranibizumab treatment arms over vPDT (p-value <0.05)in terms of improvement in the composite score and several subscales (general vision, near activities,mental health and dependency) of the NEI VFQ-25.

Treatment of visual impairment due to CNV (other than secondary to PM and wet AMD)

The clinical safety and efficacy of ranibizumab in patients with visual impairment due to CNV havebeen assessed based on the 12-month data of the double-masked, sham-controlled pivotal study G2301(MINERVA). In this study 178 adult patients were randomised in a 2:1 ratio to receive:

* ranibizumab 0.5 mg at baseline, followed by an individualised dosing regimen driven by diseaseactivity as assessed by visual acuity and/or anatomical parameters (e.g. visual acuity impairment,intra/sub-retinal fluid, haemorrhage or leakage);

* sham injection at baseline, followed by an individualised treatment regimen driven by diseaseactivity.

At Month 2, all patients received open-label treatment with ranibizumab as needed.

Key outcome measures from MINERVA are summarised in Table 3 and Figure 3. An improvement ofvision was observed and was accompanied by a reduction in central subfield thickness over the 12-month period.

The mean number of injections given over 12 months was 5.8 in the ranibizumab arm versus 5.4 inthose patients in the sham arm who were eligible to receive ranibizumab from Month 2 onwards. Inthe sham arm 7 out of 59 patients did not receive any treatment with ranibizumab in the study eyeduring the 12-month period.

Table 3 Outcomes at Month 2 (MINERVA)

Ranibizumab Sham (n=59)0.5 mg (n=119)

Mean BCVA change from baseline to Month 2 a 9.5 letters -0.4 letters

Patients gaining ≥15 letters from baseline or reaching 31.4% 12.3%84 letters at Month 2

Patients not losing >15 letters from baseline 99.2% 94.7%at Month 2

Reduction in CSFTbfrom baseline to Month 2 a77 μm -9.8 μma

One-sided p<0.001 comparison with sham controlb CSFT - central retinal subfield thickness

Figure 3 Mean change from baseline BCVA over time to Month 12 (MINERVA)

When comparing ranibizumab versus sham control at Month 2, a consistent treatment effect bothoverall and across baseline aetiology subgroups was observed:

Table 4 Treatment effect overall and across baseline aetiology subgroups

Overall and per baseline aetiology Treatment effect over Patient numbers [n]sham [letters] (treatment +sham)

Overall 9.9 178

Angioid streaks 14.6 27

Post-inflammatory 6.5 28retinochoroidopathy

Central serous chorioretinopathy 5.0 23

Idiopathic chorioretinopathy 11.4 63

Miscellaneous aetiologies a 10.6 37aencompasses different aetiologies of low frequency of occurrence not included in the other subgroups

In the pivotal study G2301 (MINERVA), five adolescent patients aged 12 to 17 years with visualimpairment secondary to CNV received open-label treatment with ranibizumab 0.5 mg at baselinefollowed by an individualised treatment regimen as for the adult population. BCVA improved frombaseline to Month 12 in all five patients, ranging from 5 to 38 letters (mean of 16.6 letters). Theimprovement of vision was accompanied by a stabilisation or reduction in central subfield thicknessover the 12-month period. The mean number of ranibizumab injections given in the study eye over12 months was 3 (ranged from 2 to 5). Overall, ranibizumab treatment was well tolerated.

Treatment of visual impairment due to DME

The efficacy and safety of ranibizumab have been assessed in three randomised, controlled studies ofat least 12 months duration. A total of 868 patients (708 active and 160 control) were enrolled in thesestudies.

In the phase II study D2201 (RESOLVE), 151 patients were treated with ranibizumab (6 mg/ml, n=51,10 mg/ml, n=51) or sham (n=49) by monthly intravitreal injections. The mean average change in

BCVA from Month 1 to Month 12 compared to baseline was +7.8 (±7.72) letters in the pooledranibizumab-treated patients (n=102), compared to -0.1 (±9.77) letters for sham-treated patients; andthe mean change in BCVA at Month 12 from baseline was 10.3 (±9.1) letters compared to -1.4 (±14.2)letters, respectively (p<0.0001 for the treatment difference).

