Voretigene neparvovec is an adeno-associated virus vector-based gene therapy indicated for the treatment of children and adults with biallelic RPE65 mutation-associated retinal dystrophy, an inherited form of vision loss. Biallelic RPE65 mutation-associated retinal dystrophy affects approximately 1,000 to 2,000 patients in the U.S. Mutations in the RPE65 gene lead to reduced or absent concentrations of RPE65 isomerohydrolase activity, blocking the visual cycle and resulting in impaired vision. Vision loss often begins during childhood or adolescence and ultimately progresses to complete blindness. Voretigene neparvovec delivers a normal copy of the gene encoding RPE65 to cells of the retina, which then facilitates normal protein production to allow phototransduction and restoration of vision loss. A short course of an oral corticosteroid is started prior to the administration of voretigene neparvovec to limit the potential immune reaction. Voretigene neparvovec is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Starting 3 days before voretigene neparvovec administration to the first eye, administer systemic oral corticosteroids equivalent to prednisone 1 mg/kg/day (Max: 40 mg/day) for a total of 7 days, followed by dosage taper over the next 10 days. Repeat the same corticosteroid dosing regimen for voretigene neparvovec administration to the second eye. If the corticosteroid taper after voretigene neparvovec administration to the first eye is not complete, then the corticosteroid regimen for the second eye replaces the taper for the first eye.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Voretigene neparvovec should be free of particulates, cloudiness, and discoloration.
Other Administration Route(s)
-Follow universal biohazard precautions for handling.
-Prepare voretigene neparvovec within 4 hours of administration using sterile technique under aseptic conditions in a Class II vertical laminar flow biological safety cabinet (BSC).
-Thaw 1 single-dose vial of voretigene neparvovec and 2 diluent vials at room temperature.
-Storage: After thaw of vials, store at room temperature.
-A 1:10 dilution is required prior to administration.
-Gently invert the thawed diluent vials approximately 5 times to mix contents.
-Using a 3 mL sterile syringe with a 20-gauge 1-inch needle, transfer 2.7 mL of diluent to the 10 mL glass vial. Dispose of the needle and syringe.
-Gently invert the thawed voretigene neparvovec vial approximately 5 times to mix contents.
-Draw 0.3 mL of voretigene neparvovec into a 1 mL sterile syringe with a 27-gauge half-inch sterile needle.
-Transfer 0.3 mL of voretigene neparvovec to the glass vial containing 2.7 mL of diluent. Gently invert the 10 mL glass vial approximately 5 times to mix the contents.
-Using a sterile plain label and sterile skin marker, label the 10-mL glass vial containing the diluted voretigene neparvovec.
-Remove all items from the BSC except the labeled glass vial and the sterile skin marker. Re-sanitize the BSC.
-Storage: Store diluted voretigene neparvovec at room temperature.
-To keep the syringes sterile, 2 operators are required for transfer of the contents of the 10 mL labeled glass vial into each of the 2 sterile 1 mL syringes.
-Using sterile technique, the primary operator withdraws 0.8 mL of the diluted voretigene neparvovec into a sterile 1 mL syringe using a 27-gauge half-inch sterile needle while the secondary operator holds the 10 mL glass vial.
-After insertion of the needle, the secondary operator inverts the 10 mL glass vial enabling the primary operator to withdraw 0.8 mL without touching the 10 mL glass vial.
-The primary operator removes the needle and affixes a sterile cap to the sterile syringe.
-The steps are repeated to prepare a second, back-up syringe.
-Label the syringes using the sterile skin marker. The second syringe will serve as a back-up for the surgeon performing the subretinal administration procedure.
-Place the syringes into a sterile plastic bag after visual inspection and seal the bag. Place the sterile plastic bag with syringes into an appropriate secondary container (e.g., hard plastic cooler) for delivery to the surgical suite at room temperature.
-Discard the back-up syringe after surgery if not used.
-Voretigene neparvovec should be administered in the surgical suite under controlled aseptic conditions by a surgeon experienced in performing intraocular surgery.
