LUCENTIS

Novartis Israel Ltd.

36 Shacham St., Ramat Siv, Petach-Tikva

P.O.B 7759, Petach Tikva 4951729, Israel

Tel: 972-3-9201123 Fax: 972-3-9229331

לארשי סיטרבונ

מ"עב

'חר םחש

,ביס תמר

חתפ

הוקת

.ד.ת

7759

חתפ

הוקת

4951729

:ןופלט

03-9201123

:סקפ

03-9229331

ראוני

2019

,ה/דבכנ ה/אפור ,ה/דבכנ ת/חקור

:ןודנה

, 10 mg/ml

ject

, solution for in

Lucentis

סיטנסול

יוותהה תבחרה/תפסות

:ה

)

CNV

(

cularization

s

a

v

Choroidal Neo

םושר ןודנבש רישכתה יוותהל לארשיב תו

אבה תו

Treatment of patients with neovascular (wet) age-related macular degeneration (AMD).

Treatment of adult patients with visual impairment due to diabetic macular oedema

(DME).

The treatment of visual impairment due to macular oedema secondary to retinal vein

occlusion (RVO).

The treatment of visual impairment due to choroidal neovascularization (CNV)

secondary to pathologic myopia (PM).

כר

ליעפה

Ranibizumab 10 mg /mL

לע םכעידוהל וננוצרב ל היוותהה תבחרה/תפסוה

-

CNV

לעו רישכתה לש אפורל ןולעב םינוכדע

ש

.ןודנב

:אוה תבחרומה היוותהה חסונ

The treatment of visual impairment due to choroidal neovascularization (CNV)

ןולעב שי אפורל ה ץומיא בקע םיפסונ םירחא םייונישו הכירעב םיבחרנ םייוניש

EU SmPC

ןכלו סנרפרכ ןולעה הז בתכמל ףרוצמ ,ואולמב אפורל

.םינוכדעה ןומיס אלל

עדימל

ףסונ שי

ןייעל

ןולעב

ל

ר

אפו

ינכדעה

יפכ

רשואש

י"ע

דרשמ

תואירבה

ילארשיה

.

ולעה

אפורל ל חלשנ לבקל ןתינו ,תואירבה דרשמ רתאבש תופורתה רגאמ

ספדומ

לע

.םושירה לעבל הינפ ידי

,הכרבב

'ץיבודיוד ינור

הנוממ תחקור

LUC API DEC18 CL V9

EU SmPC November 2016

1.

NAME OF THE MEDICINAL PRODUCT

Lucentis 10 mg/ml solution for injection in pre-filled syringe.

Lucentis 10 mg/ml solution for injection in a vial.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Pre-filled syringe

One ml contains 10 mg ranibizumab*. One pre-filled syringe contains 0.165 ml, equivalent to 1.65 mg

ranibizumab. The extractable volume of one pre-filled syringe is 0.1 ml. This provides a usable amount to

deliver a single dose of 0.05 ml containing 0.5 mg ranibizumab.

Vial

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.

*Ranibizumab is a humanised monoclonal antibody fragment produced in

Escherichia coli

cells by

recombinant DNA technology.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection.

Clear to slightly opalescent, colourless to pale yellow aqueous solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of patients with neovascular (wet) age-related macular degeneration (AMD)

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

Treatment of adult patients with visual impairment due to diabetic macular oedema (DME)

The treatment of visual impairment due to macular oedema secondary to retinal vein occlusion

(RVO)

4.2

Posology and method of administration

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

Posology

The recommended dose for Lucentis is 0.5 mg given as a single intravitreal injection. This corresponds to

an injection volume of 0.05 ml. The interval between two doses injected into the same eye should be at

least four weeks.

Treatment is initiated with one injection per month until maximum visual acuity is achieved and/or there

are no signs of disease activity.

Thereafter, monitoring and treatment intervals should be determined by the physician and should be based

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on disease activity, as assessed by visual acuity and/or anatomical parameters.

Monitoring for disease activity may include clinical examination, functional testing or imaging techniques

(e.g. optical coherence tomography or fluorescein angiography).

If patients are being treated according to a treat-and-extend regimen, for example, the treatment intervals

can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval

should be extended by two weeks at a time for wet AMD and central RVO (CRVO) or by one month at a

time for DME and branch RVO (BRVO). If disease activity recurs, the treatment interval should be

shortened accordingly.

The treatment of visual impairment due to CNV should be determined individually per patient based on

disease activity. Some patients may only need one injection during the first 12 months; others may need

more frequent treatment, including a monthly injection. For CNV secondary to pathologic myopia (PM),

many patients may only need one or two injections during the first year (see section 5.1).

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

There is some experience of Lucentis administered concomitantly with laser photocoagulation (see

section 5.1). When given on the same day, Lucentis should be administered at least 30 minutes after laser

photocoagulation. Lucentis can be administered in patients who have received previous laser

photocoagulation.

Lucentis and verteporfin photodynamic therapy in CNV secondary to PM

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

Special populations

Hepatic impairment

Lucentis has not been studied in patients with hepatic impairment. However, no special considerations are

needed in this population.

Renal impairment

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

Elderly

No dose adjustment is required in the elderly.

Paediatric population

Lucentis is not indicated for use in children and adolescents

Method of administration

Pre-filled syringe

Single-use pre-filled syringe for intravitreal use only.

The pre-filled syringe contains more than the recommended dose of 0.5 mg. The extractable volume of

the pre-filled syringe (0.1 ml) is not to be used in total. The excess volume should be expelled prior to

injection. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air

bubble along with the excess medicinal product, slowly push the plunger until the edge below the dome

of the rubber stopper is aligned with the black dosing line on the syringe (equivalent to 0.05 ml, i.e.,

0.5 mg ranibizumab).

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EU SmPC November 2016

Vial

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), a

portion of the volume contained in the vial must be discarded prior to administration.

Use of more than one injection from a vial can lead to product contamination and subsequent ocular

infection.

Pre-filled syringe and Vial

Lucentis 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 of surgical

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 for hypersensitivity

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 the periocular skin, eyelid

and ocular surface should be administered prior to the injection, in accordance with local practice.

For information on preparation of Lucentis, see section 6.6.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity,

avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of

0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

Each pre-filled syringe should only be used for the treatment of a single eye.

4.3

Contraindications

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.

4.4

Special warnings and precautions for use

Intravitreal injection-related reactions

Intravitreous injections, including those with Lucentis, have been associated with endophthalmitis,

intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic

cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering

Lucentis. In addition, patients should be monitored during the week following the injection to permit

early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of

endophthalmitis or any of the above mentioned events without delay.

