Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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.

Pre-existing immunity against AAV9
Anti-AAV9 antibody formation can take place after natural exposure. There have been several studies on the prevalence of AAV9 antibodies in the general population that show low rates of prior exposure to AAV9 in the paediatric population. Patients should be tested for the presence of AAV9 antibodies prior to infusion with onasemnogene abeparvovec. Re-testing may be performed if AAV9 antibody titres are reported as above 1:50. It is not yet known whether or under what conditions onasemnogene abeparvovec can be safely and effectively administered in the presence of anti-AAV9 antibodies above 1:50 (see sections 4.2 and 5.1).

Advanced SMA
Since SMA results in progressive and non-reversible damage to motor neurons, the benefit of onasemnogene abeparvovec in symptomatic patients depends on the degree of disease burden at the time of treatment, with earlier treatment resulting in potential higher benefit. While advanced symptomatic SMA patients will not achieve the same gross motor development as unaffected healthy peers they may clinically benefit from gene replacement therapy, dependent on the advancement of disease at the time of treatment (see section 5.1).
ZOL API APR24 V5                                          5                                   EU SmPC Mar2024 The treating physician should consider that the benefit is seriously reduced in patients with profound muscle weakness and respiratory failure, patients on permanent ventilation, and patients not able to swallow.

The benefit/risk profile of onasemnogene abeparvovec in patients with advanced SMA, kept alive through permanent ventilation and without the ability to thrive, is not established.

Immunogenicity
An immune response to the AAV9 capsid will occur after infusion of onasemnogene abeparvovec, including antibody formation against the AAV9 capsid and T-cell mediated immune response, despite the immunomodulatory regimen recommended in section 4.2 (see also sub-section ‘Systemic immune response’ below).

Hepatotoxicity
Immune-mediated hepatotoxicity is generally manifested as elevated ALT and/or AST levels. Acute serious liver injury and acute liver failure, including fatal cases, have been reported with onasemnogene abeparvovec use, typically within 2 months after infusion and despite receiving corticosteroids before and after infusion.
Immune-mediated hepatotoxicity may require adjustment of the immunomodulatory regimen including longer duration, increased dose, or prolongation of the corticosteroid taper (see section 4.8).

•     The risks and benefits of onasemnogene abeparvovec therapy should be carefully considered in patients with pre-existing hepatic impairment.
•     Patients with pre-existing hepatic impairment or acute hepatic viral infection may be at higher risk of acute serious liver injury (see section 4.2).
•     Data from a small study in children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 to 9 years), indicate a higher frequency of AST or ALT elevations (in 23 out of 24 patients) compared with frequencies of AST/ALT elevations observed in other studies in patients weighing <8.5 kg (in 31 out of 99 patients) (see section 4.8).
•     Administration of AAV vector often results in aminotransferase elevations.
•     Acute serious liver injury and acute liver failure have occurred with onasemnogene abeparvovec. Cases of acute liver failure with fatal outcome have been reported (see section 4.8).
•     Prior to infusion, liver function of all patients should be assessed by clinical examination and laboratory testing (see section 4.2).
•     In order to mitigate potential aminotransferase elevations, a systemic corticosteroid should be administered to all patients before and after onasemnogene abeparvovec infusion (see section 4.2).
•     Liver function should be monitored at regular intervals for at least 3 months after infusion, and at other times as clinically indicated (see section 4.2).
•     Patients with worsening liver function test results and/or signs or symptoms of acute illness should be promptly clinically assessed and monitored closely.
•     In case hepatic injury is suspected, prompt consultation with a paediatric gastroenterologist or hepatologist, adjustment of the recommended immunomodulatory regimen and further testing is recommended (e.g.
albumin, prothrombin time, PTT, and INR).

AST/ALT/total bilirubin should be assessed weekly for the first month after onasemnogene abeparvovec infusion and during the entire corticosteroid taper period. Tapering of prednisolone should not be considered until AST/ALT levels are less than 2 × ULN and all other assessments (e.g. total bilirubin) return to normal range (see section 4.2). If the patient is clinically stable with unremarkable findings at the end of the corticosteroid taper period, liver function should continue to be monitored every two weeks for another month.

Thrombocytopenia
Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were observed in onasemnogene abeparvovec clinical studies. In most cases, the lowest platelet value occurred the first week following onasemnogene abeparvovec infusion.

Post-marketing cases with platelet count <25 x 109/L have been reported to occur within three weeks following administration.

