LUXTURNA Concentrate and solvent for solution for injection Ref.[8763] Active ingredients: Voretigene neparvovec

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of 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. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.
• Retinal disorder (foveal thinning, loss of foveal function), macular hole, maculopathy (epiretinal membrane, macular pucker) and eye disorder (foveal dehiscence).
• Increase in intraocular pressure. Intraocular pressure should be monitored prior to and following administration of the medicinal product and managed appropriately. Patients should be instructed to avoid air travel or other travel to high elevations until the air bubble formed as a result of administration of Luxturna has completely dissipated from the eye. A time period of up to 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 air bubble 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 occur during the weeks that follow the treatment. Patients should be instructed to contact their healthcare professional if visual disturbances persist. Patients should avoid swimming because of an increased risk of infection in the eye. Patients should avoid strenuous physical activity because of an increased risk of injury to the eye. Patients may resume swimming and strenuous activity, after a minimum of one 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 and nasal secretion appropriately, which may include storage of waste material in sealed bags prior to disposal. These handling precautions should be followed for 14 days after administration of voretigene neparvovec. It is recommended that patients/caregivers wear gloves for dressing changes and waste disposal, especially in case of underlying pregnancy, breast-feeding and immunodeficiency of caregivers.

Blood, organ, tissue and cell donation

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

Immunogenicity

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

Sodium content

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 the subretinal route of administration of Luxturna, inadvertent germ-line transmission with AAV vectors is highly unlikely.

Pregnancy

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

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

In the phase 1 and phase 3 clinical studies, there were three non-serious adverse reactions of retinal deposits in three of 41 (7%) subjects that were considered to be related to voretigene neparvovec. All three of these events were a transient appearance of asymptomatic subretinal precipitates inferior to the 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 during the clinical programme. One of 41 (2%) subjects reported a serious event of intraocular pressure increased (secondary to administration of depo-steroid) that was associated with treatment for endophthalmitis related to the administration procedure and resulted in optic atrophy, and one of 41 (2%) subjects reported a serious event of retinal disorder (loss of foveal function) that was assessed as related to the administration procedure. One of 41 (2%) subjects reported a serious event of retinal detachment that was assessed as related to the administration procedure.

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

Tabulated list of adverse reactions

The adverse reactions are listed by system organ class and frequency using the following convention: very common (≥1/10), common ≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 2. Adverse reactions related to voretigene neparvovec:

^* Includes retinal degeneration, retinal depigmentation and injection site atrophy

Table 3. Adverse reactions related to administration procedure:

^* 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 and reported as progressive in some patients. Events were temporally related to treatment and occurred in the estimated treated area of the bleb site and outside of the bleb area. Retinal atrophy may involve the fovea with possible negative effects on central vision.

Following reports of chorioretinal atrophy in the post-marketing setting, a retrospective review of fundus 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 to treatment, in 42.6% at year 1 and in 55.6% after year 1. In the phase 1 study, chorioretinal atrophy of the 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 and 11.1% at year 1 in the phase 3 study; 40% at baseline, 42.9% at year 1 and 41.7% after year 1 in the phase 1 study.

Some of these atrophies involved the fovea. In the phase 3 study, there was involvement of the fovea in 1.9% of treated eyes prior to treatment, as well as at year 1, and in 5.6% after year 1. In the phase 1 study, the fovea was involved in 30% of treated eyes prior to treatment, in 38.9% at year 1 and in 47.8% 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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