ZOLGENSMA Solution for infusion Ref.[10923] Active ingredients: Onasemnogene abeparvovec

Treatment should be initiated and administered in clinical centres and supervised by a physician experienced in the management of patients with SMA.

Before administration of onasemnogene abeparvovec, baseline laboratory testing is required, including:

• AAV9 antibody testing using an appropriately validated assay,
• liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin,
• platelet count, and
• troponin-I.

The need for close monitoring of liver function, platelet count and troponin-I after administration and the need for corticosteroid treatment are to be considered when establishing the timing of onasemnogene abeparvovec treatment (see section 4.4).

In case of acute or chronic uncontrolled active infections, treatment should be postponed until the infection has resolved or is controlled (see sub-sections 4.2 and 4.4 immunomodulatory regimen).

Posology

For single-dose intravenous infusion only.

Patients will receive a dose of nominal 1.1 x 10¹⁴ vg/kg onasemnogene abeparvovec. The total volume is determined by patient body weight.

Table 1 gives the recommended dosing for patients who weigh 2.6 kg to 21.0 kg.

Table 1. Recommended dosing based on patient body weight:

^a NOTE: Number of vials per kit and required number of kits is weight-dependent. Dose volume is calculated using the upper limit of the patient weight range.

Immunomodulatory regimen

An immune response to the adeno-associated viral vector serotype 9 (AAV9) capsid will occur after administration of onasemnogene abeparvovec (see section 4.4). This can lead to elevations in liver transaminases, elevations of troponin I, or decreased platelet counts (see sections 4.4 and 4.8). To dampen the immune response immunomodulation with corticosteroids is recommended. Where feasible, the patient's vaccination schedule should be adjusted to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec infusion (see section 4.5).

Prior to initiation of the immunomodulatory regimen and prior to administration of onasemnogene abeparvovec, the patient must be checked for symptoms of active infectious disease of any nature.

Starting 24 hours prior to infusion of onasemnogene abeparvovec it is recommended to initiate an immunomodulatory regimen following the schedule below (see Table 2). Deviations from these recommendations are at the discretion of the treating physician (see section 4.4).

Table 2. Pre- and post-infusion immunomodulatory regimen:

Consult expert(s) if patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone.

If another corticosteroid is used by the physician in place of prednisolone, similar considerations and approach to taper the dose after 30 days should be taken as appropriate.

Special populations

Renal impairment

The safety and efficacy of onasemnogene abeparvovec have not been established in patients with renal impairment and onasemnogene abeparvovec therapy should be carefully considered. A dose adjustment should not be considered.

Hepatic impairment

Onasemnogene abeparvovec has not been studied in patients with hepatic impairment. Onasemnogene abeparvovec should not be infused unless elevated bilirubin is associated with neonatal jaundice. Onasemnogene abeparvovec therapy should be carefully considered in patients with hepatic impairment (see sections 4.4 and 4.8). A dose adjustment should not be considered.

0SMN1/1SMN2 genotype

No dose adjustment should be considered in patients with a bi-allelic mutation of the SMN1 gene and only one copy of SMN2 (see section 5.1).

Anti-AAV9 antibodies

No dose adjustment should be considered in patients with baseline anti-AAV9 antibody titres above 1:50 (see section 4.4).

Paediatric population

The safety and efficacy of onasemnogene abeparvovec in premature neonates before reaching fullterm gestational age have not been established. No data are available. Administration of onasemnogene abeparvovec should be carefully considered because concomitant treatment with corticosteroids may adversely affect neurological development.

There is limited experience in patients 2 years of age and older or with body weight above 13.5 kg. The safety and efficacy of onasemnogene abeparvovec in these patients have not been established. Currently available data are described in section 5.1. A dose adjustment should not be considered (see Table 1).

Method of administration

For intravenous use.

Onasemnogene abeparvovec is administered as a single-dose intravenous infusion. It should be administered with a syringe pump as a single intravenous infusion with a slow infusion of approximately 60 minutes. It must not be administered as an intravenous push or bolus.

Insertion of a secondary ('back-up') catheter is recommended in case of blockage in the primary catheter. Following completion of infusion, the line should be flushed with saline.

For instructions on dilution of the product before administration, see section 6.6

Precautions to be taken before handling or administering the medicinal product

This medicinal product contains a genetically-modified organism. Personal protective equipment (to include gloves, safety goggles, laboratory coat and sleeves) should be worn while preparing or administering onasemnogene abeparvovec (see sections 6.6). For instructions on the preparation, handling, accidental exposure to and disposal of the medicinal product, including proper handling of bodily waste see section 6.6.

