voretigene neparvovec (Rx)

>10%

Incidence based on by number of eyes treated

Cataract (19%)

Conjunctival hyperemia (11%)

1-10%

Incidence based on by number of eyes treated

Increased intraocular pressure (10%)

Retinal tear (5%)

Eye inflammation (5%)

Dellen (thinning of the corneal stroma) (4%)

Macular hole (4%)

Subretinal deposits (4%)

Maculopathy (wrinkling on the surface of the macula) (4%)

Eye irritation (2%)

Eye pain (2%)

Foveal thinning and loss of function (2%)

Endophthalmitis (1%)

Fovea dehiscence (separation of the retinal layers in the center of the macula) (1%)

Retinal hemorrhage (1%)

Postmarketing Reports

Eye disorders: Chorioretinal atrophy (also reported as retinal degeneration, retinal depigmentation, and injection site atrophy)

Contraindications

None

Cautions

Endophthalmitis may occur following any intraocular surgical procedure or injection; monitor and advise any signs or symptoms of infection or inflammation without delay

Permanent decline in visual acuity may occur following subretinal injection; monitor for visual disturbances

Retinal abnormalities (eg, macular holes, foveal thinning, loss of foveal function, foveal dehiscence, retinal hemorrhage) may occur; monitor and manage retinal abnormalities appropriately; do not administer voretigene neparvovex-rzyl in the immediate vicinity of the fovea

During or following vitrectomy, retinal abnormalities (eg, retinal tears, epiretinal membrane, retinal detachment) may occur; monitor during and following injection to permit early treatment of these retinal abnormalities; advise patients to report any signs or symptoms of retinal tears and/or detachment without delay

Increased intraocular pressure may occur

Avoid air travel, travel to high elevation or scuba diving until the air bubble formed following administration has completely dissipated from the eye; may take >1 week or more following injection for the air bubble to dissipate; changes in altitude while the air bubble is still present can result in irreversible vision loss

Subretinal injection of voretigene neparvovex-rzyl, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression

Pregnancy

Well-controlled human and animal reproductive studies with voretigene neparvovex-rzyl have not been conducted in pregnant women

No nonclinical or clinical studies were performed to evaluate the effect of voretigene neparvovex-rzyl on fertility

Lactation

No information regarding the presence of voretigene neparvovex-rzyl in human milk, the effects on the breastfed infant, or the effects on milk production

Development and health benefits of breastfeeding should be considered along with the mother’s clinical need for voretigene neparvovex-rzyl and any potential adverse effects on the breastfed infant from voretigene neparvovex-rzyl

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

RPE65 is produced in the retinal pigment epithelial (RPE) cells and converts all-trans-retinol to 11-cis-retinol, which subsequently forms the chomophore, 11-cis-retinal, during the visual (retinoid) cycle

Visual cycle is critical for biological conversion of a photon of light into an electrical signal in the retina

RPE65 gene mutations lead to reduced or absent levels of RPE65 isomerohydrolase activity, blocking the visual cycle and resulting in impairment of vision

An adeno-associated virus vector-based gene therapy designed to deliver a normal copy of the gene encoding the human retinal pigment epithelial 65-kd protein (RPE65) to cells of the retina in persons with reduced or absent levels of biologically active RPE65

Distribution

Biodistribution of voretigene neparvovex-rzyl was evaluated at 3 months following subretinal administration in nonhuman primates

Highest levels of vector DNA sequences were detected in intraocular 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, and liver, and, sporadically, in the lymph nodes

Vector DNA sequences were not detected in the gonads

Subretinal Preparation

Prepare voretigene neparvovex-rzyl within 4 hr of administration using sterile technique under aseptic conditions in a Class II vertical laminar flow biological safety cabinet (BSC)