In the phase III study D2301 (RESTORE), 345 patients were randomised in a 1:1:1 ratio to receiveranibizumab 0.5 mg monotherapy and sham laser photocoagulation, combined ranibizumab 0.5 mgand laser photocoagulation or sham injection and laser photocoagulation. 240 patients, who hadpreviously completed the 12-month RESTORE study, were enrolled in the open-label, multicentre24-month extension (RESTORE Extension) study. Patients were treated with ranibizumab 0.5 mg prore nata (PRN) in the same eye as the core study (D2301 RESTORE).

Key outcome measures are summarised in Table 5 (RESTORE and Extension) and Figure 4(RESTORE).

Figure 4 Mean change in visual acuity from baseline over time in study D2301 (RESTORE)

The effect at 12 months was consistent in most subgroups. However, subjects with a baseline BCVA>73 letters and macular oedema with central retinal thickness <300 μm did not appear to benefit fromtreatment with ranibizumab compared to laser photocoagulation.

Table 5 Outcomes at Month 12 in study D2301 (RESTORE) and at Month 36 in study

D2301-E1 (RESTORE Extension)

Outcome measures at Month 12 compared Ranibizumab Ranibizumab Laserto baseline in study D2301 (RESTORE) 0.5 mg 0.5 mg + Lasern=115 n=118 n=110

Mean average change in BCVA from 6.1 (6.4)a5.9 (7.9)a0.8 (8.6)

Month 1 to Month 12a (±SD)

Mean change in BCVA at Month 12 6.8 (8.3)a6.4 (11.8)a0.9 (11.4)(±SD)

Gain of ≥15 letters or BCVA ≥84 letters at 22.6 22.9 8.2

Month 12 (%)

Mean number of injections (Months 0-11) 7.0 6.8 7.3 (sham)

Outcome measure at Month 36 compared Prior ranibizumab Prior ranibizumab Prior laserto D2301 (RESTORE) baseline in study 0.5 mg 0.5 mg + laser

D2301-E1 (RESTORE Extension) n=83 n=83 n=74

Mean change in BCVA at Month 24 (SD) 7.9 (9.0) 6.7 (7.9) 5.4 (9.0)

Mean change in BCVA at Month 36 (SD) 8.0 (10.1) 6.7 (9.6) 6.0 (9.4)

Gain of ≥15 letters or BCVA ≥84 letters at 27.7 30.1 21.6

Month 36 (%)

Mean number of injections 6.8 6.0 6.5(Months 12-35)*ap<0.0001 for comparisons of ranibizumab arms vs. laser arm.

n in D2301-E1 (RESTORE Extension) is the number of patients with a value at both D2301(RESTORE) baseline (Month 0) and at the Month 36 visit.

* The proportion of patients who did not require any ranibizumab treatment during the extensionphase was 19%, 25% and 20% in the prior ranibizumab, prior ranibizumab + laser and prior lasergroups, respectively.

Statistically significant patient-reported benefits for most vision-related functions were observed withranibizumab (with or without laser) treatment over the control group as measured by the NEI VFQ-25.

For other subscales of this questionnaire no treatment differences could be established.

The long-term safety profile of ranibizumab observed in the 24-month extension study is consistentwith the known ranibizumab safety profile.

In the phase IIIb study D2304 (RETAIN), 372 patients were randomised in 1:1:1 ratio to receive:

* ranibizumab 0.5 mg with concomitant laser photocoagulation on a treat-and-extend (TE)regimen,

* ranibizumab 0.5 mg monotherapy on a TE regimen,

* ranibizumab 0.5 mg monotherapy on a PRN regimen.

In all groups, ranibizumab was administered monthly until BCVA was stable for at least threeconsecutive monthly assessments. On TE, ranibizumab was administered at treatment intervals of2-3 months. In all groups, monthly treatment was re-initiated upon a decrease in BCVA due to DMEprogression and continued until stable BCVA was reached again.

The number of scheduled treatment visits after the initial 3 injections, was 13 and 20 for the TE and

PRN regimens, respectively. With both TE regimens, more than 70% of patients maintained their

BCVA with an average visit frequency of ≥2 months.

The key outcome measures are summarised in Table 6.