Intraocular pressure increases

Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of

Lucentis. Sustained IOP increases have also been identified (see section 4.8). Both intraocular pressure

and the perfusion of the optic nerve head must be monitored and managed appropriately.

Patients should be informed of the symptoms of these potential adverse reactions and instructed to inform

their physician if they develop signs such as eye pain or increased discomfort, worsening eye redness,

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blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity

to light (see section 4.8).

Bilateral treatment

Limited data on bilateral use of Lucentis (including same-day administration) do not suggest an increased

risk of systemic adverse events compared with unilateral treatment.

Immunogenicity

There is a potential for immunogenicity with Lucentis. Since there is a potential for an increased systemic

exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient

population cannot be excluded. Patients should also be instructed to report if an intraocular inflammation

increases in severity, which may be a clinical sign attributable to intraocular antibody formation.

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

Lucentis should not be administered concurrently with other anti-VEGF medicinal products (systemic or

ocular).

Withholding Lucentis

The dose should be withheld and treatment should not be resumed earlier than the next scheduled

treatment in the event of:

a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment

of visual acuity;

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;

Retinal pigment epithelial tear

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy

for wet AMD and potentially also other forms of CNV, include a large and/or high pigment epithelial

retinal detachment. When initiating ranibizumab therapy, caution should be used in patients with these

risk factors for retinal pigment epithelial tears.

Rhegmatogenous retinal detachment or macular holes

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4

macular holes.

Populations with limited data

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

has not been studied in patients who have previously received intravitreal injections, in patients with

active systemic infections, proliferative diabetic retinopathy, or in patients with concurrent eye conditions

such as retinal detachment or macular hole. There is also no experience of treatment with Lucentis in

LUC API DEC18 CL V9

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diabetic patients with an HbA1c over 12% and uncontrolled hypertension. This lack of information

should be considered by the physician when treating such patients.

There are insufficient data to conclude on the effect of Lucentis in patients with RVO presenting

irreversible ischaemic visual function loss.

In patients with PM, there are limited data on the effect of Lucentis in patients who have previously

undergone unsuccessful verteporfin photodynamic therapy (vPDT) treatment. Also, while a consistent

effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficient data to

conclude on the effect of Lucentis in PM subjects with extrafoveal lesions.

Systemic effects following intravitreal use

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have

been reported following intravitreal injection of VEGF inhibitors.

There are limited data on safety in the treatment of DME, macular oedema due to RVO and CNV

secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be

exercised when treating such patients (see section 4.8)

4.5

Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed.

For the adjunctive use of verteporfin photodynamic therapy (PDT) and Lucentis in wet AMD and PM, see

section 5.1.

For the adjunctive use of laser photocoagulation and Lucentis in DME and BRVO, see sections 4.2 and

5.1.

In clinical studies for the treatment of visual impairment due to DME, the outcome with regard to visual

acuity or central retinal subfield thickness (CSFT) in patients treated with Lucentis was not affected by

concomitant treatment with thiazolidinediones.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/contraception in females

Women of childbearing potential should use effective contraception during treatment.

Pregnancy

For ranibizumab no clinical data on exposed pregnancies are available.

Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to

pregnancy or embryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is

low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as

potentially teratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during

pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to

become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months

after the last dose of ranibizumab before conceiving a child.

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Breast-feeding

It is unknown whether Lucentis is excreted in human milk. Breast-feeding is not recommended during the

use of Lucentis.

Fertility

There are no data available on fertility.

4.7

Effects on ability to drive and use machines

The treatment procedure may induce temporary visual disturbances, which may affect the ability to drive

or use machines (see section 4.8). Patients who experience these signs must not drive or use machines

until these temporary visual disturbances subside.

4.8

Undesirable effects

Summary of the safety profile

The majority of adverse reactions reported following administration of Lucentis are related to the

intravitreal injection procedure.

The most frequently reported ocular adverse reactions following injection of Lucentis are: eye pain,

ocular hyperaemia, increased intraocular pressure, vitritis, vitreous detachment, retinal haemorrhage,

visual disturbance, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in

eyes, 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, retinal

detachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).

The adverse reactions experienced following administration of Lucentis in clinical trials are summarised

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 each

frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations

Very common

Nasopharyngitis

Common

Influenza, Urinary tract infection*

Blood and lymphatic system disorders

Common

Anaemia

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Immune system disorders

Common

Hypersensitivity

Psychiatric disorders

Common

Anxiety

Nervous system disorders

Very common

Headache

Common

Stroke

Eye disorders

Very common

Intraocular inflammation, vitritis, vitreous detachment, retinal

haemorrhage, visual disturbance, eye pain, vitreous floaters,

conjunctival haemorrhage, eye irritation, foreign body

sensation in eyes, lacrimation increased, blepharitis, dry eye,

ocular hyperaemia, 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 capsule opacification,

punctuate keratitis, corneal abrasion, anterior chamber flare,

vision blurred, injection site haemorrhage, eye haemorrhage,

conjunctivitis, conjunctivitis allergic, eye discharge, photopsia,

photophobia, ocular discomfort, eyelid oedema, 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.

Respiratory, thoracic and mediastinal disorders

Common

Cough

Gastrointestinal disorders

Common

Nausea

Skin and subcutaneous tissue disorders

Common

Allergic reactions (rash, urticaria, pruritus, erythema)

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Investigations

Very common

Intraocular pressure increased

Adverse reactions were defined as adverse events (in at least 0.5 percentage points of patients)

which occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with

Lucentis 0.5 mg than in those receiving control treatment (sham or verteporfin PDT).

* observed only in DME population

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Product-class-related adverse reactions

In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse event

potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly

increased in ranibizumab-treated patients. However, there was no consistent pattern among the different

haemorrhages. 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 Lucentis clinical trials in patients with AMD, CNV, DME

and RVO and there were no major differences between the groups treated with ranibizumab compared to

control.

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.

Any suspected adverse event should be reported to the Ministry of Health according to the National

Regulation by using an online form:

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

4.9

Overdose

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 pressure

increased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If an

overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the

attending physician.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

Mechanism of action

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular

endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g.

VEGF

, VEGF

and VEGF

), 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 proliferation and

neovascularisation, as well as vascular leakage, all of which are thought to contribute to the progression

of the neovascular form of age-related macular degeneration, pathologic myopia and CNV or to visual

impairment caused by either diabetic macular oedema or macular oedema secondary to RVO.

