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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT Lucentis 10 mg/ml solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml contains 10 mg ranibizumab. Each vial contains 3.0 mg of ranibizumab in 0.3 ml solution. Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection Sterile, clear, colourless to pale yellow aqueous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Lucentis is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD) (see section 5.1). 4.2 Posology and method of administration Single-use vial for intravitreal use only. Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections. The recommended dose for Lucentis is 0.5 mg (0.05 ml). Lucentis treatment is initiated with a loading phase of one injection per month for three consecutive months, followed by a maintenance phase in which patients should be monitored for visual acuity on a monthly basis. If the patient experiences a loss of greater than 5 letters in visual acuity (ETDRS or one Snellen line equivalent), Lucentis should be administered. The interval between two doses should not be shorter than 1 month. As with all medicinal products for parenteral use, Lucentis should be inspected visually for particulate matter and discoloration prior to administration. Before treatment, the patient should be instructed to self-administer antimicrobial drops (four times daily for 3 days before and following each injection). 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). The periocular skin, eyelid and ocular surface should be disinfected and adequate anaesthesia and a broad-spectrum topical microbicide should be administered prior to the injection. Before withdrawal, the outer part of the rubber stopper of the vial should be disinfected. A 5 µm filter needle

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should be assembled onto a 1 ml syringe. The entire contents of the Lucentis vial should be withdrawn, keeping the vial in an upright position. The filter needle should be discarded after withdrawal of the vial contents and should not be used for the intravitreal injection. The filter needle should then be replaced with a sterile needle for the intravitreal injection. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 ml on the syringe. 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. Additional information on 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). Children and adolescents Lucentis is not recommended for use in children and adolescents due to a lack of data on safety and efficacy in these sub-populations. Elderly No dose adjustment is required in the elderly. Ethnicity Experience with treatment is limited in groups other than Caucasians. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. Patients with active or suspected ocular or periocular infections. Patients with active severe intraocular inflammation. 4.4 Special warnings and precautions for use Treatment with Lucentis is for intravitreal injection only. 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. Increases in intraocular pressure have been seen within 60 minutes of injection of Lucentis (see section 4.8). Both intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately. The safety and efficacy of Lucentis therapy administered to both eyes concurrently have not been studied. If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events. As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis. Patients should be

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instructed to report if an intraocular inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody formation. Lucentis has not been studied in patients who have previously received intravitreal injections. Lucentis should not be administered concurrently with other anti-VEGF agents (systemic or ocular). 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.

Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes. 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, see section 5.1. 4.6 Pregnancy and lactation Pregnancy There are no data from the use of ranibizumab in pregnant women. There are no animal studies. The systemic exposure to ranibizumab is expected to be very 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. Women of childbearing potential Women of childbearing potential should use effective contraception during treatment. Lactation It is not known whether Lucentis is excreted in human milk. Breast-feeding is not recommended during the use of Lucentis. 4.7 Effects on ability to drive and use machines The Lucentis 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 A total of 1,323 patients were enrolled in the three phase III studies. A total of 859 patients had at least 12 months exposure and 452 had 24 months exposure to Lucentis. 9,200 Lucentis injections were administered during the first treatment year and more than 13,000 injections when the second year of study FVF2598g (MARINA) was included. 440 patients were treated with the recommended dose of 0.5 mg. Serious adverse events related to the injection procedure and occurring in <0.1% of intravitreal injections included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract

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(see section 4.4). Other serious ocular events observed among Lucentis-treated patients and occurring in <1% of patients included intraocular inflammation and increased intraocular pressure (see section 4.4). The adverse events listed below occurred at a higher rate (at least 3 percentage points) in patients receiving treatment with Lucentis 0.5 mg than in those receiving control treatment (sham or verteporfin PDT) in the three controlled phase III studies FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER). These were therefore considered potential adverse drug reactions (ADRs). The safety data described below also include all adverse events suspected to be at least potentially related to the injection procedure or medicinal product in the 440 patients of the combined 0.5 mg treatment groups. The adverse events 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, undesirable effects are presented in order of decreasing seriousness. Cardiac disorders Uncommon Atrial fibrillation Nervous system disorders Very common Headache Eye disorders Very common Conjunctival haemorrhage, eye pain, vitreous floaters, retinal

haemorrhage, intraocular pressure increased, vitreous detachment, intraocular inflammation, eye irritation, cataract, foreign body sensation in eyes, visual disturbance, blepharitis, subretinal fibrosis, ocular hyperaemia, visual acuity blurred/decreased, dry eye, vitritis.

