Luxturna - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

Package leaflet: Information for the patient

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

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor or nurse.

• – If you get any side effects, talk to your doctor or nurse. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet :

• 1. What Luxturna is and what it is used for

• 2. What you need to know before you are given Luxturna

• 3. How Luxturna is given to you

• 4. Possible side effects

• 5. How Luxturna is stored

• 6. Contents of the pack and other information

1. What Luxturna is and what it is used for

Luxturna is a gene therapy product that contains the active substance voretigene neparvovec.

Luxturna is used for the treatment of adults and children with vision loss due to inherited retinal dystrophy caused by mutations in the RPE65 gene. These mutations prevent the body from producing a protein needed for vision and so lead to loss of sight and eventual blindness.

The active substance in Luxturna, voretigene neparvovec, is a modified virus that contains a working copy of the RPE65 gene. After injection it delivers this gene into the cells of the retina, the layer at the back of the eye that detects light. This enables the retina to produce the proteins needed for vision. The virus used to deliver the gene does not cause disease in humans.

Luxturna will be given to you only if genetic testing shows that your vision loss is caused by mutations in the RPE65 gene.

2. What you need to know before you are given Luxturna

You will not be given Luxturna

• – if you are allergic to voretigene neparvovec or any of the other ingredients of this medicine

(listed in section 6)

• – if you have an eye infection

• – if you have eye inflammation

If any of the above applies to you, or if you are unsure of any of the above, please talk to your doctor before you receive Luxturna.

Warnings and precautions

Before receiving treatment with Luxturna:

• Tell your doctor if you have signs of an eye infection or eye inflammation, for example if you

have eye redness, sensitivity to light, eye swelling or eye pain.

• Tell your doctor if you have an active infection of any sort. Your doctor may delay your

treatment until your infection is gone because this medicine may make it more difficult for you to fight an infection. See also section 3.

After receiving Luxturna:

• Get immediate care from your doctor if your eye or eyes become red, painful, sensitive to light,

you see flashes or floaters in your vision, or if you notice any worsening or blurred vision.

• You should avoid air travel or other travel to high elevations until advised by your doctor.

During treatment with this medicine, the doctor inserts an air bubble in the eye, which is slowly absorbed by your body. Until the bubble is fully absorbed, air travel or other travel to high elevations may make the bubble expand and lead to eye damage, including vision loss. Please talk to your doctor before travelling.

• You should avoid swimming because of an increased risk of infection in the eye. Please talk to

your doctor before going to swim after receiving treatment with Luxturna.

• You should avoid strenuous physical activity because of an increased risk of injury to the eye.

Please talk to your doctor before beginning to engage in strenuous physical activity after receiving Luxturna.

• Some people develop cataracts. A cataract is clouding of the natural lens inside the eye that can

make it harder to see clearly. The development or worsening of cataracts is a known complication of the eye surgery that will be required before you receive Luxturna. There is an additional risk of cataract if the lens inside the eye is damaged by the needle used to inject the medicine into the back of the eye.

• You may have temporary visual disturbances, such as light sensitivity, and blurred vision. Tell

your doctor about any visual disturbances that you experience. Your doctor may be able to help reduce any discomfort caused by these temporary disturbances.

• Some medicine may be present in your tears. You and your caregiver should place any used

dressings and waste material with tears and nasal secretions in sealed bags before disposing of them. You should follow these precautions for 14 days.

• You and your caregiver, especially if pregnant, breast-feeding or with a suppressed immune

system, should wear gloves during dressing changes and when disposing of the dressings and other waste material. Follow these precautions for 14 days after the treatment.

• You will not be able to donate blood, organs, tissues and cells for transplantation after you have

been treated with Luxturna.

Children and adolescents

Luxturna has not been studied in children under four years of age.

Other medicines and Luxturna

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you might be pregnant, or are planning to have a baby, ask your doctor or nurse for advice before being treated with Luxturna.

The effects of this medicine on pregnancy and the unborn child are not known. As a precaution, you should not receive Luxturna while you are pregnant.