Clinical efficacy and safety

Treatment of wet AMD

In wet AMD, the clinical safety and efficacy of Lucentis 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 lesions

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were randomised in a 1:1:1 ratio to receive monthly injections of Lucentis 0.3 mg, Lucentis 0.5 mg or

sham.

In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV lesions were randomised

in a 1:1:1 ratio to receive Lucentis 0.3 mg monthly, Lucentis 0.5 mg monthly or verteporfin PDT (at

baseline and every 3 months thereafter if fluorescein angiography showed persistence 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

(n=238)

Lucentis

0.5 mg

(n=240)

Verteporfin

PDT (n=143)

Lucentis

0.5 mg

(n=140)

Loss of <15 letters in

visual acuity (%)

(maintenance of

vision, primary

endpoint)

Month 12

Month 24

Gain of ≥15 letters in

visual acuity (%)

Month 12

Month 24

Mean change in

visual acuity (letters)

(SD)

Month 12

-10.5 (16.6)

+7.2 (14.4)

-9.5 (16.4)

+11.3 (14.6)

Month 24

-14.9 (18.7)

+6.6 (16.5)

-9.8 (17.6)

+10.7 (16.5)

p<0.01

Figure 1

Mean change in visual acuity from baseline to Month 24 in study FVF2598g

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(MARINA) and study FVF2587g (ANCHOR)

Results from both trials indicated that continued ranibizumab treatment may also be of benefit in patients

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 MARINA and

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 a

1:1:1 ratio to receive Lucentis 0.3 mg, Lucentis 0.5 mg or sham injections once a month for 3 consecutive

doses, followed by a dose administered once every 3 months. From Month 14 of the study, sham-treated

patients were allowed to receive ranibizumab and from Month 19, more frequent treatments were

Month

Mean change in visual acuity ± SE

(letters)

-14.9

+6.6

Study FVF2598g (MARINA)

Month

Mean change in visual acuity ± SE

(letters)

-9.8

+10.7

Study FVF2587g (ANCHOR)

Sham (n=238)

LUCENTIS 0.5 mg (n=240)

Verteporfin PDT (n=143)

LUCENTIS 0.5 mg (n=140)

MARINA

ANCHOR

+ 21.5

+20.5

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possible. Patients treated with Lucentis in PIER received a mean of 10 total treatments.

After an initial increase in visual acuity (following monthly dosing), on average, patients’ visual acuity

declined with quarterly dosing, returning to baseline at Month 12 and this effect was maintained in most

ranibizumab-treated patients (82%) at Month 24. Limited data from sham subjects who later received

ranibizumab suggested that early initiation of treatment may be associated with better preservation of

visual acuity.

Data from two studies (MONT BLANC, BPD952A2308 and DENALI, BPD952A2309) conducted post

approval confirmed the efficacy of Lucentis but did not demonstrate additional effect of the combined

administration of verteporfin (Visudyne PDT) and Lucentis compared to Lucentis monotherapy.

Treatment of visual impairment due to CNV secondary to PM

The clinical safety and efficacy of Lucentis in patients with visual impairment due to CNV in PM have

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 change in

BCVA compared to two preceding monthly evaluations).

Group II (ranibizumab 0.5 mg, dosing regimen driven by “disease activity” criteria defined as

vision impairment attributable to intra- or subretinal fluid or active leakage due to the CNV lesion

as 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 or

2 injections, 34.5% required 3 to 5 injections and 14.7% required 6 to 12 injections over the 12-month

study period. 62.9% of Group II patients did not require injections in the second 6 months of the study.

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

Table 2

Outcomes at Month 3 and 12 (RADIANCE)

Group I

Ranibizumab

0.5 mg

“vision stability”

(n=105)

Group II

Ranibizumab

0.5 mg

“disease activity”

(n=116)

Group III

vPDT

b

(n=55)

Month 3

Mean average BCVA change from Month 1

to Month 3 compared to baseline

(letters)

+10.5

+10.6

+2.2

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

Median

Mean average BCVA change from Month 1

to Month 12 compared to baseline (letters)

+12.8

+12.5

Proportion of patients who gained:

≥15 letters, or reached ≥84 letters in BCVA

53.3%

51.7%

p<0.00001 comparison with vPDT control

Comparative control up to Month 3. Patients randomised to vPDT were allowed to receive ranibizumab

treatment as of Month 3 (in Group III, 38 patients received ranibizumab as of Month 3)

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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 Lucentis in patients with visual impairment due to CNV have been

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 disease

activity as assessed by visual acuity and/or anatomical parameters (e.g. VA impairment, intra/sub-

retinal fluid, haemorrhage or leakage);

sham injection at baseline, followed by an individualised treatment regimen driven by disease

activity.

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

Mean VA change from BL + - SE (letters)

Month

Ranibizumab 0.5 mg Group I

by stabilisation (n=105)

Verteporfin PDT Group III (n=55)

Ranibizumab 0.5 mg Group II

by disease activity (n=116)

Ranibizumab 0.5 mg/Verteporfin PDT

Group III from Month 3 onwards (n=55)

Ranibizumab allowed

+1.4

+12.1

+12.5

+14.4

+13.8

+9.3

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Key outcome measures from MINERVA are summarised in Table 3 and Figure 3. An improvement of

vision 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 in those

patients in the sham arm who were eligible to receive ranibizumab from Month 2 onwards. In the sham

arm 7 out of 59 patients did not receive any treatment with ranibizumab in the study eye during the 12-

month period.

Table 3

Outcomes at Month 2 (MINERVA)

Ranibizumab

0.5 mg (n=119)

Sham (n=59)

Mean BCVA change from baseline to Month 2

9.5 letters

-0.4 letters

Patients gaining ≥15 letters from baseline or reaching

84 letters at Month 2

31.4%

12.3%

Patients not losing >15 letters from baseline at Month 2

99.2%

94.7%

Reduction in CSFT

from baseline to Month 2

77 µm

-9.8 µm

One-sided p<0.001 comparison with sham control

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 both overall

Double-masked,

randomised,

Ranibizumab vs Sham

Open-label,

Ranibizumab allowed in both arms

Month

Treatment:

Ranibizumab 0.5 mg (N=119)

Sham (N=59)

Mean BCVA change +/- 95% CI (letters)

* Observed mean BCVA may differ from the Least Squares Mean BCVA (applicable only at Month 2)

-0.3*

9.4*

11.0

9.3

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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

sham [letters]

Patient numbers [n]

(treatment +sham)

Overall

Angioid streaks

14.6

Post-inflammatory retinochoroidopathy

Central serous chorioretinopathy

Idiopathic chorioretinopathy

11.4

Miscellaneous aetiologies

10.6

encompasses different aetiologies of low frequency of occurrence not included in the other subgroups

Treatment of visual impairment due to DME

The efficacy and safety of Lucentis have been assessed in three randomised, controlled studies of at least

12 months duration. A total of 868 patients (708 active and 160 control) were enrolled in these studies.