Common Ocular discomfort, conjunctival hyperaemia, posterior capsule opacification, retinal exudates, injection site reactions, lacrimation increased, eye pruritis, conjunctivitis, maculopathy, detachment of the retinal pigment epithelium

Uncommon Retinal degeneration, iritis, iridocyclitis, punctuate keratitis, keratopathy, dellen, corneal striae, retinal disorder, vitreous disorder, photophobia, cataract nuclear, anterior chamber flare, corneal abrasion, angle closure glaucoma, vitreous haemorrhage, uveitis, endophthalmitis, retinal detachment, retinal tear, eye haemorrhage, eyelid oedema, eyelid irritation, blindness, corneal oedema, hypopyon

Respiratory, thoracic and mediastinal disorders Uncommon Cough, wheezing, increased upper airway secretion Gastrointestinal disorders Common Nausea Skin and subcutaneous tissue disorders Uncommon Lichenoid keratosis Musculoskeletal and connective tissue disorders Common Arthralgia, back pain Infections and infestations Common Bronchitis, anaemia Vascular disorders Very common Hypertension/elevated blood pressure

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Arterial thromboembolic events, as defined by the Antiplatelet Trialists’ Collaboration, including vascular deaths, non-fatal myocardial infarctions, non-fatal ischaemic strokes and non-fatal haemorrhagic strokes, have been linked to the systemic availability of highly potent VEGF (vascular endothelial growth factor) inhibitors. When the first-year data from all three phase III studies (MARINA, ANCHOR and PIER) were combined, the overall incidence of arterial thromboembolic events was higher for patients treated with Lucentis 0.5 mg (2.5%) compared with the control arm (1.1%). However, in the second year of the MARINA study, the rate of arterial thromboembolic events was similar in patients treated with Lucentis 0.5 mg (2.6%) compared to patients in the control arm (3.2%). 4.9 Overdose Because Lucentis is administered by qualified ophthalmologists experienced in intravitreal injections, the likelihood of an overdose is very low. Only two cases of accidental overdose have been reported from the clinical studies. One patient received 1.2 mg Lucentis instead of the randomised dose (0.3 mg) while the second patient was treated with 2.0 mg instead of 0.5 mg. No adverse events were associated with these overdoses except for mild and transient increases in intraocular pressure. 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: Other ophthalmologicals, ATC code: S01LA04 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. 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 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. The clinical safety and efficacy of Lucentis have been assessed in three randomised, double-masked, sham- or active-controlled studies 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), patients with minimally classic or occult with no classic choroidal neovascularisation (CNV) received monthly intravitreal injections of Lucentis 0.3 mg or 0.5 mg or sham injections. A total of 716 patients were enrolled in this study (sham, 238; Lucentis 0.3 mg, 238; Lucentis 0.5 mg, 240). Data are available up to the end of month 24. In study FVF2587g (ANCHOR), patients with predominantly classic CNV lesions received either: 1) monthly intravitreal injections of Lucentis 0.3 mg and sham PDT; 2) monthly intravitreal injections of Lucentis 0.5 mg and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham or active verteporfin PDT was given with the initial Lucentis injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage. A total of 423 patients were enrolled in this study (sham, 143; Lucentis 0.3 mg, 140; Lucentis 0.5 mg, 140). Data are available up to the end of month 12. In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all Lucentis-treated patients (approximately 95%) maintained their visual acuity. 34% - 40% of Lucentis-treated patients experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. In general, patients with poor visual acuity (<20/200) at the onset of treatment experienced a benefit of treatment. However, neovascular AMD that has evolved into lesions characterised by subretinal fibrosis and advanced geographic atrophy is not

