LUXTURNA 5 X 10^12 GENOMURI VECTOR/ml 5 x 10^12 vg / ml concentrate+solvent for solution for injection medication leaflet

Luxturna 5 × 1012 vector genomes/mL concentrate and solvent for solution for injection

2.1 General description

Voretigene neparvovec is a gene transfer vector that employs an adeno-associated viral vectorserotype 2 (AAV2) capsid as a delivery vehicle for the human retinal pigment epithelium 65 kDaprotein (hRPE65) cDNA to the retina. Voretigene neparvovec is derived from wild-type AAV2 usingrecombinant DNA techniques.

2.2 Qualitative and quantitative composition

Each mL of concentrate contains 5 × 1012 vector genomes (vg).

Each vial of Luxturna contains 0.5 extractable mL of concentrate (corresponding to 2.5 × 1012 vectorgenomes) which requires a 1:10 dilution prior to administration, see section 6.6.

After dilution of 0.3 mL of concentrate with 2.7 mL of solvent, each mL contains 5 × 1011 vectorgenomes. Each dose of 0.3 mL Luxturna contains 1.5 x 1011 vector genomes.

For the full list of excipients, see section 6.1.

Concentrate and solvent for solution for injection.

Following thaw from their frozen state, both the concentrate and the solvent are clear, colourlessliquids with a pH of 7.3.

Luxturna is indicated for the treatment of adult and paediatric patients with vision loss due to inheritedretinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viableretinal cells.

Treatment should be initiated and administered by a retinal surgeon experienced in performingmacular surgery.

Patients will receive a single dose of 1.5 × 1011 vector genomes voretigene neparvovec in each eye.

Each dose will be delivered into the subretinal space in a total volume of 0.3 mL. The individualadministration procedure to each eye is performed on separate days within a close interval, but nofewer than 6 days apart.

Immunomodulatory regimen

Prior to initiation of the immunomodulatory regimen and prior to administration of voretigeneneparvovec, the patient must be checked for symptoms of active infectious disease of any nature, andin case of such infection the start of treatment must be postponed until after the patient has recovered.

Starting 3 days prior to the administration of voretigene neparvovec to the first eye, it is recommendedthat an immunomodulatory regimen is initiated following the schedule below (Table 1). Initiation ofthe immunomodulatory regimen for the second eye should follow the same schedule and supersedecompletion of the immunomodulatory regimen of the first eye.

Table 1 Pre- and post-operative immunomodulatory regimen for each eye

Prednisone (or equivalent)3 days prior to Luxturna

Pre-operative 1 mg/kg/dayadministration(maximum of 40 mg/day)4 days Prednisone (or equivalent)(including the day of 1 mg/kg/dayadministration) (maximum of 40 mg/day)

Prednisone (or equivalent)

Post-operative Followed by 5 days 0.5 mg/kg/day(maximum of 20 mg/day)

Prednisone (or equivalent)

Followed by 5 days of one dose0.5 mg/kg every other dayevery other day(maximum of 20 mg/day)

The safety and efficacy of voretigene neparvovec in patients ≥65 years old have not been established.

Data are limited. However, no adjustment in dose is necessary for elderly patients.

The safety and efficacy of voretigene neparvovec have not been established in patients with hepatic orrenal impairment. No dose adjustment is required in these patients (see section 5.2).

The safety and efficacy of voretigene neparvovec in children aged up to 4 years have not beenestablished. Data are limited. No adjustment in dose is necessary for paediatric patients.

Subretinal use.

Luxturna is a sterile concentrate solution for subretinal injection that requires thawing and dilutionprior to administration (see section 6.6).

This medicinal product must not be administered by intravitreal injection.

Luxturna is a single-use vial for a single administration in one eye only. The product is administeredas a subretinal injection after vitrectomy in each eye. It should not be administered in the immediatevicinity of the fovea to maintain foveal integrity (see section 4.4).

The administration of voretigene neparvovec should be carried out in the surgical suite undercontrolled aseptic conditions. Adequate anaesthesia should be given to the patient prior to theprocedure. The pupil of the eye to be injected must be dilated and a broad-spectrum microbicideshould be topically administered prior to the surgery according to standard medical practice.

