Zolgensma

Treatment should be initiated and administered in clinical centres and supervised by a physician experienced in the management of patients with SMA. 3 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.

4). g. hydration and nutritional status, absence of infection) prior to onasemnogene abeparvovec infusion. 4 ‘Systemic immune response’). Posology For single-dose intravenous infusion only. 1 x 1014 vg/kg onasemnogene abeparvovec. The total volume is determined by patient body weight.

0 kg. 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. 4). 8). To dampen the immune response immunomodulation with corticosteroids is recommended.

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).

4). If oral corticosteroid therapy is not tolerated intravenous corticosteroid may be considered as clinically indicated. 5 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 Systemic corticosteroids should be tapered gradually.

g. g. total bilirubin) return to normal range, followed by tapering over 28 days or longer if needed. 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.

1 x 1014 vg/kg) in 5 open-label clinical studies. 4). Tabulated list of adverse reactions The adverse reactions identified with onasemnogene abeparvovec in all patients treated with intravenous infusion at the recommended dose with a causal association to treatment are presented in Table 3.

Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 11 Table 3 Tabulated list of adverse reactions to onasemnogene abeparvovec Adverse Reactions by MedDRA SOC/PT and Frequency Blood and lymphatic system disorders Common Thrombocytopenia1) Uncommon Thrombotic microangiopathy2)3) Immune system disorders Rare Anaphylactic reactions Gastrointestinal disorders Common Vomiting Hepatobiliary disorders Common Hepatotoxicity4) Uncommon Acute liver failure2)3) General disorders and administration site conditions Common Pyrexia Uncommon Infusion-related reactions Investigations Very common Hepatic enzyme increased5) Common Troponin increased6) 1)Thrombocytopenia includes thrombocytopenia and platelet count decreased.

2)Treatment-related adverse reactions reported outside of pre-marketing clinical studies, including in the post-marketing setting. 3)Includes fatal cases. 4)Hepatotoxicity includes hepatic steatosis and hypertransaminasaemia. 5)Hepatic enzyme increased includes: alanine aminotransferase increased, ammonia increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, liver function test increased and transaminases increased.

6)Troponin increased includes troponin increased, troponin-T increased, and troponin-I increased (reported outside of clinical studies, including in the post-marketing setting). 1), elevated transaminases > 2 × ULN (and in some cases > 20 × ULN) were observed in 31% of patients treated at the recommended dose.

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. 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.

1). 7 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.

8). Patients should be monitored closely for clinical signs and symptoms of infusion-related reactions. If a reaction occurs, the infusion should be interrupted and treatment should be provided as needed. Based on clinical evaluation and standard practices, administration may be cautiously resumed.

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.

1.