ZOLGENSMA® NSS - Qatar
ZOLGENSMA® NSS - Qatar
Regulatory Affairs
ZOLGENSMA® (onasemnogene abeparvovec)
Solution for intravenous infusion
National Succinct Statement (NSS)
Version 1.6
Effective date: 14-Apr-2023
Safety Label Change (SLC) 2023-PSB/GLC-1351-s
Tracking number:
Document status: Final
Property of Novartis Gene Therapies
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis Gene Therapies
Zolgensma®
►This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
Important note: Before prescribing, consult full prescribing information: https://www.ema.europa.eu/en.
Disclaimer: This link will contain the most updated product information approved by the reference country.
Presentation
Solution for intravenous infusion: Each mL contains onasemnogene abeparvovec with a nominal concentration of 2 × 1013 vector genomes (vg). Two vial sizes of either 5.5 mL or 8.3 mL.
Indications
Zolgensma is indicated for the treatment of:
- patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1
gene and a clinical diagnosis of SMA Type 1, or
- patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies
of the SMN2 gene.
Dosage and administration
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, but not limited to:
• AAV9 antibody testing using an appropriately validated assay,
• liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total
bilirubin, albumin, prothrombin time, partial thromboplastin time (PTT), and international
normalised ratio (INR),
• creatinine,
• complete blood count (including haemoglobin and 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).
Due to the increased risk of serious systemic immune response, it is recommended that patients are clinically stable in their overall health status (e.g. hydration and nutritional status, absence of infection) prior to onasemnogene abeparvovec infusion. In case of acute or chronic uncontrolled active infections, treatment should be postponed until the infection has resolved and the patient is clinically stable (see sub-sections 4.2 ‘Immunomodulatory regimen’ and 4.4 ‘Systemic immune response’).
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
Patient weight range (kg) | Dose (vg) | Total volume of dose a (mL) |
2.6 – 3.0 | 3.3 × 1014 | 16.5 |
3.1 – 3.5 | 3.9 × 1014 | 19.3 |
3.6 – 4.0 | 4.4 × 1014 | 22.0 |
4.1 – 4.5 | 5.0 × 1014 | 24.8 |
4.6 – 5.0 | 5.5 × 1014 | 27.5 |
5.1 – 5.5 | 6.1 × 1014 | 30.3 |
5.6 – 6.0 | 6.6 × 1014 | 33.0 |
6.1 – 6.5 | 7.2 × 1014 | 35.8 |
6.6 – 7.0 | 7.7 × 1014 | 38.5 |
7.1 – 7.5 | 8.3 × 1014 | 41.3 |
7.6 – 8.0 | 8.8 × 1014 | 44.0 |
8.1 – 8.5 | 9.4 × 1014 | 46.8 |
8.6 – 9.0 | 9.9 × 1014 | 49.5 |
9.1 – 9.5 | 1.05 × 1015 | 52.3 |
9.6 – 10.0 | 1.10 × 1015 | 55.0 |
10.1 – 10.5 | 1.16 × 1015 | 57.8 |
10.6 – 11.0 | 1.21 × 1015 | 60.5 |
11.1 – 11.5 | 1.27 × 1015 | 63.3 |
11.6 – 12.0 | 1.32 × 1015 | 66.0 |
12.1 – 12.5 | 1.38 × 1015 | 68.8 |
12.6 – 13.0 | 1.43 × 1015 | 71.5 |
13.1 – 13.5 | 1.49 × 1015 | 74.3 |
Patient weight range (kg) | Dose (vg) | Total volume of dose a (mL) |
13.6 – 14.0 | 1.54 × 1015 | 77.0 |
14.1 – 14.5 | 1.60 × 1015 | 79.8 |
14.6 – 15.0 | 1.65 × 1015 | 82.5 |
15.1 – 15.5 | 1.71 × 1015 | 85.3 |
15.6 – 16.0 | 1.76 × 1015 | 88.0 |
16.1 – 16.5 | 1.82 × 1015 | 90.8 |
16.6 – 17.0 | 1.87 × 1015 | 93.5 |
17.1 – 17.5 | 1.93 × 1015 | 96.3 |
17.6 – 18.0 | 1.98 × 1015 | 99.0 |
18.1 – 18.5 | 2.04 × 1015 | 101.8 |
18.6 – 19.0 | 2.09 × 1015 | 104.5 |
19.1 – 19.5 | 2.15 × 1015 | 107.3 |
19.6 – 20.0 | 2.20 × 1015 | 110.0 |
20.1 – 20.5 | 2.26 × 1015 | 112.8 |
20.6 – 21.0 | 2.31 × 1015 | 115.5 |
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 AAV9 capsid will occur after administration of onasemnogene abeparvovec (see section 4.4). This can lead to elevations in liver aminotransferases, 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 signs and 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). If at any time patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone, based on the patient’s clinical course, prompt consultation with a paediatric gastroenterologist or hepatologist and adjustment to the recommended immunomodulatory regimen, including increased dose, longer duration or prolongation of corticosteroid taper, should be considered (see section 4.4). If oral corticosteroid therapy is not tolerated intravenous corticosteroid may be considered as clinically indicated.