For instructions for preparation, accidental exposure to and disposal of Luxturna, see section 6.6.

Follow the steps below to administer voretigene neparvovec to patients:

* Diluted Luxturna should be inspected visually prior to administration. If particulates,cloudiness, or discoloration are visible, the medicinal product must not be used.

* Connect the syringe containing the diluted product to the extension tube and subretinal injectioncannula. The product is slowly injected through the extension tube and subretinal injectioncannula to eliminate any air bubbles in the system.

* The volume of product available for injection is confirmed in the syringe, by aligning theplunger tip with the line that marks 0.3 mL.

* After vitrectomy is completed, Luxturna is administered by subretinal injection using asubretinal injection cannula introduced via pars plana (Figure 1A).

* Under direct visualisation, the tip of the subretinal injection cannula is placed in contact withthe retinal surface. The recommended site of injection should be located along the superiorvascular arcade, at least 2 mm distal to the centre of the fovea (Figure 1B). A small amount ofthe product is slowly injected until an initial subretinal bleb is observed, and then the remainingvolume is slowly injected until the total 0.3 mL is delivered.

Figure 1A Subretinal injection cannula introduced via pars plana

Figure 1B Tip of the subretinal injection cannula placed within the recommended site ofinjection (surgeon’s view)

* At the completion of the injection, the subretinal injection cannula is removed from the eye.

* After injection, any unused product must be discarded. The back-up syringe may not beretained.

* Fluid-air exchange is performed, carefully avoiding fluid drainage near the retinotomy createdfor the subretinal injection.

* Supine head positioning is initiated immediately in the post-operative period and upondischarge should be maintained by the patient for 24 hours.

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

Ocular or periocular infection.

Active intraocular inflammation.

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

Subretinal injection-related reactions

Proper aseptic techniques should always be used for the preparation and administration of Luxturna.

The following adverse reactions have been observed with the administration procedure:

* Eye inflammation (including endophthalmitis), retinal tear and retinal detachment. Patientsshould be instructed to report any symptoms suggestive of endophthalmitis or retinaldetachment without delay and should be managed appropriately.

* Retinal disorder (foveal thinning, loss of foveal function), macular hole, maculopathy (epiretinalmembrane, macular pucker) and eye disorder (foveal dehiscence).

* Increase in intraocular pressure. Intraocular pressure should be monitored prior to and followingadministration of the medicinal product and managed appropriately. Patients should beinstructed to avoid air travel or other travel to high elevations until the air bubble formed as aresult of administration of Luxturna has completely dissipated from the eye. A time period of upto one week or more following injection may be required before dissipation of the air bubble;this should be verified on ophthalmic examination. A rapid increase in altitude while the airbubble is still present can cause a rise in eye pressure and irreversible vision loss.

Temporary visual disturbances, such as blurred vision and photophobia (see section 4.8), may occurduring the weeks that follow the treatment. Patients should be instructed to contact their healthcareprofessional if visual disturbances persist. Patients should avoid swimming because of an increasedrisk of infection in the eye. Patients should avoid strenuous physical activity because of an increasedrisk of injury to the eye. Patients may resume swimming and strenuous activity, after a minimum ofone to two weeks, on the advice of their healthcare professional.

Shedding

Transient and low-level vector shedding may occur in patient tears (see section 5.2).

Patients/caregivers should be advised to handle waste material generated from dressings, tears andnasal secretion appropriately, which may include storage of waste material in sealed bags prior todisposal. These handling precautions should be followed for 14 days after administration of voretigeneneparvovec. It is recommended that patients/caregivers wear gloves for dressing changes and wastedisposal, especially in case of underlying pregnancy, breast-feeding and immunodeficiency ofcaregivers.

Blood, organ, tissue and cell donation

Patients treated with Luxturna should not donate blood, organs, tissues and cells for transplantation.

To reduce the potential for immunogenicity patients should receive systemic corticosteroids beforeand after the subretinal injection of voretigene neparvovec to each eye (see section 4.2). Thecorticosteroids may decrease the potential immune reaction to either vector capsid (adeno-associatedvirus serotype 2 [AAV2] vector) or transgene product (retinal pigment epithelial 65 kDa protein[RPE65]).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

There are no known clinically significant interactions. No interaction studies have been performed.