Table 6 Outcomes in study D2304 (RETAIN)

Outcome measure TE ranibizumab TE ranibizumab PRN ranibizumabcompared to baseline 0.5 mg + laser 0.5 mg alone 0.5 mgn=117 n=125 n=117

Mean average change in 5.9 (5.5) a 6.1 (5.7) a 6.2 (6.0)

BCVA from Month 1 to

Month 12 (SD)

Mean average change in 6.8 (6.0) 6.6 (7.1) 7.0 (6.4)

BCVA from Month 1 to

Month 24 (SD)

Mean change in BCVA 8.3 (8.1) 6.5 (10.9) 8.1 (8.5)at Month 24 (SD)

Gain of ≥15 letters or 25.6 28.0 30.8

BCVA ≥84 letters at

Month 24(%)

Mean number of 12.4 12.8 10.7injections(months 0-23)ap<0.0001 for assessment of non-inferiority to PRN

In DME studies, the improvement in BCVA was accompanied by a reduction over time in mean CSFTin all the treatment groups.

Treatment of PDR

The clinical safety and efficacy of ranibizumab in patients with PDR have been assessed in Protocol Swhich evaluated the treatment with ranibizumab 0.5 mg intravitreal injections compared withpanretinal photocoagulation (PRP). The primary endpoint was the mean visual acuity change at year 2.

Additionally, change in diabetic retinopathy (DR) severity was assessed based on fundus photographsusing the DR severity score (DRSS).

Protocol S was a multicentre, randomised, active-controlled, parallel-assignment, non-inferiority phase

III study in which 305 patients (394 study eyes) with PDR with or without DME at baseline wereenrolled. The study compared ranibizumab 0.5 mg intravitreal injections to standard treatment with

PRP. A total of 191 eyes (48.5%) were randomised to ranibizumab 0.5 mg and 203 eyes (51.5%) eyeswere randomised to PRP. A total of 88 eyes (22.3%) had baseline DME: 42 (22.0%) and 46 (22.7%)eyes in the ranibizumab and PRP groups, respectively.

In this study, the mean visual acuity change at year 2 was +2.7 letters in the ranibizumab groupcompared to -0.7 letters in the PRP group. The difference in least square means was 3.5 letters (95%

CI: [0.2 to 6.7]).

At year 1, 41.8% of eyes experienced a ≥2-step improvement in the DRSS when treated withranibizumab (n=189) compared to 14.6% of eyes treated with PRP (n=199). The estimated differencebetween ranibizumab and laser was 27.4% (95% CI: [18.9, 35.9]).

Table 7 DRSS improvement or worsening of ≥2 or ≥3 steps at year 1 in Protocol S (LOCF

Method)

Categorised change Protocol Sfrom baseline Ranibizumab PRP Difference in0.5 mg (N=199) proportion (%), CI(N=189)≥2-step improvementn (%) 79 29 27.4(41.8%) (14.6%) (18.9, 35.9)≥3-step improvementn (%) 54 6 25.7(28.6%) (3.0%) (18.9, 32.6)≥2-step worseningn (%) 3 23 -9.9(1.6%) (11.6%) (-14.7, -5.2)≥3-step worseningn (%) 1 8 -3.4(0.5%) (4.0%) (-6.3, -0.5)

DRSS = diabetic retinopathy severity score, n = number of patients who satisfied the condition atthe visit, N = total number of study eyes.

At year 1 in the ranibizumab-treated group in Protocol S, ≥2-step improvement in DRSS wasconsistent in eyes without DME (39.9%) and with baseline DME (48.8%).

An analysis of year 2 data from Protocol S demonstrated that 42.3% (n=80) of eyes in theranibizumab-treated group had ≥2-step improvement in DRSS from baseline compared with 23.1%(n=46) of eyes in the PRP group. In the ranibizumab-treated group, ≥2-step improvement in DRSSfrom baseline was observed in 58.5% (n=24) of eyes with baseline DME and 37.8% (n=56) of eyeswithout DME.

DRSS was also assessed in three separate active-controlled phase III DME studies (ranibizumab 0.5mg PRN vs laser) that included a total of 875 patients, of whom approximately 75% were of Asianorigin. In a meta-analysis of these studies, 48.4% of the 315 patients with gradable DRSS scores in thesubgroup of patients with moderately severe non- proliferative DR (NPDR) or worse at baselineexperienced a ≥2-step improvement in the DRSS at Month 12 when treated with ranibizumab (n=192)vs 14.6% of patients treated with laser (n=123). The estimated difference between ranibizumab andlaser was 29.9% (95% CI: [20.0, 39.7]). In the 405 DRSS gradable patients with moderate NPDR orbetter, a ≥2-step DRSS improvement was observed in 1.4% and 0.9% of the ranibizumab and lasergroups, respectively.