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likely to respond to Lucentis. Detailed results are shown in the tables below. Table 1 Outcomes at month 12 and month 24 in study FVF2598g (MARINA) Outcome measure Month Sham

(n=238) Lucentis 0.5 mg

(n=240) Month 12 62% 95% Loss of <15 letters in visual

acuity (%)a Month 24 53% 90% Month 12 5% 34% Gain of ≥15 letters in visual

acuity (%)a Month 24 4% 33% Month 12 -10.5 (16.6) +7.2 (14.4) Mean change in visual acuity

(letters) (SD)a Month 24 -14.9 (18.7) +6.6 (16.5) a p<0.01 Table 2 Outcomes at month 12 in study FVF2587g (ANCHOR) Outcome measure Verteporfin PDT (n=143) Lucentis 0.5 mg (n=140) Loss of <15 letters in visual acuity (%)a 64% 96% Gain of ≥15 letters in visual acuity (%)a 6% 40% Mean change in visual acuity (letters) (SD)a -9.5 (16.4) +11.3 (14.6) a p<0.01

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Figure 1 Mean change in visual acuity from baseline to month 24 in study FVF2598g (MARINA) and to month 12 in study FVF2587g (ANCHOR)

Patients in the group treated with Lucentis had minimal observable CNV lesion growth, on average. At month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 DA for Lucentis versus 2.3-2.6 DA for the control arms. The use of Lucentis beyond 24 months has not been studied. Study FVF3192g (PIER) was a randomised, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of Lucentis in patients with neovascular AMD (79% of the patients had minimally classic or occult AMD, 21% had a predominantly classic CNV component). Data are available up to the end of month 12. Patients received Lucentis 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months. A total of 184 patients were enrolled in this study (Lucentis 0.3 mg, 60; Lucentis 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with Lucentis in PIER received a mean of 6 total

(lette

rs)

Study FVF2598g(le

tters

)

Sham (n=238) Lucentis 0.5 mg (n=240)

Verteporfin PDT (n=143) Lucentis 0.5 mg (n=139)

MARIN ANCHOR

Mea

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ange

in v

isua

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SE

M

ean

chan

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±S

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+21.5

-15 -10

10 15

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Study FVF2587g

+20.8

0 2 4 6 8 10 120 2 4 6 8 10-15 -10 -5 0

5

10 15

-9.5

+11.3

Mont

-14.9

+6.6

0 2 4 6 8 10 12 14 16 18 20 22 24

-5 0

5

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treatments out of possible 6 from day 0 to month 12. In PIER, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every three months with Lucentis lost visual acuity, returning to baseline at month 12. In PIER, almost all Lucentis-treated patients (90%) maintained their visual acuity at month 12. Figure 2 Mean change in visual acuity from baseline to month 12 in study FVF3192g (PIER)

Preliminary data from an open study (PROTECT), in which the safety of the same-day administration of verteporfin PDT and Lucentis 0.5 mg was evaluated, shows that the incidence of intraocular inflammation following the initial combination treatment was low (two of 32 patients, 6.3%). In both the MARINA and ANCHOR studies, the improvement in visual acuity seen with Lucentis 0.5 mg at 12 months translated into patient-reported benefits as measured on the three subscales of the National Eye Institute Visual Function Questionnaire (VFQ-25) which were pre-specified secondary efficacy endpoints (near activities, distance activities, and vision-specific dependency). All three scores improved, on average, in Lucentis-treated patients and worsened in the sham control group of the MARINA study. On verteporfin PDT in the ANCHOR study, mean scores for near and distance activities improved to a smaller extent, while vision-specific dependency increased. All differences between Lucentis 0.5 mg and the two control groups were statistically significant and clinically meaningful, with p-values ranging from 0.009 to <0.0001. In study MARINA, the differences versus sham treatment had further increased at 24 months (p <0.0001 for all three subscales). 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 (Cmax) 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). Cmax was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Based on analysis of population pharmacokinetics and disappearance of ranibizumab from serum for patients treated with the 0.5 mg dose, the average vitreous elimination half-life of ranibizumab is approximately 10 days. Upon monthly intravitreal administration of Lucentis 0.5 mg/eye, serum ranibizumab Cmax, attained approximately 1 day after dosing, is predicted to generally range between 0.79 and 2.90 ng/ml, and Cmin is