Based on non-clinical studies and clinical data from trials of AAV2 vectors, and considering thesubretinal route of administration of Luxturna, inadvertent germ-line transmission with AAV vectorsis highly unlikely.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of voretigeneneparvovec in pregnant women. Animal studies do not indicate direct or indirect harmful effects withrespect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Luxturna during pregnancy.

Luxturna has not been studied in breast-feeding women. It is unknown whether voretigene neparvovecis excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must bemade whether to discontinue breast-feeding or to discontinue/abstain from voretigene neparvovectherapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

No clinical data on the effect of the medicinal product on fertility are available. Effects on male andfemale fertility have not been evaluated in animal studies.

Voretigene neparvovec has minor influence on the ability to drive and use machines. Patients mayexperience temporary visual disturbances after receiving subretinal injection of Luxturna. Patientsshould not drive or use heavy machines until visual function has recovered sufficiently, as advised bytheir ophthalmologist.

In the phase 1 and phase 3 clinical studies, there were three non-serious adverse reactions of retinaldeposits in three of 41 (7%) subjects that were considered to be related to voretigene neparvovec. Allthree of these events were a transient appearance of asymptomatic subretinal precipitates inferior tothe retinal injection site, 1-6 days after injection and resolved without sequelae.

Serious adverse reactions related to the administration procedure were reported in three subjects. Oneof 41 (2%) subjects reported a serious event of intraocular pressure increased (secondary toadministration of depo-steroid) that was associated with treatment for endophthalmitis related to theadministration procedure and resulted in optic atrophy, and one of 41 (2%) subjects reported a seriousevent of retinal disorder (loss of foveal function) that was assessed as related to the administrationprocedure. One of 41 (2%) subjects reported a serious event of retinal detachment that was assessed asrelated to the administration procedure.

The most common adverse reactions (incidence ≥5%) related to the administration procedure wereconjunctival hyperaemia, cataract, increased intraocular pressure, retinal tear, dellen, macular hole,subretinal deposits, eye inflammation, eye irritation, eye pain and maculopathy (wrinkling on thesurface of the macula).

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 000to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data).

Table 2 Adverse reactions related to voretigene neparvovec

System organ class Frequency Adverse reaction

Eye disorders Common Retinal deposits

Not known Chorioretinal atrophy*

*Includes retinal degeneration, retinal depigmentation and injection site atrophy

Table 3 Adverse reactions related to administration procedure

System organ class Frequency Adverse reactions

Psychiatric disorders Common Anxiety

Nervous system disorders Common Headache, dizziness

Very common Conjunctival hyperaemia, cataract

Common Retinal tear, dellen, macular hole, eye inflammation,eye irritation, eye pain, maculopathy, choroidalhaemorrhage, conjunctival cyst, eye disorder, eye

Eye disordersswelling, foreign body sensation in eyes, maculardegeneration, endophthalmitis, retinal detachment,retinal disorder, retinal haemorrhage

Not known Vitreous opacities, chorioretinal atrophy*

Gastrointestinal disorders Common Nausea, vomiting, abdominal pain upper, lip pain

Skin and subcutaneous tissue Common Rash, swelling facedisorders

Very common Intraocular pressure increased

Common Electrocardiogram T wave inversion

Injury, poisoning and Common Endotracheal intubation complication, woundprocedural complications dehiscence

*Includes retinal degeneration, retinal depigmentation and injection site atrophy

Description of select adverse reactions

Chorioretinal atrophy

Chorioretinal atrophy has been reported as an adverse reaction during post-marketing experience andreported as progressive in some patients. Events were temporally related to treatment and occurred inthe estimated treated area of the bleb site and outside of the bleb area. Retinal atrophy may involve thefovea with possible negative effects on central vision.

Following reports of chorioretinal atrophy in the post-marketing setting, a retrospective review offundus photographs available from 39 out of 41 patients enrolled in the clinical studies was performed.