ZOL API APR24 V5                                        6                                  EU SmPC Mar2024 Platelet counts should be obtained before onasemnogene abeparvovec infusion and should be closely monitored within the first three 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.

Data from a small study in children weighing ≥8.5 kg to ≤21 kg (aged approximately 1.5 to 9 years), indicate a higher frequency of thrombocytopenia (in 20 out of 24 patients) compared with frequencies of thrombocytopenia observed in other studies in patients weighing <8.5 kg (in 22 out of 99 patients) (see section 4.8).

Thrombotic microangiopathy
Several cases of thrombotic microangiopathy (TMA) have been reported with onasemnogene abeparvovec (see section 4.8). Cases generally occurred within the first two weeks after onasemnogene abeparvovec infusion. TMA is an acute and life-threatening condition, which is characterised by thrombocytopenia and microangiopathic haemolytic anaemia. Fatal outcomes have been reported. Acute kidney injury has also been observed. In some cases, concurrent immune system activation (e.g. infections, vaccinations) has been reported (see sections 4.2 and 4.5 for information on administration of vaccinations).

Thrombocytopenia is a key feature of TMA, therefore platelet counts should be closely monitored within the first three weeks following infusion and on a regular basis afterwards (see sub-section ‘Thrombocytopenia’). In case of thrombocytopenia, further evaluation including diagnostic testing for haemolytic anaemia and renal dysfunction should be undertaken promptly. If patients show clinical signs, symptoms or laboratory findings consistent with TMA, a specialist should be consulted immediately to manage TMA as clinically indicated.
Caregivers should be informed about signs and symptoms of TMA and should be advised to seek urgent medical care if such symptoms occur.

Elevated troponin-I
Increases in cardiac troponin-I levels following infusion with onasemnogene abeparvovec were observed (see section 4.8). Elevated troponin-I levels found in some patients may indicate potential myocardial tissue injury.
Based on these findings and the observed cardiac toxicity in mice, troponin-I levels should be obtained before onasemnogene abeparvovec infusion and monitored for at least 3 months following onasemnogene abeparvovec infusion or until levels return to within normal reference range for SMA patients. Consider consultation with a cardiac expert as needed.

Systemic immune response
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. Treatment should not be initiated concurrently to active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B), until the infection has resolved and the patient is clinically stable (see sections 4.2 and 4.4).

The immunomodulatory regimen (see section 4.2) might also impact the immune response to infections (e.g.
respiratory), potentially resulting in more severe clinical courses of the infection. Patients with infection were excluded from participation in clinical trials with onasemnogene abeparvovec. Increased vigilance in the prevention, monitoring, and management of infection is recommended before and after onasemnogene abeparvovec infusion. Seasonal prophylactic treatments, that prevent respiratory syncytial virus (RSV) infections, are recommended and should be up to date. 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).

If the duration of corticosteroid treatment is prolonged or the dose is increased, the treating physician should be aware of the possibility of adrenal insufficiency.

Risk of tumourigenicity as a result of vector integration
There is a theoretical risk of tumourigenicity due to integration of AAV vector DNA into the genome.

Onasemnogene abeparvovec is composed of a non-replicating AAV9 vector whose DNA persists largely in episomal form. Rare instances of random vector integration into human DNA are possible with recombinant AAV. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumourigenicity.
ZOL API APR24 V5                                         7                                  EU SmPC Mar2024 So far, no cases of malignancies associated with onasemnogene abeparvovec treatment have been reported. In the event of a tumour, the marketing authorisation holder should be contacted for guidance on collecting patient samples for testing.

Shedding
Temporary onasemnogene abeparvovec shedding occurs, primarily through bodily waste. Caregivers and patient families should be advised on the following instructions for the proper handling of patient stools:
•     good hand-hygiene is required when coming into direct contact with patient bodily waste for a minimum of 1 month after onasemnogene abeparvovec treatment.
•     Disposable nappies can be sealed in double plastic bags and disposed of in household waste.

Blood, organ, tissue and cell donation
Patients treated with Zolgensma should not donate blood, organs, tissues or cells for transplantation.

Sodium content
This medicinal product contains 4.6 mg sodium per mL, equivalent to 0.23% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Each 5.5 mL vial contains 25.3 mg sodium, and each 8.3 mL vial contains 38.2 mg sodium.

Effects on Driving

4.7   Effects on ability to drive and use machines

Onasemnogene abeparvovec has no or negligible influence on the ability to drive and use machines.