Luxturna has not been studied in breast-feeding women. It is not known whether it passes into breast milk. Ask your doctor whether you should stop breast-feeding after receiving Luxturna.

There is no information on the effect of Luxturna on male or female fertility.

Driving and using machines

You may have temporary visual disturbances after receiving Luxturna. Do not drive or use heavy machines until your vision has recovered. Talk to your doctor before resuming these activities.

Luxturna contains sodium

Luxturna contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

• 3. How Luxturna is given to you

Luxturna will be given to you in an operating room by surgeons experienced in performing eye surgery.

Luxturna is given under anaesthesia. Your doctor will talk to you about the anaesthesia and how it will be given to you.

Your doctor will carry out eye surgery to remove the clear gel inside the eye, and then inject Luxturna directly under your retina, the thin light-sensing layer at the back of that eye. This will be repeated on your other eye at least 6 days afterwards. You will need to stay for post-operative observation for a few hours after each procedure to monitor your recovery and watch for any side effects from the surgery or the anaesthesia.

Before Luxturna treatment is started, your doctor may prescribe a medicine that will suppress your immune system (the body’s natural defences) so that it will not try to fight the Luxturna when it is given. It is important that you take this medicine according to the instructions given. Do not stop taking the medicine without first talking to your doctor.

If you are given more Luxturna than you should be

As this medicine is given to you by a doctor, it is unlikely that you will be given too much. If it does occur, your doctor will treat the symptoms as necessary. Tell your doctor or nurse if you have any visual problems.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects may happen with Luxturna:

Common (may affect up to 1 in 10 people)

• Deposits under the retina

The following side effects may happen with the injection procedure:

Very common (may affect more than 1 in 10 people)

• Redness of the eye
• Cataract (clouding of the lens)
• Increased pressure in the eye

Common (may affect up to 1 in 10 people)

• Break in the retina
• Eye pain
• Eye swelling
• Detachment of the retina
• Nausea (feeling sick), vomiting, abdominal (belly) pain, lip pain
• Change of the electrical activity of the heart
• Headache, dizziness
• Rash, facial swelling
• Anxiety
• Problems associated with the placement of a breathing tube in the windpipe
• Breakdown of the surgical wound

Not known (frequency cannot be estimated from the available data)

• Clouding in the gel-like substance inside the eye (vitreous opacities)
• Atrophy of the (chorio)retina

Damage to the tissues of the eye may be accompanied by bleeding and swelling and an increased risk of infection. There is reduced vision in the days after surgery that usually improves; tell your doctor if vision does not return.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in By reporting side effects, you can help provide more information on the safety of this medicine.

• 5. How Luxturna is stored

Luxturna will be stored by the healthcare professionals at your healthcare facility.

Concentrate and solvent must be stored and transported frozen at ← 65 °C. Once thawed, the medicine should not be re-frozen and should be left at room temperature (below 25 °C).

Do not use this medicine after the expiry date which is stated on the label and carton after EXP.

6. Contents of the pack and other information

What Luxturna contains

• – The active substance is voretigene neparvovec. Each mL of concentrate contains 5 × 1012 vector

genomes (vg). The concentrate (0.5 mL extractable volume in a single-dose 2 mL vial) requires a 1:10 dilution prior to administration.

• – Each dose of diluted solution contains 1.5 × 1011 vector genomes of voretigene neparvovec in a

deliverable volume of 0.3 mL.

• – The other ingredients of the concentrate are sodium chloride (see end of section 2), sodium

dihydrogen phosphate monohydrate (for pH adjustment), disodium hydrogen phosphate dihydrate (for pH adjustment), poloxamer 188 and water for injections.

• – The solvent contains sodium chloride (see end of section 2), sodium dihydrogen phosphate

monohydrate (for pH adjustment), disodium hydrogen phosphate dihydrate (for pH adjustment), poloxamer 188 and water for injections.

What Luxturna looks like and contents of the pack

Luxturna is a clear, colourless concentrate for solution for subretinal injection, supplied in a clear plastic vial. The solvent is a clear, colourless liquid supplied in a clear plastic vial.

Each foil pouch includes a carton containing 1 vial of concentrate and 2 vials of solvent.

