Posology : מינונים

4.2    Posology and method of 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.

ZOL API APR24 V5                                           2                                   EU SmPC Mar2024 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 × 10 14
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 × 10 14
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 × 10 14
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 × 10  15
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 × 10  15
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 × 10  15
74.3
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 × 10  15
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 × 10  15
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 × 10  15
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 ZOL API APR24 V5                                          3                                  EU SmPC Mar2024 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              Prednisolone orally 1 mg/kg/day abeparvovec                                 (or equivalent if another corticosteroid is used)
Post-infusion 30 days (including the day of administration Prednisolone orally 1 mg/kg/day of onasemnogene abeparvovec)                (or equivalent if another corticosteroid is used)
Followed by 28 days:                        Systemic corticosteroids should be tapered gradually.
For patients with unremarkable findings
(normal clinical exam, total bilirubin, and Tapering of prednisolone (or whose ALT and AST values are both below     equivalent if another corticosteroid 2 × upper limit of normal (ULN) at the end  is used), e.g. 2 weeks at of the 30 days period:                      0.5 mg/kg/day and then 2 weeks at 0.25 mg/kg/day oral prednisolone or

For patients with liver function                 Systemic corticosteroids abnormalities at the end of the 30 days          (equivalent to oral prednisolone period: continuing until the AST and ALT         1 mg/kg/day) values are below 2 × ULN and all other assessments (e.g. total bilirubin) return to     Systemic corticosteroids should be normal range, followed by tapering over          tapered gradually.
28 days or longer if needed.

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).


ZOL API APR24 V5                                         4                                  EU SmPC Mar2024 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.