Treatment of visual impairment due to macular oedema secondary to RVO

The clinical safety and efficacy of ranibizumab in patients with visual impairment due to macularoedema secondary to RVO have been assessed in the randomised, double-masked, controlled studies

BRAVO and CRUISE that recruited subjects with BRVO (n=397) and CRVO (n=392), respectively.

In both studies, subjects received either 0.3 mg or 0.5 mg ranibizumab or sham injections. After6 months, patients in the sham-control arms switched to 0.5 mg ranibizumab.

Key outcome measures from BRAVO and CRUISE are summarised in Table 8 and Figures 5 and 6.

Table 8 Outcomes at Month 6 and 12 (BRAVO and CRUISE)

BRAVO CRUISE

Sham/ Ranibizumab Sham/ Ranibizumab

Ranibizumab 0.5 mg Ranibizumab 0.5 mg0.5 mg (n=131) 0.5 mg (n=130)(n=132) (n=130)

Mean change in visual 7.3 (13.0) 18.3 (13.2) 0.8 (16.2) 14.9 (13.2)acuity at Month 6a(letters)(SD) (primary endpoint)

Mean change in BCVA at 12.1 (14.4) 18.3 (14.6) 7.3 (15.9) 13.9 (14.2)

Month 12 (letters) (SD)

Gain of ≥15 letters in visual 28.8 61.1 16.9 47.7acuity at Month 6a (%)

Gain of ≥15 letters in visual 43.9 60.3 33.1 50.8acuity at Month 12 (%)

Proportion (%) receiving 61.4 34.4 NA NAlaser rescue over 12 monthsap<0.0001 for both studies

Figure 5 Mean change from baseline BCVA over time to Month 6 and Month 12 (BRAVO)

Figure 6 Mean change from baseline BCVA over time to Month 6 and Month 12 (CRUISE)

In both studies, the improvement of vision was accompanied by a continuous and significant reductionin the macular oedema as measured by central retinal thickness.

In patients with CRVO (CRUISE and extension study HORIZON): Subjects treated with sham in thefirst 6 months who subsequently received ranibizumab did not achieve comparable gains in VA by

Month 24 (~6 letters) compared to subjects treated with ranibizumab from study start (~12 letters).

Statistically significant patient-reported benefits in subscales related to near and distance activity wereobserved with ranibizumab treatment over the control group as measured by the NEI VFQ-25.

The long-term (24 months) clinical safety and efficacy of ranibizumab in patients with visualimpairment due to macular oedema secondary to RVO were assessed in the BRIGHTER (BRVO) and

CRYSTAL (CRVO) studies. In both studies, subjects received a 0.5 mg ranibizumab PRN dosingregimen driven by individualised stabilisation criteria. BRIGHTER was a 3-arm randomised active-controlled study that compared 0.5 mg ranibizumab given as monotherapy or in combination withadjunctive laser photocoagulation to laser photocoagulation alone. After 6 months, subjects in the laserarm could receive 0.5 mg ranibizumab. CRYSTAL was a single-arm study with 0.5 mg ranibizumabmonotherapy.

Key outcome measures from BRIGHTER and CRYSTAL are shown in Table 9.

Table 9 Outcomes at Months 6 and 24 (BRIGHTER and CRYSTAL)

BRIGHTER CRYSTAL

Ranibizumab Ranibizumab Laser* Ranibizumab0.5 mg 0.5 mg + Laser N=90 0.5 mg

N=180 N=178 N=356

Mean change in +14.8 +14.8 +6.0 +12.0

BCVA at Month 6a(10.7) (11.13) (14.27) (13.95)(letters) (SD)

Mean change in +15.5 +17.3 +11.6 +12.1

BCVA at (13.91) (12.61) (16.09) (18.60)

Month 24b(letters)(SD)

Gain of ≥15 letters 52.8 59.6 43.3 49.2in BCVA at

Month 24 (%)

Mean number of 11.4 11.3 NA 13.1injections (SD) (5.81) (6.02) (6.39)(Months 0-23)ap<0.0001 for both comparisons in BRIGHTER at Month 6: Ranibizumab 0.5 mg vs Laser and

Ranibizumab 0.5 mg + Laser vs Laser.bp<0.0001 for null hypothesis in CRYSTAL that the mean change at Month 24 from baselineis zero.