Mea

n ch

ange

in v

isua

l acu

ity ±

SE

(le

tters

)

Sham (n=63)Lucentis 0.5 mg (n=61)

Study FVF3192g

Mont

+16.1

0 2 4 6 8 10 120 2 4

-20 -15 -10 -5 0

5

10

-16.3

-0.2

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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. Sixty-eight percent (136 of 200) of patients in a population pharmacokinetic analysis had renal impairment (46.5% mild [50-80 ml/min], 20% moderate [30-50 ml/min], and 1.5% severe [<30 ml/min]). 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 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, mutagenicity or reproductive and developmental toxicity data are available. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients α,α-trehalose dihydrate Histidine hydrochloride, monohydrate 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 18 months. 6.4 Special precautions for storage

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Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. 6.5 Nature and contents of container 0.3 ml solution in a vial (type I glass) with a stopper (chlorobutyl rubber), with 1 filter needle, 1 injection needle and 1 syringe (polypropylene). Pack containing 1 vial. 6.6 Special precautions for disposal Vials are for single use only. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/0/00/000/00 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT

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ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 USA Name and address of the manufacturer responsible for batch release Novartis Pharma S.A.S. Centre de Biotechnologie 8, rue de l'Industrie F-68330 Huningue France B. CONDITIONS OF THE MARKETING AUTHORISATION • CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE

MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription. (See Annex I: Summary of Product Characteristics, section 4.2) • CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE

OF THE MEDICINAL PRODUCT The Marketing Authorisation Holder (MAH) shall ensure, at launch, all physicians who are expected to prescribe/use Lucentis are provided with a physician information pack containing the following: • Physician information • Intravitreal injection procedure video • Intravitreal injection procedure pictogram • Patient information pack

The physician information should contain the following key elements: • The Summary of Product Characteristics • Sterile techniques, including periocular and ocular disinfection, to minimise risk of infection • Use of antibiotics • Use of povidone iodine or equivalent • Techniques for the intravitreal injection • Key signs and symptoms of IVT injection related adverse events • Management of IVT injection related adverse events

The patient information pack should be provided in both a form of patient information booklet and audio-CD that contain following key elements: • Patient information leaflet • How to prepare for Lucentis treatment • Which are the steps following treatment with Lucentis • Key signs and symptoms of serious adverse events • When to seek urgent attention from the health care provider

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The MAH must implement this educational plan nationally, prior to marketing, and as agreed with the competent authorities in the Member States. • OTHER CONDITIONS The Marketing Authorisation Holder must ensure that the system of pharmacovigilance is in place and functioning before the product is placed on the market. The Marketing Authorisation Holder commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance plan. An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk Management Systems for medicinal products of human use. Each update should include details of the implementation and effectiveness of the risk minimisation activities in each Member State.

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ANNEX III

LABELLING AND PACKAGE LEAFLET

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A. LABELLING

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Lucentis 10 mg/ml solution for injection Ranibizumab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One ml contains 10 mg of ranibizumab. Vial containing 3 mg of ranibizumab. 3. LIST OF EXCIPIENTS Also contains: α,α-trehalose dihydrate; histidine hydrochloride, monohydrate; histidine; polysorbate 20; water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS 1 vial of 0.3 ml solution for injection 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravitreal use. Vial for single use only. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Keep the vial in the outer carton in order to protect from light.

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/0/00/000/000 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted.