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 pooled ranibizumab-

treated patients (n=102), compared to -0.1 (±9.77) letters for sham-treated patients; and the 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 receive

ranibizumab 0.5 mg monotherapy and sham laser photocoagulation, combined ranibizumab 0.5 mg and

laser photocoagulation or sham injection and laser photocoagulation. 240 patients, who had previously

completed the 12-month RESTORE study, were enrolled in the open-label, multicentre 24-month

extension (RESTORE Extension) study. Patients were treated with ranibizumab 0.5 mg

pro re nata

(PRN) in the same eye as the core study (D2301 RESTORE).

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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)

BL=baseline; SE=standard error of mean

* Difference in least square means, p

<

0.0001/0.0004 based on two-sided stratified Cochran-Mantel-

Haenszel test

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 from

treatment with ranibizumab compared to laser photocoagulation.

Table 5

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

Mean VA change from BL +/- SE (letters)

Month

Treatment group

Ranibizumab 0.5 mg (N = 115)

Ranibizumab 0.5 mg + Laser (N = 118)

Laser (N = 110)

+ 6.8/+ 6.4

+ 6.2/+ 5.4*

+ 0.9

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E1 (RESTORE Extension)

Outcome measures at Month 12 compared

to baseline in study D2301 (RESTORE)

Ranibizumab

0.5 mg

n=115

Ranibizumab

0.5 mg + Laser

n=118

Laser

n=110

Mean average change in BCVA from

Month 1 to Month 12

6.1 (6.4)

5.9 (7.9)

0.8 (8.6)

Mean change in BCVA at Month 12 (

6.8 (8.3)

6.4 (11.8)

0.9 (11.4)

Gain of ≥15 letters or BCVA ≥84 letters at

Month 12 (%)

22.6

22.9

Mean number of injections (Months 0-11)

7.3 (sham)

Outcome measure at Month 36 compared

to D2301 (RESTORE) baseline in study

D2301-E1 (RESTORE Extension)

Prior ranibizumab

0.5 mg

n=83

Prior ranibizumab

0.5 mg + laser

n=83

Prior laser

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

Month 36 (%)

27.7

30.1

21.6

Mean number of injections

(Months 12-35)*

p<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 extension phase

was 19%, 25% and 20% in the prior ranibizumab, prior ranibizumab + laser and prior laser groups,

respectively.

Statistically significant patient-reported benefits for most vision-related functions were observed with

ranibizumab (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 consistent with

the known Lucentis 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 three consecutive

monthly assessments. On TE, ranibizumab was administered at treatment intervals of 2-3 months. In all

groups, monthly treatment was re-initiated upon a decrease in BCVA due to DME progression 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

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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

compared to baseline

TE ranibizumab

0.5 mg + laser

n=117

TE ranibizumab

0.5 mg alone

n=125

PRN ranibizumab

0.5 mg

n=117

Mean average change

in BCVA from

Month 1 to Month 12

(SD)

5.9 (5.5)

6.1 (5.7)

6.2 (6.0)

Mean average change

in BCVA from

Month 1 to Month 24

(SD)

6.8 (6.0)

6.6 (7.1)

7.0 (6.4)

Mean change in BCVA

at Month 24 (SD)

8.3 (8.1)

6.5 (10.9)

8.1 (8.5)

Gain of ≥15 letters or

BCVA ≥84 letters at

Month 24(%)

25.6

28.0

30.8

Mean number of

injections

(months 0-23)

12.4

12.8

10.7

p<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 CSFT in

all the treatment groups.

Treatment of visual impairment due to macular oedema secondary to RVO

The clinical safety and efficacy of Lucentis in patients with visual impairment due to macular oedema

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. After 6 months, patients in the

sham-control arms switched to 0.5 mg ranibizumab

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Key outcome measures from BRAVO and CRUISE are summarised in Table 7 and Figures 5 and 6.

Table 7

Outcomes at Month 6 and 12 (BRAVO and CRUISE)

BRAVO

CRUISE

Sham/Lucentis

0.5 mg

(n=132)

Lucentis

0.5 mg

(n=131)

Sham/Lucentis

0.5 mg

(n=130)

Lucentis

0.5 mg

(n=130)

Mean change in visual acuity

at Month 6

(letters) (SD)

(primary endpoint)

7.3 (13.0)

18.3 (13.2)

0.8 (16.2)

14.9 (13.2)

Mean change in BCVA at

Month 12 (letters) (SD)

12.1 (14.4)

18.3 (14.6)

7.3 (15.9)

13.9 (14.2)

Gain of ≥15 letters in visual

acuity at Month 6

28.8

61.1

16.9

47.7

Gain of ≥15 letters in visual

acuity at Month 12 (%)

43.9

60.3

33.1

50.8

Proportion (%) receiving laser

rescue over 12 months

61.4

34.4

p<0.0001for both studies

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Figure 5

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

BL=baseline; SE=standard error of mean

Mean VA

change from

BL +- SE

(letters)

Month

Treatment group

Sham/Ranibizumab 0.5 mg (n=132)

Ranibizumab 0.5 mg (n=131)

sham-controlled arm

crossed-over to

ranibizumab

sham-controlled

+ 7.3

+ 18.3

+ 18.3

+ 12.1

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Figure 6

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

BL=baseline; SE=standard error of mean

In both studies, the improvement of vision was accompanied by a continuous and significant reduction in

the macular oedema as measured by central retinal thickness.

In patients with CRVO (CRUISE and extension study HORIZON): Subjects treated with sham in the first

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 were

observed with ranibizumab treatment over the control group as measured by the NEI VFQ-25.

The long-term (24 months) clinical safety and efficacy of Lucentis in patients with visual impairment 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 dosing regimen 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 with adjunctive laser

photocoagulation to laser photocoagulation alone. After 6 months, subjects in the laser arm could receive

0.5 mg ranibizumab. CRYSTAL was a single-arm study with 0.5 mg ranibizumab monotherapy.

Month

Treatment group

Sham/Ranibizumab 0.5 mg (n=130)

Ranibizumab 0.5 mg (n=130)

+ 14.9

+ 0.8

sham-controlled

sham-controlled arm

+ 13.9

+ 7.3

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Key outcome measures from BRIGHTER and CRYSTAL are shown in Table 8.