In the phase 3 study, chorioretinal atrophy of the macula of treated eyes was found in 15.4% prior totreatment, in 42.6% at year 1 and in 55.6% after year 1. In the phase 1 study, chorioretinal atrophy ofthe macula was present in 35% prior to treatment, in 66.7% at year 1 and in 73.9% after year 1.

Untreated control eyes showed the following rates of chorioretinal atrophy: 5.9% at baseline and11.1% at year 1 in the phase 3 study; 40% at baseline, 42.9% at year 1 and 41.7% after year 1 in thephase 1 study.

Some of these atrophies involved the fovea. In the phase 3 study, there was involvement of the foveain 1.9% of treated eyes prior to treatment, as well as at year 1, and in 5.6% after year 1. In the phase 1study, the fovea was involved in 30% of treated eyes prior to treatment, in 38.9% at year 1 and in47.8% after year 1. In the phase 3 study, atrophies in untreated control eyes did not involve the fovea.

In the phase 1 study, 40% of atrophies in untreated control eyes involved the fovea at baseline, 42.9%at year 1 and 33.3% after year 1.

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

There is no clinical experience with overdose of voretigene neparvovec. Symptomatic and supportivetreatment, as deemed necessary by the treating physician, is advised in case of overdose.

Pharmacotherapeutic group: Ophthalmologicals, other ophthalmologicals, ATC code: S01XA27.

The retinal pigment epithelium-specific 65 kilodalton protein (RPE65) is located in the retinal pigmentepithelial cells and converts all-trans-retinol to 11-cis-retinol, which subsequently forms thechromophore, 11-cis-retinal, during the visual (retinoid) cycle. These steps are critical in the biologicalconversion of a photon of light into an electrical signal within the retina. Mutations in the RPE65 genelead to reduced or absent RPE65 all-trans-retinyl isomerase activity, blocking the visual cycle andresulting in vision loss. Over time, accumulation of toxic precursors leads to the death of retinalpigment epithelial cells, and subsequently to progressive photoreceptor cell death. Individuals withbiallelic RPE65 mutation-associated retinal dystrophy exhibit vision loss, including impaired visualfunction parameters such as visual acuity and visual fields often during childhood or adolescence; thisloss of vision ultimately progresses to complete blindness.

Injection of voretigene neparvovec into the subretinal space results in transduction of retinal pigmentepithelial cells with a cDNA encoding normal human RPE65 protein (gene augmentation therapy),providing the potential to restore the visual cycle.

The long-term safety and efficacy of Luxturna were assessed in a phase 1 safety and dose escalationstudy (101), in which 12 subjects received unilateral subretinal injections of voretigene neparvovec; afollow-on study (102) in which voretigene neparvovec was administered to the contralateral eye in 11of the 12 subjects who participated in the dose escalation study; a one-year, open-label phase 3controlled study (301) in which 31 subjects were randomised at two sites; and the continuation of thephase 3 study, in which the 9 control subjects crossed over and received the intervention. A total of41 subjects (81 eyes injected [one phase 1 subject did not meet eligibility criteria for a secondinjection]) participated in the clinical programme. All participants had a clinical diagnosis of Lebercongenital amaurosis, and some may have also had prior or additional clinical diagnoses, includingretinitis pigmentosa. Confirmed biallelic RPE65 mutations and the presence of sufficient viable retinalcells (an area of retina within the posterior pole of >100 micron thickness, as estimated by opticalcoherence tomography [OCT]) were established for all participants.

Phase 3 study

Study 301 was an open-label, randomised, controlled study. 31 subjects were enrolled, 13 males and18 females. The average age was 15 years (range 4 to 44 years), including 64% paediatric subjects(n=20, age from 4 to 17 years) and 36% adults (n=11). All subjects had a diagnosis of Leber’scongenital amaurosis owing to RPE65 mutations confirmed by genetic analysis in a certifiedlaboratory.