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Lucentis 10 mg/ml solution for injection Ranibizumab Intravitreal use 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 vial = 3.0 mg ranibizumab. 6. OTHER

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B. PACKAGE LEAFLET

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Lucentis 10 mg/ml solution for injection Ranibizumab

Read all of this leaflet carefully before you are given this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their

symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor. In this leaflet: 1. What Lucentis is and what it is used for 2. Before you use Lucentis 3. How to use Lucentis 4. Possible side effects 5. How to store Lucentis 6. Further information 1. WHAT LUCENTIS IS AND WHAT IT IS USED FOR Lucentis is given as an injection into the eye by your eye doctor under a local anaesthetic. It is used to treat damage to the retina (the light-sensitive back part of the eye) when this damage is caused by abnormal blood vessels growing and leaking into the eye. This happens in diseases such as age-related macular degeneration (AMD). Lucentis can help to improve the damaged vision or stop it from getting worse. The active substance in Lucentis is ranibizumab. Ranibizumab helps to stop the growth and leakage of new blood vessels in the eye, abnormal processes that contribute to the progression of AMD. 2. BEFORE YOU USE LUCENTIS You must not receive Lucentis - if you are allergic (hypersensitive) to ranibizumab or any of the other ingredients of Lucentis listed at

the end of this leaflet (see section 6). - if you have an infection in or around your eye. - if you have pain or redness (severe intraocular inflammation) in your eye. Take special care with Lucentis - Lucentis is given as an injection into the eye. Occasionally, an infection in the internal portion of the

eye, pain or redness (inflammation), detachment or tear of the layer in the back of the eye (retinal detachment or tear), or clouding of the lens (cataract) may occur after Lucentis treatment. It is important to identify and treat such an infection or retinal detachment as soon as possible. Please tell your doctor immediately if you develop signs such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in your vision or increased sensitivity to light.

- In some patients the eye pressure may increase for a short period directly after the injection. This is something you may not notice, therefore your doctor may monitor this after each injection.

Children and adolescents (below 18 years of age) The use of Lucentis in children and adolescents has not been studied and is therefore not recommended.

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Using other medicines Please tell your doctor if you are using or have recently used any other medicines, including medicines bought without a prescription. Pregnancy and breast-feeding - There is no experience of using Lucentis in pregnant women; therefore the potential risks are

unknown. If you are pregnant or planning to become pregnant, please discuss this with your doctor before Lucentis treatment.

- Lucentis is not recommended during breast-feeding because it is not known whether Lucentis passes into human milk. Ask your doctor or pharmacist for advice before Lucentis treatment.

Driving and using machines After Lucentis treatment you may experience some temporary vision blurring. If this happens, do not drive or use machines until this resolves. 3. HOW TO USE LUCENTIS All Lucentis injections will be administered by your doctor. Lucentis is administered as a single injection into your eye. The injection is given once a month in the first 3 months. Afterwards, your doctor will monitor your vision on a monthly basis. If your condition is found to be worsening, your doctor will administer Lucentis to your affected eye again. The interval between two doses should not be shorter than 1 month. Before the injection, your doctor will use antibiotic eye drops and wash your eye carefully to prevent infection. Your doctor will also give you a local anaesthetic to reduce or prevent any pain you might have with the injection. Before and after each injection your doctor will ask you to use antimicrobial eye drops four times daily for 3 days before and after each injection in order to prevent any possible eye infection. Older people (age 65 years and over) Lucentis can be used for people of 65 years of age and over without dose adjustment. If a dose of Lucentis is missed Contact your doctor or hospital as soon as possible to re-schedule your appointment. Before stopping Lucentis treatment If you are considering stopping Lucentis treatment, please go to your next appointment and discuss this with your doctor. Your doctor will advise you and decide how long you should be treated with Lucentis. If you have any further questions on the use of this product, ask your doctor. 4. POSSIBLE SIDE EFFECTS Like all medicines, Lucentis can cause side effects, although not everybody gets them. Please do not be alarmed by this list of possible side effects. You may not experience any of them. With administration of Lucentis, there may be some side effects, mostly in the eye and due to the injection procedure. Occasionally an infection in the internal portion of the eye, detachment or tear of the layer in the back of the eye (retinal detachment or tear), or clouding of the lens (cataract) may occur in the two weeks after Lucentis treatment. Other side effects include pain or redness (inflammation) and increased eye pressure. The symptoms you might experience are described in section 2 of this leaflet (“Take special care with Lucentis”). Please read section 2. It tells you what to do if you have any of these symptoms.