Marketing Authorisation Holder

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Manufacturer

Novartis Pharma GmbH

Roonstrasse 25

90429 Nuremberg

Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Lietuva

SIA Novartis Baltics Lietuvos filialas

Tel: +370 5 269 16 50

Luxembourg/Lu­xemburg

Novartis Pharma N.V.

Tél/Tel: +32 2 246 16 11

Magyarorszag

Novartis Hungaria Kft.

Tel.: +36 1 457 65 00

Malta

Novartis Pharma Services Inc.

Tel: +356 2122 2872

Nederland

Novartis Pharma B.V.

Tel: +31 88 04 52 111

Norge

Novartis Norge AS

Tlf: +47 23 05 20 00

Österreich

Novartis Pharma GmbH

Tel: +43 1 86 6570

Polska

Novartis Poland Sp. z o.o.

Tel.: +48 22 375 4888

Portugal

Novartis Farma – Produtos Farmacêuticos, S.A.

Tel: +351 21 000 8600

România

Novartis Pharma Services Romania SRL

Tel: +40 21 31299 01

Slovenija

Novartis Pharma Services Inc.

Tel: +386 1 300 75 50

Slovenská republika

Novartis Slovakia s.r.o.

Tel: +421 2 5542 5439

Suomi/Finland

Novartis Finland Oy

Puh/Tel: +358 (0)10 6133 200

Sverige

Novartis Sverige AB

Tel: +46 8 732 32 00

United Kingdom (Northern Ireland)

Novartis Ireland Limited

Tel: +44 1276 698370

This leaflet was last revised in

Other sources of information

This leaflet is available as an audio file and in a large print from the web site:

Detailed information on this medicine is available on the European Medicines Agency web site:

.

The following information is intended for healthcare professionals only:

Instructions for preparation, accidental exposure and disposal of Luxturna

Each carton containing 1 vial of concentrate and 2 vials of solvent is for single use only.

Accidental exposure must be avoided. Local biosafety guidelines for preparation, administration and handling of Luxturna should be followed.

• – Personal protective equipment (to include laboratory coat, safety glasses and gloves) should be

worn while preparing or administering voretigene neparvovec.

• – Accidental exposure to voretigene neparvovec, including contact with skin, eyes and mucous

membranes, is to be avoided. Any exposed wounds should be covered before handling.

• – Treat all Luxturna spills with a virucidal agent such as 1% sodium hypochlorite and blot using

absorbent materials.

• – All materials that may have come in contact with Luxturna (e.g. vial, syringe, needle, cotton

gauze, gloves, masks or dressings) must be disposed of in accordance with local biosafety guidelines.

Accidental exposure

• – In the event of an accidental occupational exposure (e.g. through a splash to the eyes or mucous

membranes), flush with clean water for at least 5 minutes.

• – In the event of exposure to broken skin or needlestick injury, clean the affected area thoroughly

with soap and water and/or a disinfectant.

This medicine contains genetically modified organisms. Unused medicinal product must be disposed of in compliance with the local biosafety guidelines.

Preparation

Preparation of Luxturna should be performed, within 4 hours of beginning the administration procedure, in accordance with the following recommended procedures performed under aseptic conditions.

Thaw one single-dose vial of concentrate and two single-use vials of solvent at room temperature. Gently invert the thawed solvent vials five times to mix the contents.

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

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

For dilution, transfer 0.3 mL of thawed concentrate into a 1 mL syringe and add it to the 10 mL sterile vial containing the solvent. Gently invert the 10 mL glass vial at least five times for proper mixing. Label the 10 mL glass vial containing the diluted concentrate as follows: ‘Diluted Luxturna’.

Do not prepare syringes for injection if the vials show any damage or if any visual particulates are observed. Prepare the syringes for injection by drawing 0.8 mL of the diluted solution into each sterile 1 mL syringe. The product filled syringes should then be transferred in a designated transport container to the surgical suite.

Posology

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

Luxturna is a single-use vial for a single administration in one eye only. Each single dose of

• 1.5 × 1011 vg will be delivered into the subretinal space in a total volume of 0.3 mL per eye. The individual administration procedure to each eye should be performed on separate days within a close interval, but no fewer than 6 days apart.