Table 8

Outcomes at Months 6 and 24 (BRIGHTER and CRYSTAL)

BRIGHTER

CRYSTAL

Lucentis 0.5 mg

N=180

Lucentis 0.5 mg +

Laser

N=178

Laser*

N=90

Lucentis 0.5 mg

N=356

Mean change in

BCVA at

Month 6

(letters)

(SD)

+14.8

(10.7)

+14.8

(11.13)

+6.0

(14.27)

+12.0

(13.95)

Mean change in

BCVA at

Month 24

(letters) (SD)

+15.5

(13.91)

+17.3

(12.61)

+11.6

(16.09)

+12.1

(18.60)

Gain of

≥15 letters in

BCVA at

Month 24 (%)

52.8

59.6

43.3

49.2

Mean number of

injections (SD)

(months 0-23)

11.4

(5.81)

11.3 (6.02)

13.1 (6.39)

p<0.0001for both comparisons in BRIGHTER at Month 6: Lucentis 0.5 mg vs Laser and

Lucentis 0.5 mg + Laser vs Laser.

p<0.0001for null hypothesis in CRYSTAL that the mean change at Month 24 from baseline is

zero.

Starting at Month 6 ranibizumab 0.5 mg treatment was allowed (24 patients were treated with

laser only).

In BRIGHTER, ranibizumab 0.5 mg with adjunctive laser therapy demonstrated non-inferiority versus

ranibizumab 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 subfield

thickness 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 ranibizumab

monotherapy 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 with ranibizumab

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 mg ranibizumab

monotherapy regardless of their disease duration in both BRIGHTER and CRYSTAL. In patients with

<3 months disease duration an increase in visual acuity of 13.3 and 10.0 letters was seen at Month 1; and

17.7 and 13.2 letters at Month 24 in BRIGHTER and CRYSTAL, respectively. The corresponding visual

acuity gain in patients with ≥12 months disease duration was 8.6 and 8.4 letters in 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 the

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known Lucentis safety profile.

Paediatric population

The safety and efficacy of ranibizumab have not yet been established in paediatric patients.

5.2

Pharmacokinetic properties

Following monthly intravitreal administration of Lucentis to patients with neovascular AMD, serum

concentrations of ranibizumab were generally low, with maximum levels (C

) generally below 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). C

was dose proportional over the dose range of

0.05 to 1.0 mg/eye. Serum concentrations in a limited number of DME patients indicate that a slightly

higher systemic exposure cannot be excluded compared to those observed in neovascular AMD patients.

Serum ranibizumab concentrations in RVO patients were similar or slightly higher compared to those

observed in neovascular AMD patients.

Based on analysis of population pharmacokinetics and disappearance of ranibizumab from serum for

patients with neovascular AMD treated with the 0.5 mg dose, the average vitreous elimination half-life of

ranibizumab is approximately 9 days. Upon monthly intravitreal administration of Lucentis 0.5 mg/eye,

serum ranibizumab C

, attained approximately 1 day after dosing, is predicted to generally range

between 0.79 and 2.90 ng/ml, and C

is predicted to generally range between 0.07 and 0.49 ng/ml.

Serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal

ranibizumab concentrations.

Patients with renal impairment: No formal studies have been conducted to examine the pharmacokinetics

of Lucentis in patients with renal impairment. In a population pharmacokinetic analysis 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 RVO patients, 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 of Lucentis

in patients with hepatic impairment.

5.3

Preclinical safety data

Bilateral intravitreal administration of ranibizumab to cynomolgus monkeys at doses between

0.25 mg/eye and 2.0 mg/eye once every 2 weeks for up to 26 weeks resulted in dose-dependent ocular

effects.

Intraocularly, there were dose-dependent increases in anterior chamber flare and cells with a peak 2 days

after injection. The severity of the inflammatory response generally diminished with subsequent

injections or during recovery. In the posterior segment, there were vitreal cell infiltration and floaters,

which also tended to be dose-dependent and generally persisted to the end of the treatment period. In the

26-week study, the severity of the vitreous inflammation increased with the number of injections.

However, evidence of reversibility was observed after recovery. The nature and timing 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 relatively long period of intense

inflammation, suggesting that the lens changes were secondary to severe inflammation. A transient

increase in post-dose intraocular pressure was observed following intravitreal injections, irrespective of

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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 posterior segment

changes diminished, and in some instances resolved, during the recovery period.

Following intravitreal administration, no signs of systemic toxicity were detected. Serum and vitreous

antibodies 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

no effect on weight or structure of the placenta, although, based on its pharmacological effect

ranibizumab should be regarded as potentially teratogenic and embryo-/foetotoxic.

The absence of ranibizumab-mediated effects on embryo-foetal development is plausibly related mainly

to the inability of the Fab fragment to cross the placenta. Nevertheless, a case was described with high

maternal ranibizumab serum levels and presence of ranibizumab in foetal serum, suggesting that 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 as diabetes) may modify the

permeability of the placenta towards a Fab fragment, the study should be interpreted with caution.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

α,α-trehalose dihydrate

L-histidine HCl monohydrate

L-histidine

Polysorbate 20

Water for injections

6.2

Incompatibilities

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

products.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Pre-filled syringe

Store in a refrigerator (2

C - 8

Do not freeze.

Keep the pre-filled syringe in its sealed tray in the carton in order to protect from light.

Vial

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Store in a refrigerator (2

C - 8

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.

6.5

Nature and contents of container

Pre-filled syringe

0.165 ml sterile solution in a pre-filled syringe (glass) with a bromobutyl rubber plunger stopper and a

syringe cap consisting of a white, tamper-evident rigid seal with a grey bromobutyl rubber tip cap

including a Luer lock adapter. The pre-filled syringe has a plunger rod and a finger grip, and is packed in

a sealed tray.

Pack size of one pre-filled syringe.

Vial + injection kit

One vial (type I glass) with a stopper (chlorobutyl rubber) containing 0.23 ml sterile solution, 1 blunt

filter needle (18G, 5 µm), 1 injection needle (30G) and 1 plastic syringe (1 ml).

Vial-only pack

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

Vial + filter needle pack

One vial (type I glass) with a stopper (chlorobutyl rubber) containing 0.23 ml sterile solution and 1 blunt

filter needle (18G, 5 µm).

6.6

Special precautions for disposal and other handling

Pre-filled syringe

The pre-filled syringe is for single use only. The pre-filled syringe is sterile. Do not use the product if the

packaging is damaged. The sterility of the pre-filled syringe cannot be guaranteed unless the tray remains

sealed. Do not use the pre-filled syringe if the solution is discoloured, cloudy or contains particles.