Table 2 Pre- and post-infusion immunomodulatory regimen
Pre-infusion | 24 hours prior to onasemnogene abeparvovec | Prednisolone orally 1 mg/kg/day (or equivalent if another corticosteroid is used) |
Post-infusion | 30 days (including the day of administration of onasemnogene abeparvovec) | Prednisolone orally 1 mg/kg/day (or equivalent if another corticosteroid is used) |
Followed by 28 days:
For patients with unremarkable findings (normal clinical exam, total bilirubin, and whose ALT and AST values are both below 2 × upper limit of normal (ULN) at the end of the 30 days period: or
For patients with liver function abnormalities at the end of the 30 days period: continuing until the AST and ALT values are below 2 × ULN and all other assessments (e.g. total bilirubin) return to normal range, followed by tapering over 28 days or longer if needed. |
Systemic corticosteroids should be tapered gradually.
Tapering of prednisolone (or equivalent if another corticosteroid is used), e.g. 2 weeks at 0.5 mg/kg/day and then 2 weeks at 0.25 mg/kg/day oral prednisolone
Systemic corticosteroids (equivalent to oral prednisolone 1 mg/kg/day)
Systemic corticosteroids should be tapered gradually. |
Liver function (ALT, AST, total bilirubin) should be monitored at regular intervals for at least
3 months following onasemnogene abeparvovec infusion (weekly in the first month and during the entire corticosteroid taper period, followed by every two weeks for another month), and at other times as clinically indicated. Patients with worsening liver function test results and/or signs or symptoms of acute illness should be promptly clinically assessed and monitored closely (see section 4.4).
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
Patients with ALT, AST, total bilirubin levels (except due to neonatal jaundice) >2 × ULN or positive serology for hepatitis B or hepatitis C have not been studied in clinical studies with onasemnogene abeparvovec. 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 full- term 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 sodium chloride 9 mg/mL (0.9%) solution for injection.
Precautions to be taken before handling or administering the medicinal product
This medicinal product contains a genetically-modified organism. Healthcare professionals should therefore take appropriate precautions (use of gloves, safety goggles, laboratory coat and sleeves) when handling or administering the product (see section 6.6).
For detailed instructions on the preparation, handling, accidental exposure and disposal (including proper handling of bodily waste) of onasemnogene abeparvovec, see section 6.6.
Contraindications:
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Warnings and precautions
♦Advanced SMA: The benefit/risk profile of Zolgensma in patients with advanced SMA kept alive through permanent ventilation and without the ability to thrive is not established. ♦Hepatotoxicity: Administration of AAV vector often result in aminotransferase elevations. Acute serious liver injury and
acute liver failure have occurred with Zolgensma. Cases of acute liver failure with fatal outcomes have been reported. A systemic corticosteroid should be administered to all patients before and after Zolgensma infusion. Liver function should be assessed prior to infusion and monitored for at least 3 months after infusion, and at other times as clinically indicated. Promptly clinically assess and closely monitor patients with worsening liver function test results and/or signs or symptoms of acute illness. In case hepatic injury is suspected, further testing is recommended (e.g., albumin, prothrombin time, PTT and INR). The risks and benefits of Zolgensma therapy should be carefully considered in patients with pre-existing hepatic impairment. ♦Systemic immune response: It is recommended that patients are clinically stable in their overall health status (e.g., hydration and nutritional status, absence of infection) prior to Zolgensma infusion. Zolgensma should should not be initiated concurrently to active infections until the infection has resolved and the patient is clinically stable. Increased vigilance in the prevention, monitoring, and management of infection is recommended before and after Zolgensma infusion. Seasonal prophylaxis against respiratory syncytial virus (RSV) is recommended and should be up-to- date. ♦Immunogenicity: An immune response to the adeno-associated viral vector serotype 9 (AAV9) capsid will occur after infusion of Zolgensma. ♦Thrombocytopenia: Platelet counts should be obtained before Zolgensma infusion and should be closely monitored for significant decreases within the first two weeks following infusion and on a regular basis afterwards; at least weekly for the first month and every other week for the second and third months until platelet counts return to baseline. ♦Thrombotic microangiopathy (TMA): Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes. If clinical signs, symptoms and/or laboratory findings occur, a pediatric hematologist and/or pediatric nephrologist should be consulted immediately to manage TMA as clinically indicated. ♦Elevated troponin-I: Troponin-I levels should be obtained before Zolgensma infusion and monitored for at least 3 months following Zolgensma infusion or longer at the discretion of the healthcare professional. Consider consultation with a cardiac expert as needed. ♦Theoretical risk of tumorigenicity as a result of vector integration: There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome.
Pregnancy, lactation, females and males of reproductive potential
Human data on use during pregnancy or lactation are not available and animal fertility or reproduction studies have not been performed.
Adverse drug reactions
Very common (≥10%): Hepatic enzyme increased.
Common (≥1 to <10%): Thrombocytopenia, vomiting, pyrexia, hepatotoxicity, troponin increased.
Frequency not known: Thrombotic microangiopathy, acute liver failure (including fatal cases), acute liver injury.