-After confirming the availability of voretigene neparvovec, dilate the eye and give adequate anesthesia to the patient.
-Administer a topical broad spectrum microbicide to the conjunctiva, cornea, and eyelids prior to surgery.
-Connect the syringe containing the diluted voretigene neparvovec to the extension tube and subretinal injection cannula. The extension tube should not exceed 15.2 cm in length and 1.4 mm in inner diameter to avoid excess priming volume.
-Inject the product slowly through the extension tube and the subretinal injection cannula to eliminate any air bubbles.
-Confirm the volume of the product in the syringe by aligning the plunger tip with the line that marks 0.3 mL.
-After the vitrectomy is complete, identify the intended site of administration. The subretinal injection cannula can be introduced via pars plana.
-Under direct visualization, place the tip of the subretinal injection cannula 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 center of the fovea. Avoid direct contact with the retinal vasculature or with areas of pathologic features, such as dense atrophy or intraretinal pigment migration.
-Inject a small amount of the product slowly until an initial subretinal bleb is observed. Then inject the remaining volume slowly until the total 0.3 mL is delivered.
-Remove the subretinal injection cannula from the eye once the injection is complete.
-After 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 post-operative period.
-Advise patients to rest in a supine position as much as possible for 24 hours after discharge.
Safety data were obtained from 2 clinical trials consisting of 41 patients (81 eyes) with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The average age of the patients was 17 years (range from 4 to 44 years). Ocular adverse reactions occurred in 66% of patients and 57% of treated eyes.
During clinical trials evaluating all doses of voretigene neparvovec, immune reactions and extra-ocular exposure were mild. No patients had a clinically significant cytotoxic T-cell response to either adeno-associated virus serotype 2 vector (AAV2) or retinal pigment epithelial 65 kDa protein (RPE65). Corticosteroid administration before and after voretigene neparvovec injection may have decreased the potential immune reaction to either vector capsid (AAV2) or transgene product (RPE65).
Endophthalmitis occurred in 2% of patients and 1% of treated eyes. Monitor patients who have received voretigene neparvovec subretinal injection for signs and symptoms of endophthalmitis (e.g., eye pain, floaters, or any change in vision) to permit early treatment, and counsel them to report any signs or symptoms of ocular infection or inflammation without delay.
Permanent decline in visual acuity may occur after subretinal injection of voretigene neparvovec. Monitor patients for any type of visual impairment.
During or after the subretinal injection of voretigene neparvovec, retinal abnormalities may occur, including macular holes (7% of patients; 4% of treated eyes), foveal thinning and loss of foveal function (2% of patients; 2% of treated eyes), foveal dehiscence (2% of patients; 1% of treated eyes), and retinal hemorrhage (2% of patients; 1% of treated eyes). Do not administer voretigene neparvovec in the immediate vicinity of the fovea. Retinal abnormalities may also occur during or after vitrectomy including retinal tears (10% of patients; 5% of treated eyes), epiretinal membrane, or retinal detachment. Monitor patients during and after the 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.
During clinical trials, increased intraocular pressure was reported in 15% of patients and 10% of treated eyes after subretinal injection of voretigene neparvovec. Monitor and manage intraocular pressure appropriately. Additional ocular adverse events included ocular pain (5% of patients; 2% of treated eyes), ocular inflammation (5% of patients; 5% of treated eyes), ocular irritation (5% of patients; 2% of treated eyes), maculopathy (wrinkling on the surface of the macula) (5% of patients; 4% of treated eyes), conjunctival hyperemia (22% of patients; 11% of treated eyes), dellen (thinning of the corneal stroma) (7% of patients; 4% of treated eyes), and subretinal deposits (7% of patients; 4% of treated eyes), which were the transient appearance of symptomatic subretinal precipitates inferior to the retinal injection site at 1 to 6 days after injection.
Subretinal injection of voretigene neparvovec, especially vitrectomy surgery, is associated with an increased incidence of the development and/or progression of cataracts. During clinical trials, cataracts occurred in 20% of patients and 19% of treated eyes.