21 subjects were randomised to receive subretinal injection of voretigene neparvovec. Visual acuity(LogMAR) of the first eye of these subjects at baseline was 1.18 (0.14), mean (SE). One subjectdiscontinued from the study prior to treatment. 10 subjects were randomised to the control(non-intervention) group. Visual acuity (LogMAR) of the first eye of these subjects at baseline was1.29 (0.21), mean (SE). One subject in the control group withdrew consent and was discontinued fromthe study. The nine subjects who were randomised to the control group were crossed over to receivesubretinal injection of voretigene neparvovec after one year of observation. Each eye was administereda single subretinal injection of 1.5 × 1011 vector genomes voretigene neparvovec in a total volume of300 μL. The interval between injection to the eyes for each subject was from 6 to 18 days.

The primary endpoint of the phase 3 study measured the mean change from baseline to one year inbinocular multi-luminance mobility testing (MLMT) between the intervention and control groups. The

MLMT was designed to measure changes in functional vision, specifically the ability of a subject tonavigate a course accurately and at a reasonable pace at different levels of environmental illumination.

This ability depends on the subject’s visual acuity, visual field and the extent of nyctalopia (decreasedability to perceive and/or see in dim light), each of which are functions specifically affected by theretinal disease associated with RPE65 mutations. In the phase 3 study, the MLMT used seven levels ofillumination ranging from 400 lux to 1 lux (corresponding to, for example, a brightly lit office down toa moonless summer night). The testing of each subject was videotaped and assessed by independentgraders. A positive change score reflects passing the MLMT at a lower light level and a lux score of 6reflects the maximum possible MLMT improvement. Three secondary endpoints were also tested:

full-field light sensitivity threshold (FST) testing using white light; the change in MLMT score for thefirst assigned eye; and visual acuity (VA) testing.

At baseline, subjects achieved pass marks on the mobility test at between 4 and 400 ambient lux.

Table 4 Changes in MLMT score: year 1, compared to baseline (ITT population: n=21intervention, n=10 control)

Difference

Change in MLMT score (95% CI) p-value

Intervention-Controlusing binocular vision 1.6 (0.72, 2.41) 0.001using assigned first eye only 1.7 (0.89, 2.52) 0.001using assigned second eye only 2.0 (1.14, 2.85) <0.001

The monocular MLMT change score significantly improved in the treatment group and was similar tothe binocular MLMT results (see Table 4).

Figure 2 shows the effect of the medicinal product over the three-year period in the voretigeneneparvovec treatment group, as well as the effect in the control group after crossing over to receivesubretinal injection of voretigene neparvovec. Significant differences in binocular MLMTperformance were observed for the voretigene neparvovec treatment group at day 30 and weremaintained over the remaining follow-up visits throughout the three-year period, compared to nochange in the control group. However, after crossing-over to receive subretinal injection of voretigeneneparvovec, the subjects in the control group showed a similar response to the voretigene neparvovecas compared to the subjects in the voretigene neparvovec treatment group.

Figure 2 Change in MLMT score using binocular vision versus time before/after exposure tovoretigene neparvovec

BL D30 D90 D180 Y1 Y2 Y3

XBLX D30 XD90 XD180 XY1 XY2

Each box represents the middle 50% of distribution of MLMT score change. Vertical dotted lines representadditional 25% above and below the box. The horizontal bar within each box represents the median. The dotwithin each box represents the mean. The solid line connects the mean MLMT score changes over visits for thetreatment group. The dotted line connects the mean MLMT score change over visits for the control group,including five visits during the first year without receiving voretigene neparvovec. The control group wasadministered voretigene neparvovec after 1 year of observation.

BL: baseline;

D30, D90, D180: 30, 90 and 180 days after start of study;

Y1, Y2, Y3: one, two and three years after start of study;

XBL; XD30; XD90; XD180: baseline, 30, 90 and 180 days after start of study for control crossover group;

XY1; XY2: one and two years after start of study for control crossover group.

Results of full-field light sensitivity testing at the first study year: white light [Log10(cd.s/m2)] areshown in Table 5 below.