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Very common side effects (These may affect 10 or more in every 100 patients) The most common side effects in the eye reported to be possibly caused by the medicinal product or by the injection procedure include: bloodshot eye (bleeding of the conjunctiva), eye pain, small particles or spots in your vision (vitreous floaters), bleeding in the back of the eye (retinal bleeding), increased eye pressure, displacement of the jelly-like portion inside the eye (vitreous detachment), inflammation of the eye, eye irritation, clouding of the lens (cataract), a feeling of having something in the eye, visual disturbance, inflammation or infection of the eyelid margins (blepharitis), formation of fibrous tissue under the retina (subretinal fibrosis), redness of the eye, blurred or decreased sharpness of vision, dry eye, inflammation of the jelly-like portion inside the eye (vitritis). The most common non-visual side effects reported to be possibly caused by the medicinal product or by the injection procedure include: headache, elevated blood pressure. Common side effects (These may affect between 1 and 10 in every 100 patients) Other common side effects in the eye reported to be possibly caused by the medicinal product or by the injection procedure include: discomfort of the eye, redness of the eye (conjunctival hyperaemia), clouding of a part of the lens (posterior capsule opacification), deposits in the back of the eye (retinal exudates), reactions at the site of the injection into the eye, increased tear production, itching of the eye, infection of the surface of the eye (conjunctivitis), changes in the part of the retina responsible for central vision (maculopathy), detachment of a layer of the retina (retinal pigment epithelium detachment). Other common non-visual side effects reported to be possibly caused by the medicinal product or by the injection procedure include: infection of the lower part of the airways (bronchitis), reduced number of red blood cells (anaemia), nausea, back pain, pains in the joints (arthralgia). Uncommon side effects (These may affect less than 1 in every 100 patients) Uncommon side effects in the eye reported to be possibly caused by the medicinal product or by the injection procedure include: degeneration of the retina, inflammation of the coloured part of the eye, the ciliary body or an internal part of the eye (iritis, iridocyclitis, uveitis), small marks on the surface of the eye (punctuate keratitis), changes in or thickening or thinning of the central part of the surface of the eye (keratopathy, corneal edema, dellen and corneal striae), disorder in the back of the eye or the jelly-like portion inside the eye, light sensitivity, clouding of the central part of the lens (nuclear cataract), signs of inflammation of the front part of the eye, abrasion of the outer surface of the cornea, and a specific type of glaucoma (angle closure glaucoma), bleeding in the jelly-like portion inside the eye (vitreous haemorrhage), infection of the eye globe (endophthalmitis), tear or detachment of the retina, bleeding in the eye, irritation and edema of the eyelids, blindness, inflammatory deposits in the front part of the eye (hypopyon). Other uncommon non-visual side effects reported to be possibly caused by the medicinal product or by the injection procedure include: cough, wheezing (sudden onset of breathing difficulty), increased secretion of the upper airways, changes in heart rhythm (atrial fibrillation) and inflammatory disease of the skin (lichenoid keratosis). If any of the side effects you experience gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor. 5. HOW TO STORE LUCENTIS - Keep Lucentis out of the reach and sight of children. - Do not use Lucentis after the expiry date which is stated on the carton and vial label after EXP. The

expiry date refers to the last day of that month. - Store in a refrigerator (2°C – 8°C). Do not freeze. - Keep the vial in the outer carton in order to protect from light. - Do not use any pack that is damaged. 6. FURTHER INFORMATION