The pre-filled syringe contains more than the recommended dose of 0.5 mg. The extractable volume of

the pre-filled syringe (0.1 ml) is not to be used in total. The excess volume should be expelled prior to

injection. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air

bubble along with the excess medicinal product, slowly push the plunger until the edge below the dome

of the rubber stopper is aligned with the black dosing line on the syringe (equivalent to 0.05 ml, i.e.,

0.5 mg ranibizumab).

For the intravitreal injection, a 30G sterile injection needle should be used.

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To prepare Lucentis for intravitreal administration, please adhere to the instructions for use:

Introduction

Read all the instructions carefully before using the pre-filled syringe.

The pre-filled syringe is for single use only. The pre-filled syringe is sterile. Do

not use the product if the packaging is damaged. The opening of the sealed tray

and all subsequent steps should be done under aseptic conditions.

Note: The dose must be set to 0.05 ml.

Pre-filled

syringe

description

Prepare

Make sure that the pack contains:

a sterile pre-filled syringe in a sealed tray.

Peel the lid off the syringe tray and, using aseptic technique, carefully

remove the syringe.

Check syringe

Check that:

the syringe cap is not detached from the

Luer lock.

the syringe is not damaged.

the solution looks clear, colourless to pale

yellow and does not contain any particles.

If any of the above is not true, discard the

pre-filled syringe and use a new one.

Remove

syringe cap

Snap off (do not turn or twist) the syringe

cap (see Figure 2).

Dispose of the syringe cap (see Figure 3).

Figure 2

Syringe cap

0.05 ml dose mark

Finger grip

Plunger rod

Rubber stopper

Luer lock

Figure 1

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Figure 3

Attach needle

Attach a 30G x ½″ sterile injection needle

firmly onto the syringe by screwing it

tightly onto the Luer lock (see Figure 4).

Carefully remove the needle cap by

pulling it straight off (see Figure 5).

Note: Do not wipe the needle at any time.

Figure 4

Figure 5

Dislodge air

bubbles

Hold the syringe upright.

If there are any air bubbles, gently tap the

syringe with your finger until the bubbles

rise to the top (see Figure 6).

Figure 6

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Set dose

Hold the syringe at eye level and

carefully push the plunger until the

edge

below the dome of the rubber stopper

is aligned with the dose mark (see

Figure 7). This will expel the air and the

excess solution and set the dose to

0.05 ml.

Note: The plunger rod is not attached to the

rubber stopper – this is to prevent air being

drawn into the syringe.

Figure 7

Inject

The injection procedure should be carried out under aseptic conditions.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus

into the vitreous cavity, avoiding the horizontal meridian and aiming towards

the centre of the globe.

Inject slowly until the rubber stopper reaches the bottom of the syringe to

deliver the volume of 0.05 ml.

A different scleral site should be used for subsequent injections.

After injection, do not recap the needle or detach it from the syringe. Dispose

of the used syringe together with the needle in a sharps disposal container or

in accordance with local requirements.

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Vial + injection kit

The vial, injection needle, filter needle and syringe are for single use only. Re-use may lead to infection

or other illness/injury. All components are sterile. Any component with packaging showing signs of

damage or tampering must not be used. The sterility cannot be guaranteed unless the component

packaging seal remains intact.

Vial-only pack

The vial is for single use only. After injection any unused product must be discarded. Any vial showing

signs of damage or tampering must not be used. The sterility cannot be guaranteed unless the packaging

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)

an injection needle (30G x ½″).

These medical devices are not included within this pack.

Vial + filter needle pack

The vial and filter needle are for single use only. Re-use may lead to infection or other illness/injury. All

components are sterile. Any component with packaging showing signs of damage or tampering must not

be used. The sterility cannot be guaranteed unless the component packaging seal remains intact.

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

a 5 µm filter needle (18G x 1½″, 1.2 mm x 40 mm, provided)

a 1 ml sterile syringe (including a 0.05 ml mark, not included within this pack)

an injection needle (30G x ½″; not included within this pack)

To prepare Lucentis for intravitreal administration, please adhere to the following instructions:

1. Before withdrawal, the outer part of the rubber stopper of

the vial should be disinfected.

2. Assemble a 5 µm filter needle (18G x 1½″,

1.2 mm x 40 mm, 5 µm) onto a 1 ml syringe using aseptic

technique. Push the blunt filter needle into the centre of the

vial stopper until the needle touches the bottom edge of the

vial.

3. Withdraw all the liquid from the vial, keeping the vial in

an upright position, slightly inclined to ease complete

withdrawal.

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4. Ensure that the plunger rod is drawn sufficiently back

when emptying the vial in order to completely 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 be used for the intravitreal injection.

6. Aseptically and firmly assemble an injection needle

(30G x ½″, 0.3 mm x 13 mm) onto the syringe.

7. Carefully remove the cap from the injection needle

without disconnecting the injection needle from 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

from the syringe and adjust the dose to the 0.05 ml mark on

the syringe. The syringe is ready for injection.

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

the plunger.

The injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous cavity,

avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of

0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together

with the needle in a sharps disposal container or in accordance with local requirements.

0.05 ml

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7.

REGISTRATION HOLDER

Novartis Israel Ltd., 36 Shacham St., Petach-Tikva

8.

REGISTRATION NUMBER

136-75-31520

9.

MANUFACTURER

Novartis Pharma Stein AG, Stein, Switzerland for Novartis Pharma AG, Basel, Switzerland

This leaflet format has been determined by the Ministry of Health and the content has been

checked and approved in December 2018.

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1.

NAME OF THE MEDICINAL PRODUCT

Lucentis 10 mg/ml solution for injection in pre-filled syringe.

Lucentis 10 mg/ml solution for injection in a vial.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Pre-filled syringe

One ml contains 10 mg ranibizumab*. One pre-filled syringe contains 0.165 ml, equivalent to 1.65 mg

ranibizumab. The extractable volume of one pre-filled syringe is 0.1 ml. This provides a usable amount to

deliver a single dose of 0.05 ml containing 0.5 mg ranibizumab.

Vial

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

to adult

patients and a single dose of 0.02 ml containing 0.2 mg ranibizumab to preterm infants.

*Ranibizumab is a humanised monoclonal antibody fragment produced in

Escherichia coli

cells by

recombinant DNA technology.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection.