Dilution

• Thaw 1 single-dose vial of voretigene neparvovex-rzyl and 2 vials of diluent at room temperature
• Mix thawed diluent vials by gently inverting them ~5 times
• Visually inspect diluent and voretigene neparvovex-rzyl single-dose vials for particulates, cloudiness, or discoloration; do not use the vial(s) if particulates are present; new vial(s) of diluent should be used
• Using the 3-mL syringe with 20G 1-inch needle, transfer 2.7 mL of diluent to 10-mL glass vial
• Mix contents of thawed voretigene neparvovex-rzyl single-dose vial by gently inverting ~5 times
• Draw 0.3 mL voretigene neparvovex-rzyl into a 1-mL sterile syringe with a 27G ½-inch sterile needle
• Transfer 0.3 mL of voretigene neparvovex-rzyl to glass vial containing 2.7 mL of diluent
• Gently invert the 10-mL glass vial approximately 5 time to mix contents
• Label the 10-mL glass vial containing the diluted voretigene neparvovex-rzyl as follows: ‘Diluted LUXTURNA’

Preparation

• To keep the syringes sterile, 2 operators are required for transfer of the contents of the 10-mL glass vial labeled ‘Diluted LUXTURNA’ into each of 2 sterile 1-mL syringes
• Primary operator withdraws 0.8 mL of the diluted voretigene neparvovex-rzyl into a sterile 1-mL syringe using a 27G ½-inch sterile needle while the secondary operator holds the 10-mL glass vial
• Prepare a total of two administration syringes
• Label the first syringe “Diluted LUXTURNA” and label the second syringe “Backup Diluted LUXTURNA” using the sterile skin marker
• The second syringe serves as a backup for the surgeon performing the subretinal administration procedure
• Discard the backup syringe after surgery if not used
• Visually inspect both syringes; if particulates, cloudiness, or discoloration are visible, do not use the syringe
• Place the syringes into the sterile plastic bag after visual inspection and seal the bag
• Place the sterile plastic bag with syringes containing diluted voretigene neparvovex-rzyl into an appropriate secondary container (eg, hard plastic cooler) for delivery to the surgical suite at room temperature

Subretinal Administration

For subretinal injection only

Items are required for administration

• Syringe containing diluted voretigene neparvovex-rzyl
• Subretinal injection cannula with a polyamide micro tip with an inner diameter of 41G
• Extension tube made of polyvinyl chloride <6 inch (15.2 cm) in length and with an inner diameter <1.4 mm

Subretinal injection

• Dilate eye and give adequate anesthesia to the patient
• Administer a topical broad-spectrum microbiocide to the conjunctiva, cornea, and eyelids prior to surgery
• Visually inspect voretigene neparvovex-rzyl prior to administration; if particulates, cloudiness, or discoloration are visible, do not use the product
• Connect the syringe containing the diluted voretigene neparvovex-rzyl to the extension tube and subretinal injection cannula
• Avoid excess priming volume; extension tube should not exceed 15.2 cm in length and 1.4 mm in inner diameter
• Inject drug slowly through extension tube and subretinal injection cannula to eliminate any air bubbles
• Confirm the volume of product available in the syringe for injection by aligning the plunger tip with the line that marks 0.3 mL
• After completing a vitrectomy, identify the intended site of administration (see prescribing information for further illustrated information)
• Recommended site of injection: Along the superior vascular arcade, >2 mm distal to the center of the fovea, avoiding direct contact with the retinal vasculature or with areas of pathologic features, such as dense atrophy or intraretinal pigment migration
• Inject drug slowly until an initial subretinal bleb is observed; then inject remaining volume slowly until the total 0.3 mL is delivered
• After completing the injection, remove subretinal injection cannula from the eye
• Following injection, discard all unused product
• Perform a fluid-air exchange, carefully avoiding fluid drainage near the retinotomy created for the subretinal injection
• Initiate supine head positioning immediately in the postoperative period
• Upon discharge, advise patients to rest in a supine position as much as possible for 24 hr

Storage

Drug and diluent: Store frozen at ≤-65°C

Following thaw of vials: Store at room temperature; further dilute and administer within 4 hr

Diluted drug: Store at room temperature just prior to injection procedure