Table 5 Full-field light sensitivity testing

Full-field light sensitivity testing - First assigned eye (ITT)

Intervention, N = 21

Baseline Year 1 Change

N 20 20 19

Mean (SE) -1.23 (0.10) -3.44 (0.30) -2.21 (0.30)

Control, N = 10

N 9 9 9

Mean (SE) -1.65 (0.14) -1.54 (0.44) 0.12 (0.45)

Difference (95% CI) (Intervention-Control)

- 2.33 (-3.44, -1.22), p<0.001

Full-field light sensitivity testing - Second assigned eye (ITT)

Intervention, N = 21

Baseline Year 1 Change

N 20 20 19

Mean (SE) -1.35 (0.09) -3.28 (0.29) -1.93 (0.31)

Control, N = 10

N 9 9 9

Mean (SE) -1.64 (0.14) -1.69 (0.44) 0.04 (0.46)

Difference (95% CI) (Intervention-Control)

- 1.89 (-3.03, -0.75), p=0.002

Full-field light sensitivity testing - Averaged across both eyes (ITT)

Difference (95% CI) (Intervention-Control): -2.11 (-3.19, -1.04), p<0.001

Improvement in full-field light sensitivity was maintained for up to 3 years after exposure tovoretigene neparvovec.

At one year after exposure to voretigene neparvovec, improvement in visual acuity of at least0.3 LogMAR occurred in 11/20 (55%) of the first-treated eyes and 4/20 (20%) of the second-treatedeyes in the intervention group; no one in the control group displayed such an improvement of visualacuity in either the first or second eye.

Voretigene neparvovec is expected to be taken up by cells through heparin sulphate proteoglycanreceptors and be degraded by endogenous proteins and DNA catabolic pathways.

Non-clinical biodistribution

Biodistribution of voretigene neparvovec was evaluated at three months following subretinaladministration in non-human primates. The highest levels of vector DNA sequences were detected inintraocular fluids (anterior chamber fluid and vitreous) of vector-injected eyes. Low levels of vector

DNA sequences were detected in the optic nerve of the vector-injected eye, optic chiasm, spleen andliver, and sporadically in the stomach and lymph nodes. In one animal administered with voretigeneneparvovec at 7.5 × 1011 vector genomes (5 times the recommended per eye dose), vector DNAsequences were detected in colon, duodenum and trachea. Vector DNA sequences were not detected ingonads.

Clinical pharmacokinetics and shedding

The vector shedding and biodistribution were evaluated in tears from both eyes, serum and wholeblood of subjects in the phase 3 clinical study. In 13/29 (45%) subjects receiving bilateraladministrations, voretigene neparvovec vector DNA sequences were detected in tear samples; most ofthese subjects were negative after the day 1 post-injection visit, however, four of these subjects hadpositive tear samples beyond the first day, one subject up to day 14 post-second eye injection. Vector

DNA sequences were detected in serum in 3/29 (10%) subjects, including two with positive tearsamples, and only up to day 3 following each injection. Overall, transient and low levels of vector

DNA were detected in tear and occasional serum samples from 14/29 (48%) of subjects in the phase 3study.

No pharmacokinetic studies with voretigene neparvovec have been conducted in special populations.

Luxturna is injected directly into the eye. Liver and kidney function, cytochrome P450 polymorphismsand ageing are not expected to influence the clinical efficacy or safety of the product. Therefore, noadjustment in dose is necessary for patients with hepatic or renal impairment.

Ocular histopathology of dog and non-human primate eyes exposed to voretigene neparvovec showedonly mild changes, which were mostly related to healing from surgical injury. In an earlier toxicologystudy, a similar AAV2 vector administered subretinally in dogs at a dose of 10 times therecommended dose resulted in focal retinal toxicity and inflammatory cell infiltrates histologically inregions exposed to the vector. Other findings from voretigene neparvovec non-clinical studiesincluded occasional and isolated inflammatory cells in the retina, with no apparent retinaldegeneration. Following a single vector administration, dogs developed antibodies to the AAV2 vectorcapsid which were absent in naïve non-human primates.

Sodium chloride

Sodium dihydrogen phosphate monohydrate (for pH adjustment)

Disodium hydrogen phosphate dihydrate (for pH adjustment)

Poloxamer 188

Water for injections

Sodium chloride

Sodium dihydrogen phosphate monohydrate (for pH adjustment)

Disodium hydrogen phosphate dihydrate (for pH adjustment)

Poloxamer 188

Water for injections

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

Unopened frozen vials3 years

After thawing

Once thawed, the medicinal product should not be re-frozen and should be left at room temperature(below 25 °C).