Clear to slightly opalescent, colourless to pale yellow aqueous solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of patients with neovascular (wet) age-related macular degeneration (AMD)

Treatment of adult patients with visual impairment due to diabetic macular oedema (DME)

The treatment of visual impairment due to macular oedema secondary to retinal vein occlusion

(RVO)

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

Lucentis is indicated in preterm infants for:

The treatment of retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II

(stage 3+) or AP-ROP (aggressive posterior ROP) disease.

4.2

Posology and method of administration

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

Posology

Adults

The recommended dose for Lucentis in adults is 0.5 mg given as a single intravitreal injection. This

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corresponds to an injection volume of 0.05 ml. The interval between two doses injected into the same eye

should be at least four weeks.

Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved

and/or there are no signs of disease activity.

Thereafter, monitoring and treatment intervals should be determined by the physician and should be based

on disease activity, as assessed by visual acuity and/or anatomical parameters.

Monitoring for disease activity may include clinical examination, functional testing or imaging techniques

(e.g. optical coherence tomography or fluorescein angiography).

If patients are being treated according to a treat-and-extend regimen, for example, the treatment intervals

can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval

should be extended by two weeks at a time for wet AMD and central RVO (CRVO) or by one month at a

time for DME and branch RVO (BRVO). If disease activity recurs, the treatment interval should be

shortened accordingly.

The treatment of visual impairment due to CNV should be determined individually per patient based on

disease activity. Some patients may only need one injection during the first 12 months; others may need

more frequent treatment, including a monthly injection. For CNV secondary to pathologic myopia (PM),

many patients may only need one or two injections during the first year (see section 5.1).

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

There is some experience of Lucentis administered concomitantly with laser photocoagulation (see

section 5.1). When given on the same day, Lucentis should be administered at least 30 minutes after laser

photocoagulation. Lucentis can be administered in patients who have received previous laser

photocoagulation.

Lucentis and verteporfin photodynamic therapy in CNV secondary to PM

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

Preterm infants

The recommended dose for Lucentis in preterm infants is 0.2 mg given as an intravitreal injection. This

corresponds to an injection volume of 0.02 ml. In preterm infants treatment of ROP is initiated with a

single injection per eye and may be given bilaterally on the same day. In total, up to three injections per

eye may be administered within six months of treatment initiation if there are signs of disease activity.

Most patients (78%) in the clinical study received one injection per eye. The administration of more than

three injections per eye has not been studied. The interval between two doses injected into the same eye

should be at least four weeks.

Special populations

Hepatic impairment

Lucentis has not been studied in patients with hepatic impairment. However, no special considerations are

needed in this population.

Renal impairment

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

Elderly

No dose adjustment is required in the elderly.

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Paediatric population

Lucentis is not indicated for use in children and adolescents.

Method of administration

Pre-filled syringe

Single-use pre-filled syringe for intravitreal use only.

The pre-filled syringe contains more than the recommended dose of 0.5 mg. The extractable volume of

the pre-filled syringe (0.1 ml) is not to be used in total. The excess volume should be expelled prior to

injection. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air

bubble along with the excess medicinal product, slowly push the plunger until the edge below the dome

of the rubber stopper is aligned with the black dosing line on the syringe (equivalent to 0.05 ml, i.e.,

0.5 mg ranibizumab).

Vial

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

for adults

and 0.02 ml for preterm infants), a portion of the volume contained in the vial must be discarded prior to

administration.

Use of more than one injection from a vial can lead to product contamination and subsequent ocular

infection.

Pre-filled syringe and Vial

Lucentis 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 of surgical

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 for hypersensitivity

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 the periocular skin, eyelid

and ocular surface should be administered prior to the injection, in accordance with local practice.

For information on preparation of Lucentis, see section 6.6.

Adults

In adults the injection needle should be inserted 3.5-4.0 mm posterior to the limbus into the vitreous

cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume

of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.

Each pre-filled syringe should only be used for the treatment of a single eye.

Paediatric population

In preterm infants, the injection needle should be inserted into the eye 1.0 to 2.0 mm posterior to the

limbus, with the needle pointing towards the optic nerve. The injection volume of 0.02 ml is then

delivered.

4.3

Contraindications

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.

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Patients with active severe intraocular inflammation.

4.4

Special warnings and precautions for use

Intravitreal injection-related reactions

Intravitreous injections, including those with Lucentis, have been associated with endophthalmitis,

intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic

cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering

Lucentis. In addition, patients should be monitored during the week following the injection to permit

early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of

endophthalmitis or any of the above mentioned events without delay.

Intraocular pressure increases

In adults transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of

Lucentis. Sustained IOP increases have also been identified (see section 4.8). Both intraocular pressure

and the perfusion of the optic nerve head must be monitored and managed appropriately.

Patients should be informed of the symptoms of these potential adverse reactions and instructed to inform

their physician if they develop signs such as eye pain or increased discomfort, worsening eye redness,

blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity

to light (see section 4.8).

Bilateral treatment

Limited data on bilateral use of Lucentis (including same-day administration) do not suggest an increased

risk of systemic adverse events compared with unilateral treatment.

Immunogenicity

There is a potential for immunogenicity with Lucentis. Since there is a potential for an increased systemic

exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient

population cannot be excluded. Patients should also be instructed to report if an intraocular inflammation

increases in severity, which may be a clinical sign attributable to intraocular antibody formation.

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

Lucentis should not be administered concurrently with other anti-VEGF medicinal products (systemic or

ocular).

Withholding Lucentis in adults

The dose should be withheld and treatment should not be resumed earlier than the next scheduled

treatment in the event of:

a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment

of visual acuity;

an intraocular pressure of ≥30 mmHg;

a retinal break;

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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;

Retinal pigment epithelial tear

Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy

for wet AMD and potentially also other forms of CNV, include a large and/or high pigment epithelial

retinal detachment. When initiating ranibizumab therapy, caution should be used in patients with 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 or 4

macular holes.

Paediatric population

The warnings and precautions for adults also apply to preterm infants with ROP. The long-term safety

profile in preterm infants has not been established.

Populations with limited data

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

has not been studied in patients who have previously received intravitreal injections, in patients with

active systemic infections, proliferative diabetic retinopathy, or in patients with concurrent eye conditions

such as retinal detachment or macular hole. There is also no experience of treatment with Lucentis in

diabetic patients with an HbA1c over 12% and uncontrolled hypertension. This lack of information

should be considered by the physician when treating such patients.

There are insufficient data to conclude on the effect of Lucentis in patients with RVO presenting

irreversible ischaemic visual function loss.