No data from clinical studies are available regarding overdose of onasemnogene abeparvovec. Adjustment of the dose of prednisolone, close clinical observation and monitoring of laboratory parameters (including clinical chemistry and haematology) for systemic immune response are recommended (see section 4.4).

1 year.

After thawing:

Once thawed, the medicinal product should not be re-frozen and may be stored refrigerated at 2°C to 8°C in the original carton for 14 days.

Once the dose volume is drawn into the syringe it must be infused within 8 hours. Discard the vector containing syringe if not infused within the 8-hour timeframe.

Store and transport frozen (≤ -60°C).

Store in a refrigerator (2°C to 8°C) immediately upon receipt.

Store in the original carton.

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

The date of receipt should be marked on the original carton before the product is stored in the refrigerator.

Onasemnogene abeparvovec is supplied in a vial (10 mL polymer crystal zenith) with stopper (20 mm chlorobutyl rubber) and seal (aluminum, flip-off) with a coloured cap (plastic), in two different vial fill volume sizes, either 5.5 mL or 8.3 mL.

The dose of onasemnogene abeparvovec and exact number of vials required for each patient is calculated according to the patient's weight (see section 4.2 and Table 5 below).

Table 5. Carton/kit configurations:

^a Vial nominal concentration is 2 × 10¹³ vg/mL and contains an extractable volume of not less than 5.5 mL.
^b Vial nominal concentration is 2 × 10¹³ vg/mL and contains an extractable volume of not less than 8.3 mL.

This medicinal product contains genetically-modified organisms. Appropriate precautions for the handling, disposal or accidental exposure of onasemnogene abeparvovec should be followed:

• The onasemnogene abeparvovec syringe should be handled aseptically under sterile conditions.
• Personal protective equipment (to include gloves, safety goggles, laboratory coat and sleeves) should be worn while handling or administering onasemnogene abeparvovec. Personnel should not work with onasemnogene abeparvovec if skin is cut or scratched.
• All spills of onasemnogene abeparvovec must be wiped with absorbent gauze pad and the spill area must be disinfected using a bleach solution followed by alcohol wipes. All clean up materials must be double bagged and disposed of per local guidelines for handling of biological waste.
• All materials that may have come in contact with onasemnogene abeparvovec (e.g. vial, all materials used for injection, including sterile drapes and needles) must be disposed of in accordance with local guidelines on handling of biological waste.
• Accidental exposure to onasemnogene abeparvovec must be avoided. In the event of exposure to skin, the affected area must be thoroughly cleaned with soap and water for at least 15 minutes. In the event of exposure to eyes, the affected area must be thoroughly flushed with water for at least 15 minutes.

Receipt and thawing vials:

• Vials will be transported frozen (≤ -60ºC). Upon receipt vials should be refrigerated at 2°C to 8°C immediately, and in the original carton. Onasemnogene abeparvovec therapy should be initiated within 14 days of receipt of vials.
• Vials must be thawed before use. Do not use onasemnogene abeparvovec unless thawed.
• For packaging configurations containing up to 9 vials, product will be thawed after approximately 12 hours in the refrigerator. For packaging configurations containing up to 14 vials, product will be thawed after approximately 16 hours in the refrigerator. Alternatively, and for immediate use, thawing may be performed at room temperature.
• For packaging configurations containing up to 9 vials, thawing will occur from frozen state after approximately 4 hours at room temperature (20°C to 25°C). For packaging configurations containing up to 14 vials, thawing will occur from frozen state after approximately 6 hours at room temperature (20°C to 25°C)
• Before drawing the dose volume into the syringe, gently swirl the thawed product. Do NOT shake.
• Do not use this medicine if you notice any particles or discolouration once the frozen product has thawed and prior to administration.
• Once thawed, the medicinal product should not be re-frozen.
• After thawing, onasemnogene abeparvovec should be given as soon as possible. Once the dose volume is drawn into the syringe it must be infused within 8 hours. Discard the vector-containing syringe if not infused within the 8-hour timeframe.

Administration of onasemnogene abeparvovec to the patient:

To administer onasemnogene abeparvovec, draw the entire dose volume into the syringe. Remove any air in the syringe and prepare the infusion bag before intravenous infusion through a venous catheter.

Any unused medicinal product or waste material should be disposed of in accordance with local guidelines on handling of biological waste.

Temporary onasemnogene abeparvovec shedding may occur, primarily through bodily waste. Caregivers and patient families should be advised on the following instructions for the proper handling of patient bodily fluids and waste:

• Good hand-hygiene (wearing protective gloves and washing hands thoroughly afterwards with soap and warm running water, or an alcohol-based hand sanitiser) is required when coming into direct contact with patient bodily fluids and waste for a minimum of 1 month after onasemnogene abeparvovec treatment.
• Disposable diapers should be sealed in double plastic bags and can be disposed of in household waste.