Following dilution under aseptic conditions, the solution must be used immediately; if not usedimmediately, the storage time at room temperature (below 25 °C) should be no longer than 4 hours.

Concentrate and solvent must be stored and transported frozen at ≤-65 ºC.

For storage conditions after thawing and dilution of the medicinal product, see section 6.3.

Concentrate0.5 mL extractable volume of concentrate in 2 mL cyclic olefin polymer vial with a chlorobutyl rubberstopper sealed in place with an aluminium flip-off seal.

Solvent1.7 mL extractable volume of solvent in a 2 mL cyclic olefin polymer vial with a chlorobutyl rubberstopper sealed in place with an aluminium flip-off seal.

Each foil pouch includes a carton containing 1 vial of concentrate of 0.5 mL and 2 vials of solvent(each containing 1.7 mL).

Precaution to be taken before handling or administering the medicinal product

This medicinal product contains genetically modified organisms. Personal protective equipment (toinclude laboratory coat, safety glasses and gloves) should be worn while handling or administeringvoretigene neparvovec.

Preparation prior to administration

Each pack contains 1 vial of concentrate and 2 vials of solvent for single use only.

Luxturna should be inspected visually prior to administration. If particulates, cloudiness, ordiscoloration are visible, the single-dose vial must not be used.

Preparation of Luxturna should be performed within 4 hours of beginning the administrationprocedure, in accordance with the following recommended procedure performed under asepticconditions.

Thaw one single-dose vial of concentrate and two vials of solvent at room temperature. Once all3 vials (1 vial of concentrate and 2 vials of diluent) are thawed, dilution should be initiated. Gentlyinvert the vials five times to mix the contents.

Inspect for any visual particulates or any anomalies. Any anomalies or appearance of visualparticulates should be reported to the Marketing Authorisation Holder and product should not be used.

Transfer 2.7 mL of solvent taken from the two thawed vials and dispense into a sterile 10 mL emptyglass vial using a 3 mL syringe.

For dilution, draw 0.3 mL of thawed concentrate into a 1 mL syringe and add it to the 10 mL sterilevial containing the solvent. Gently invert the vial at least five times for proper mixing. Inspect for anyvisual particulates. The diluted solution should be clear to slightly opalescent. Label the 10 mL glassvial containing the diluted concentrate as follows: ‘Diluted Luxturna’.

Do not prepare syringes if the vial shows any damage or if any visual particulates are observed.

Prepare the syringes for injection by drawing 0.8 mL of the diluted solution into a sterile 1 mLsyringe. Repeat the same procedure to prepare a backup syringe. The product-filled syringes shouldthen be transferred in a designated transport container to the surgical suite.

Measures to take in case of accidental exposure

Accidental exposure must be avoided. Local biosafety guidelines for preparation, administration andhandling of voretigene neparvovec should be followed.

* Personal protective equipment (to include laboratory coat, safety glasses and gloves) should beworn while handling or administering voretigene neparvovec.

* Accidental exposure to voretigene neparvovec, including contact with skin, eyes and mucousmembranes, is to be avoided. Any exposed wounds should be covered before handling.

* All spills of voretigene neparvovec must be treated with a virucidal agent such as 1% sodiumhypochlorite and blot using absorbent materials.

* All materials that may have come in contact with voretigene neparvovec (e.g. vial, syringe,needle, cotton gauze, gloves, masks or dressings) must be disposed of in accordance with localbiosafety guidelines.

Accidental exposure

* In the event of an accidental occupational exposure (e.g. through a splash to the eyes or mucousmembranes), flush with clean water for at least 5 minutes.

* In the event of exposure to broken skin or needlestick injury, clean the affected area thoroughlywith soap and water and/or a disinfectant.

Precautions to be taken for the disposal of the medicinal product

This medicinal product contains genetically modified organisms. Unused medicinal product or wastematerial must be disposed of in compliance with the local guidance for pharmaceutical waste.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/18/1331/001

Date of first authorisation: 22 November 2018

Date of latest renewal: 24 July 2023

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

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