In patients with PM, there are limited data on the effect of Lucentis in patients who have previously

undergone unsuccessful verteporfin photodynamic therapy (vPDT) treatment. Also, while a consistent

effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficient data to

conclude on the effect of Lucentis in PM subjects with extrafoveal lesions.

Systemic effects following intravitreal use

Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have

been reported following intravitreal injection of VEGF inhibitors.

There are limited data on safety in the treatment of DME, macular oedema due to RVO and CNV

secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be

exercised when treating such patients (see section 4.8)

4.5

Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed.

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For the adjunctive use of verteporfin photodynamic therapy (PDT) and Lucentis in wet AMD and PM, see

section 5.1.

For the adjunctive use of laser photocoagulation and Lucentis in DME and BRVO, see sections 4.2 and

5.1.

In clinical studies for the treatment of visual impairment due to DME, the outcome with regard to visual

acuity or central retinal subfield thickness (CSFT) in patients treated with Lucentis was not affected by

concomitant treatment with thiazolidinediones.

Paediatric population

No interaction studies have been performed.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/contraception in females

Women of childbearing potential should use effective contraception during treatment.

Pregnancy

For ranibizumab no clinical data on exposed pregnancies are available.

Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to

pregnancy or embryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is

low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as

potentially teratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during

pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to

become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months

after the last dose of ranibizumab before conceiving a child.

Breast-feeding

It is unknown whether Lucentis is excreted in human milk. Breast-feeding is not recommended during the

use of Lucentis.

Fertility

There are no data available on fertility.

4.7

Effects on ability to drive and use machines

The treatment procedure may induce temporary visual disturbances, which may affect the ability to drive

or use machines (see section 4.8). Patients who experience these signs must not drive or use machines

until these temporary visual disturbances subside.

4.8

Undesirable effects

Summary of the safety profile

The majority of adverse reactions reported following administration of Lucentis are related to the

intravitreal injection procedure.

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The most frequently reported ocular adverse reactions following injection of Lucentis are: eye pain,

ocular hyperaemia, increased intraocular pressure, vitritis, vitreous detachment, retinal haemorrhage,

visual disturbance, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in

eyes, 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, retinal

detachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).

The adverse reactions experienced following administration of Lucentis in clinical trials are summarised

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 each

frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations

Very common

Nasopharyngitis

Common

Influenza, Urinary tract infection*

Blood and lymphatic system disorders

Common

Anaemia

Immune system disorders

Common

Hypersensitivity

Psychiatric disorders

Common

Anxiety

Nervous system disorders

Very common

Headache

Common

Stroke

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Eye disorders

Very common

Intraocular inflammation, vitritis, vitreous detachment, retinal

haemorrhage, visual disturbance, eye pain, vitreous floaters,

conjunctival haemorrhage, eye irritation, foreign body

sensation in eyes, lacrimation increased, blepharitis, dry eye,

ocular hyperaemia, 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 capsule opacification,

punctuate keratitis, corneal abrasion, anterior chamber flare,

vision blurred, injection site haemorrhage, eye haemorrhage,

conjunctivitis, conjunctivitis allergic, eye discharge, photopsia,

photophobia, ocular discomfort, eyelid oedema, 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.

Respiratory, thoracic and mediastinal disorders

Common

Cough

Gastrointestinal disorders

Common

Nausea

Skin and subcutaneous tissue disorders

Common

Allergic reactions (rash, urticaria, pruritus, erythema)

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Investigations

Very common

Intraocular pressure increased

Adverse reactions were defined as adverse events (in at least 0.5 percentage points of patients)

which occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with

Lucentis 0.5 mg than in those receiving control treatment (sham or verteporfin PDT).

* observed only in DME population

Product-class-related adverse reactions

In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse event

potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly

increased in ranibizumab-treated patients. However, there was no consistent pattern among the different

haemorrhages. 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 Lucentis clinical trials in patients with AMD, CNV, DME

and RVO and there were no major differences between the groups treated with ranibizumab compared to

control.

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Paediatric population

The safety of Lucentis 0.2 mg was studied in a 6-month clinical trial (RAINBOW), which included

73 preterm infants with ROP treated with ranibizumab 0.2 mg (see section 5.1). Ocular adverse reactions

reported in more than one patient treated with ranibizumab 0.2 mg were retinal haemorrhage and

conjunctival haemorrhage. Non-ocular adverse reactions reported in more than one patient treated with

ranibizumab 0.2 mg were nasopharyngitis, anaemia, cough, urinary tract infection and allergic reactions.

Adverse reactions established for adult indications are considered applicable to preterm infants with ROP,

though not all were observed in the RAINBOW trial. The long-term safety profile in preterm infants has

not been established.

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.

Any suspected adverse event should be reported to the Ministry of Health according to the National

Regulation by using an online form: https://sideeffects.health.gov.il

4.9

Overdose

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 pressure

increased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If an

overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the

attending physician.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

Mechanism of action

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular

endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g.

VEGF

, VEGF

and VEGF

), 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 proliferation and

neovascularisation, as well as vascular leakage, all of which are thought to contribute to the progression

of the neovascular form of age-related macular degeneration, pathologic myopia and CNV or to visual

impairment caused by either diabetic macular oedema or macular oedema secondary to RVO

in adults and

retinopathy of prematurity in preterm infants.

Clinical efficacy and safety

Treatment of wet AMD

In wet AMD, the clinical safety and efficacy of Lucentis 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 lesions

were randomised in a 1:1:1 ratio to receive monthly injections of Lucentis 0.3 mg, Lucentis 0.5 mg or

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sham.

In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV lesions were randomised

in a 1:1:1 ratio to receive Lucentis 0.3 mg monthly, Lucentis 0.5 mg monthly or verteporfin PDT (at

baseline and every 3 months thereafter if fluorescein angiography showed persistence 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

(n=238)

Lucentis

0.5 mg

(n=240)

Verteporfin

PDT (n=143)

Lucentis

0.5 mg

(n=140)

Loss of <15 letters in

visual acuity (%)

(maintenance of

vision, primary

endpoint)

Month 12

Month 24

Gain of ≥15 letters in

visual acuity (%)

Month 12

Month 24

Mean change in

visual acuity (letters)

(SD)

Month 12

-10.5 (16.6)

+7.2 (14.4)

-9.5 (16.4)

+11.3 (14.6)

Month 24

-14.9 (18.7)

+6.6 (16.5)

-9.8 (17.6)

+10.7 (16.5)

p<0.01

Figure 1

Mean change in visual acuity from baseline to Month 24 in study FVF2598g