Immunomodulatory regimen

Prior to initiation of the immunomodulatory regimen and prior to administration of Luxturna, the patient must be checked for symptoms of active infectious disease of any nature, and in 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 Luxturna to the first eye, it is recommended that an immunomodulatory regimen is initiated following the schedule below (Table 1). Initiation of the immunomodulatory regimen for the second eye should follow the same schedule and supersede completion of the immunomodulatory regimen of the first eye.

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

Pre-operative	3 days prior to Luxturna administration	Prednisone (or equivalent) 1 mg/kg/day (maximum of 40 mg/day)
Post-operative	4 days (including the day of administration)	Prednisone (or equivalent) 1 mg/kg/day (maximum of 40 mg/day)
	Followed by 5 days	Prednisone (or equivalent) 0.5 mg/kg/day (maximum of 20 mg/day)
	Followed by 5 days of one dose every other day	Prednisone (or equivalent) 0.5 mg/kg every other day (maximum of 20 mg/day)

Special populations

Elderly

The safety and efficacy of voretigene neparvovec in patients >65 years old have not been established. However, no adjustment in dosage is necessary for elderly patients.

Hepatic and renal impairment

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

Paediatric population

The safety and efficacy of voretigene neparvovec in children aged up to 4 years have not been established. No data are available. No adjustment in dosage is necessary for paediatric patients.

Method of administration

Subretinal use.

Luxturna is a concentrate for solution for subretinal injection that requires thawing and dilution prior to administration.

This medicinal product must not be administered by intravitreal injection.

The product is administered as a subretinal injection after vitrectomy in each eye. It should not be administered in the immediate vicinity of the fovea to maintain foveal integrity.

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

Precaution to be taken before manipulating or administering the product

Personal protective equipment (to include laboratory coat, safety glasses and gloves) should be worn while preparing or administering voretigene neparvovec.

Intraocular pressure should be monitored prior to and following administration of the product, and managed appropriately.

Following the administration, patients should be instructed to report any symptoms suggestive of retinal detachment or endophthalmitis without delay and should be managed appropriately.

Follow the steps below to administer Luxturna to patients:

• Diluted Luxturna should be inspected visually prior to administration. If particulates,

cloudiness, or discoloration are visible, the product must not be used.

• Connect the syringe containing the diluted product to the extension tube and subretinal injection

cannula. The product is slowly injected through the extension tube and subretinal injection cannula to eliminate any air bubbles.

• The volume of product available for injection is confirmed in the syringe, by aligning the

plunger tip with the line that marks 0.3 mL.

• After vitrectomy is completed, Luxturna is administered by subretinal injection using a

commercially available subretinal injection cannula introduced via pars plana.

• Under direct visualisation, the tip of the subretinal injection cannula is placed in contact with

the retinal surface. The recommended site of injection is located along the superior vascular arcade, at least 2 mm distal to the centre of the fovea. A small amount of the product is slowly injected until an initial subretinal bleb is observed, and then, the remaining volume is slowly injected until the total 0.3 mL is delivered (Figure 1).

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

• At the completion of the injection, the subretinal injection cannula is removed from the eye.
• Fluid-air exchange is performed, carefully avoiding fluid drainage near the retinotomy created

for the subretinal injection.

• Supine head positioning is initiated immediately in the post-operative period and, upon

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for voretigene neparvovec, the scientific conclusions of CHMP are as follows:

In view of available data on (chorio)retinal atrophy from the literature and reports from the ongoing US and EU PASSs including in 21 cases a close temporal relationship, and in view of a possible mechanism of action, the PRAC Rapporteur considers a causal relationship between Voretigene neparvovec and (chorio)retinal atrophy is at least a reasonable possibility. The PRAC Rapporteur concluded that the product information of products containing Voretigene neparvovec should be amended accordingly.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for voretigene neparvovec the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing voretigene neparvovec is unchanged subject to the proposed changes to the product information.

The CHMP recommends that the terms of the marketing authorisation(s) should be varied.

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