Advise patients to avoid air or high elevation travel or scuba diving until the air bubble formed after administration of voretigene neparvovec has completely dissipated from the eye, which may take 1 week or more. Verify the dissipation of the air bubble by ophthalmic examination. A change in altitude while the air bubble is still present can result in irreversible vision loss.
Endophthalmitis may occur after any intraocular surgical procedure or injection. Prepare and administer voretigene neparvovec using aseptic technique, and apply a topical broad-spectrum ocular microbicide prior to the injection. Monitor patients who have received voretigene neparvovec subretinal injection for signs and symptoms of endophthalmitis (e.g., eye pain, floaters, or any change in vision) to permit early treatment, and counsel them to report any signs or symptoms of ocular infection or inflammation without delay.
Increased intraocular pressure may occur after subretinal injection of voretigene neparvovec. Monitor and manage intraocular pressure appropriately.
Subretinal injection of voretigene neparvovec, especially vitrectomy surgery, is associated with an increased incidence of the development and/or progression of cataracts.
Voretigene neparvovec use requires an experienced clinician, specifically a surgeon experienced in performing ocular surgery and determining retinal cell viability.
There are no adequate and well-controlled studies with voretigene neparvovec during human pregnancy. Animal reproductive studies have not been conducted.
There is no information regarding the presence of voretigene neparvovec in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for voretigene neparvovec and any potential adverse effects on the breast-fed infant from voretigene neparvovec.
For the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy:
NOTE: The FDA has designated voretigene neparvovec as an orphan drug for this indication.
Adults: 1.5 x 1011 vector genomes (vg) by subretinal injection in a total volume of 0.3 mL. Administer to each eye on separate days within a close interval but allowing at least 6 days between injections.
Geriatric: Safety and effectiveness have not been established. Patients aged 65 years and older were not included in clinical studies.
Children and Adolescents: 1.5 x 1011 vector genomes (vg) by subretinal injection in a total volume of 0.3 mL. Administer to each eye on separate days within a close interval but allowing at least 6 days between injections.
Infants: Not recommended because retinal cells are still undergoing cell proliferation, and voretigene neparvovec would potentially be diluted or lost during cell proliferation.
Maximum Dosage Limits:
1.5 x 1011 vector genomes (vg) per subretinal injection.
Safety and efficacy have not been established.
1.5 x 1011 vector genomes (vg) per subretinal injection.
1.5 x 1011 vector genomes (vg) per subretinal injection.
Use is not recommended.
Use is not recommended.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
There are no drug interactions associated with Voretigene Neparvovec products.
Mutations in the human retinal pigment epithelial 65 kDa protein (RPE65) gene lead to reduced or absent concentrations of RPE65 isomerohydrolase activity, blocking the visual cycle and resulting in vision impairment. Voretigene neparvovec is an adeno-associated virus vector-based gene therapy that delivers a normal copy of the gene encoding RPE65 to cells of the retina in people with reduced or absent concentrations of biologically active RPE65. The 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, which is critical in phototransduction.
Voretigene neparvovec is administered by subretinal injection.
Voretigene neparvovec vector shedding and biodistribution were investigated in 29 patients who received bilateral administrations. Voretigene neparvovec DNA was measured in tears, serum, and whole blood. Voretigene neparvovec vector was shed transiently and at low concentrations in tears from the injected eye in 13 patients (45%). Peak concentrations of vector DNA were detected in the tear samples on day 1 after injection; subsequently, no vector DNA was detected in a majority of the patients (8 of 13). Three patients (10%) had vector DNA in tear samples until day 3 after injection, and 2 patients (7%) had vector DNA in tear samples for about 2 weeks after injection. In another 2 subjects (7%), vector DNA was detected in tear samples from the uninjected (or previously injected) eye until day 3 after injection. Vector DNA was detected in serum in 3/29 patients (10%), including 2 with vector DNA in tear samples up to day 3 after each injection.