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What Lucentis contains - The active substance in Lucentis is ranibizumab (10 mg/ml). Each ml contains 10 mg ranibizumab. - The other ingredients are: α,α-trehalose dihydrate; histidine hydrochloride, monohydrate; histidine;

polysorbate 20; water for injections. What Lucentis looks like and contents of the pack Lucentis is a solution for injection in a vial (0.3 ml). The solution is clear, colourless to pale yellow and aqueous. Lucentis is supplied as a pack containing one glass vial of ranibizumab with chlorobutyl rubber stopper, one filter needle for withdrawal of the vial contents, one injection needle and one syringe for withdrawal of the vial contents and for intravitreal injection. Marketing Authorisation Holder Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom Manufacturer Novartis Pharma S.A.S. Centre de Biotechnologie 8, rue de l’Industrie F-68330 Huningue France For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11

Luxembourg/Luxemburg Novartis Pharma N.V. Tél/Tel: +32 2 246 16 11

България Novartis Pharma Services Inc. Тел.: +359 2 976 98 28

Magyarország Novartis Hungária Kft. Pharma Tel.: +36 1 457 65 00

Česká republika Novartis s.r.o. Tel: +420 225 775 111

Malta Novartis Pharma Services Inc. Tel: +356 2298 3217

Danmark Novartis Healthcare A/S Tlf: +45 39 16 84 00

Nederland Novartis Pharma B.V. Tel: +31 26 37 82 111

Deutschland Novartis Pharma GmbH Tel: +49 911 273 0

Norge Novartis Norge AS Tlf: +47 23 05 20 00

Eesti Novartis Pharma Services Inc. Tel: +372 60 62 400

Österreich Novartis Pharma GmbH Tel: +43 1 86 6570

Ελλάδα Polska

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Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12

Novartis Poland Sp. z o.o. Tel.: +48 22 550 8888

España Novartis Farmacéutica, S.A. Tel: +34 93 306 42 00

Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel: +351 21 000 8600

France Novartis Pharma S.A.S. Tél: +33 1 55 47 66 00

România Novartis Pharma Services Inc. Tel: +40 21 31299 01

Ireland Novartis Ireland Limited Tel: +353 1 260 12 55

Slovenija Novartis Pharma Services Inc. Tel: +386 1 300 75 50

Ísland Vistor hf. Sími: +354 535 7000

Slovenská republika Novartis s.r.o. Tel: +421 2 5542 5439

Italia Novartis Farma S.p.A. Tel: +39 02 96 54 1

Suomi/Finland Novartis Finland Oy Puh/Tel: +358 9 61 33 22 11

Κύπρος ∆ηµητριάδης και Παπαέλληνας Λτδ Τηλ: +357 22 690 690

Sverige Novartis Sverige AB Tel: +46 8 732 32 00

Latvija Novartis Pharma Services Inc. Tel: + 371 7 103 060

United Kingdom Novartis Pharmaceuticals UK Ltd. Tel: +44 1276 698370

Lietuva Novartis Pharma Services Inc. Tel. +370 5 269 16 50

This leaflet was last approved in {MM/YYYY}.

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INFORMATION FOR THE HEALTHCARE PROFESSIONAL How to prepare and administer Lucentis Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections. The recommended dose for Lucentis is 0.5 mg (0.05 ml). Lucentis treatment is initiated with a loading phase of 3 monthly injections followed by a maintenance phase in which patients should be monitored for visual acuity on a monthly basis. If the patient experiences disease progression, i.e. a loss of greater than 5 letters in visual acuity (ETDRS or one Snellen line equivalent), Lucentis should be administered. The interval between two doses should not be shorter than 1 month. As with all parenteral medicinal products, 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. Adequate anaesthesia and a broad-spectrum topical microbicide should be administered prior to the injection. Before withdrawal, the outer part of the rubber stopper of the vial should be disinfected. A 5 µm filter needle should be assembled onto a 1 ml syringe. The entire contents of the Lucentis vial should be withdrawn, keeping the vial in an upright position. The filter needle should be discarded after withdrawal of the vial contents and should not be used for the intravitreal injection. The filter needle should then be replaced with a sterile needle for the intravitreal injection. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 ml on the syringe. 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; the scleral site should be rotated for subsequent injections.