* Starting at Month 6 ranibizumab 0.5 mg treatment was allowed (24 patients were treated withlaser only).

In BRIGHTER, ranibizumab 0.5 mg with adjunctive laser therapy demonstrated non-inferiority versusranibizumab monotherapy from baseline to Month 24 (95% CI -2.8, 1.4).

In both studies, a rapid and statistically significant decrease from baseline in central retinal subfieldthickness was observed at Month 1. This effect was maintained up to Month 24.

The effect of ranibizumab treatment was similar irrespective of the presence of retinal ischaemia. In

BRIGHTER, patients with ischaemia present (N=46) or absent (N=133) and treated with ranibizumabmonotherapy had a mean change from baseline of +15.3 and +15.6 letters, respectively, at Month 24.

In CRYSTAL, patients with ischaemia present (N=53) or absent (N=300) and treated withranibizumab monotherapy had a mean change from baseline of +15.0 and +11.5 letters, respectively.

The effect in terms of visual improvement was observed in all patients treated with 0.5 mgranibizumab monotherapy regardless of their disease duration in both BRIGHTER and CRYSTAL. Inpatients with <3 months disease duration an increase in visual acuity of 13.3 and 10.0 letters was seenat Month 1; and 17.7 and 13.2 letters at Month 24 in BRIGHTER and CRYSTAL, respectively. Thecorresponding visual acuity gain in patients with ≥12 months disease duration was 8.6 and 8.4 lettersin the respective studies. Treatment initiation at the time of diagnosis should be considered.

The long-term safety profile of ranibizumab observed in the 24-month studies is consistent with theknown ranibizumab safety profile.

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing ranibizumab in all subsets of the paediatric population inneovascular AMD, visual impairment due to DME, visual impairment due to macular oedemasecondary to RVO, visual impairment due to CNV and diabetic retinopathy (see section 4.2 forinformation on paediatric use).

Following monthly intravitreal administration of ranibizumab to patients with neovascular AMD,serum concentrations of ranibizumab were generally low, with maximum levels (Cmax) generallybelow the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50% (11-27 ng/ml, as assessed in an in vitro cellular proliferation assay). Cmax was dose proportional over thedose range of 0.05 to 1.0 mg/eye. Serum concentrations in a limited number of DME patients indicatethat a slightly higher systemic exposure cannot be excluded compared to those observed inneovascular AMD patients. Serum ranibizumab concentrations in RVO patients were similar orslightly higher compared to those observed in neovascular AMD patients.

Based on analysis of population pharmacokinetics and disappearance of ranibizumab from serum forpatients with neovascular AMD treated with the 0.5 mg dose, the average vitreous elimination half-lifeof ranibizumab is approximately 9 days. Upon monthly intravitreal administration of ranibizumab0.5 mg/eye, serum ranibizumab Cmax, attained approximately 1 day after dosing, is predicted togenerally range between 0.79 and 2.90 ng/ml, and Cmin is predicted to generally range between0.07 and 0.49 ng/ml. Serum ranibizumab concentrations are predicted to be approximately 90 000-foldlower than vitreal ranibizumab concentrations.

Patients with renal impairment: No formal studies have been conducted to examine thepharmacokinetics of ranibizumab in patients with renal impairment. In a population pharmacokineticanalysis of neovascular AMD patients, 68% (136 of 200) of patients had renal impairment (46.5%mild [50-80 ml/min], 20% moderate [30-50 ml/min], and 1.5% severe [<30 ml/min]). In RVOpatients, 48.2% (253 of 525) had renal impairment (36.4% mild, 9.5% moderate and 2.3% severe).

Systemic clearance was slightly lower, but this was not clinically significant.

Hepatic impairment: No formal studies have been conducted to examine the pharmacokinetics ofranibizumab in patients with hepatic impairment.

Bilateral intravitreal administration of ranibizumab to cynomolgus monkeys at doses between0.25 mg/eye and 2.0 mg/eye once every 2 weeks for up to 26 weeks resulted in dose-dependent oculareffects.

Intraocularly, there were dose-dependent increases in anterior chamber flare and cells with a peak2 days after injection. The severity of the inflammatory response generally diminished withsubsequent injections or during recovery. In the posterior segment, there were vitreal cell infiltrationand floaters, which also tended to be dose-dependent and generally persisted to the end of thetreatment period. In the 26-week study, the severity of the vitreous inflammation increased with thenumber of injections. However, evidence of reversibility was observed after recovery. The nature andtiming of the posterior segment inflammation is suggestive of an immune-mediated antibody response,which may be clinically irrelevant. Cataract formation was observed in some animals after a relativelylong period of intense inflammation, suggesting that the lens changes were secondary to severeinflammation. A transient increase in post-dose intraocular pressure was observed followingintravitreal injections, irrespective of dose.

Microscopic ocular changes were related to inflammation and did not indicate degenerative processes.

Granulomatous inflammatory changes were noted in the optic disc of some eyes. These posteriorsegment changes diminished, and in some instances resolved, during the recovery period.

Following intravitreal administration, no signs of systemic toxicity were detected. Serum and vitreousantibodies to ranibizumab were found in a subset of treated animals.

No carcinogenicity or mutagenicity data are available.

In pregnant monkeys, intravitreal ranibizumab treatment resulting in maximal systemic exposures 0.9-7-fold a worst case clinical exposure did not elicit developmental toxicity or teratogenicity, and had noeffect on weight or structure of the placenta, although, based on its pharmacological effectranibizumab should be regarded as potentially teratogenic and embryo-/foetotoxic.

The absence of ranibizumab-mediated effects on embryo-foetal development is plausibly relatedmainly to the inability of the Fab fragment to cross the placenta. Nevertheless, a case was describedwith high maternal ranibizumab serum levels and presence of ranibizumab in foetal serum, suggestingthat the anti-ranibizumab antibody acted as (Fc region containing) carrier protein for ranibizumab,thereby decreasing its maternal serum clearance and enabling its placental transfer. As the embryo-foetal development investigations were performed in healthy pregnant animals and disease (such asdiabetes) may modify the permeability of the placenta towards a Fab fragment, the study should beinterpreted with caution.

α,α-trehalose dihydrate

Histidine hydrochloride, monohydrate

Histidine

Polysorbate 20 (E 432)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

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 (25 °C) for up to 24 hours.

One vial (type I glass) with a stopper (chlorobutyl rubber) containing 0.23 ml sterile solution.

Pack size of one vial.

The vial is for single use only. After injection any unused product must be discarded. Any vialshowing signs of damage or tampering must not be used. The sterility cannot be guaranteed unless thepackaging seal remains intact.

For preparation and intravitreal injection the following medical devices for single use are needed:

- a 5 μm filter needle (18G)

- a 1 ml sterile syringe (including a 0.05 ml mark) and an injection needle (30G x ½″), for adultpatients

These medical devices are not included within this pack. They could be obtained separately or inindependent intravitreal injection kits (for example the I2 injection kit from Vortex Surgical).

To prepare Ranivisio for intravitreal administration to adults, please adhere to the followinginstructions:

1. Before withdrawal, remove the vial cap and clean the vial septum (e.g. with 70% alcoholswab).

2. Assemble a 5 μm filter needle (18G x 1½″, 1.2 mm x 40 mm) onto a 1 ml syringe usingaseptic technique. Push the blunt filter needle into the centre of the vial stopper until theneedle touches the bottom edge of the vial.

3. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclinedto ease complete withdrawal.

4. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order tocompletely empty the filter needle.

5. Leave the blunt filter needle in the vial and disconnect the syringe from the blunt filter needle.

The filter needle should be discarded after withdrawal of the vial contents and should not beused for the intravitreal injection.

6. Aseptically and firmly assemble an injection needle (30G x ½″, 0.3 mm x 13 mm) onto thesyringe.

7. Carefully remove the cap from the injection needle without disconnecting the injection needlefrom the syringe.

Note: Grip at the hub of the injection needle while removing the cap.

8. Carefully expel the air along with the excess solution and adjust the dose to the 0.05 ml markon the syringe. The syringe is ready for injection.

Note: Do not wipe the injection needle. Do not pull back on the plunger.

After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringetogether with the needle in a sharps disposal container or in accordance with local requirements.

Midas Pharma GmbH

Rheinstraße 49

D-55218 Ingelheim

Germany

EU/1/22/1673/001

Date of first authorisation: 25 August 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.