UPSTAZA Solution for infusion Ref.[50861] Active ingredients: Eladocagene exuparvovec

Proper aseptic techniques should always be used for the preparation and infusion of Upstaza.

Monitoring

Patients undergoing gene therapy should be closely monitored for procedure-related complications, complications related to their underlying disease, and risks associated with general anaesthesia during the peri-operative period. Patients may experience exacerbations of symptoms of their underlying AADC deficiency as a result of surgery and anaesthesia (see section 4.8).

Autonomic and serotonergic symptoms of AADC may persist after treatment with eladocagene exuparvovec.

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.

Immunogenicity

Experience with eladocagene exuparvovec in patients with anti-AAV2 antibody levels >1:20 prior to treatment is not available.

Cerebrospinal fluid leaks

Cerebrospinal fluid (CSF) leaks occur when there is a tear or hole in the meninges surrounding the brain or spinal cord, allowing the CSF to escape. Upstaza is administered by bilateral intraputaminal infusion using burr holes, therefore, CSF leak may occur postoperatively. Patients undergoing eladocagene exuparvovec treatment should be carefully monitored after administration for CSF leaks, particularly in relation to the risk of meningitis and encephalitis.

Dyskinesia

AADC-deficient patients may have increased sensitivity to dopamine due to their chronic dopamine deficiency. After treatment with eladocagene exuparvovec, increase in dyskinesia have been reported in 24/28 patients (see section 4.8). The increase of dyskinesia due to this dopamine sensitivity generally starts 1 month after the administration of gene therapy and gradually decreases over several months. The use of dopamine antagonists (risperidone) may be considered to control dyskinesia symptoms (see section 5.1).

Risk of shedding

The risk of shedding is considered to be low due to very limited systemic distribution of eladocagene exuparvovec (see section 5.2). As a precautionary measure, patients/caregivers should be advised to handle waste material generated from dressings and/or any secretions (tears, blood, nasal secretions, and CSF) appropriately, which may include storage of waste material in sealed bags prior to disposal and patients/caregivers wearing gloves for dressing changes and waste disposal. These handling precautions should be followed for 14 days after administration of eladocagene exuparvovec. It is recommended that patients/caregivers wear gloves for dressing changes and waste disposal, especially in case of pregnancy, breast-feeding, or immunodeficiency of caregivers.

Blood, organ, tissue, and cell donation

Patients treated with Upstaza must not donate blood, organs, tissues, and cells for transplantation.

Sodium and potassium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

This medicinal product contains less than 1 mmol potassium (39 mg) per dose, that is to say essentially ‘potassium-free’.

No interaction studies have been performed. No interaction is expected due to very limited systemic distribution of eladocagene exuparvovec.

Vaccinations

Vaccination schedule should proceed as normal.

Based on the lack of systemic exposure and negligible biodistribution to the gonads, the risk for germline transmission is low.

Pregnancy

There are no data from the use of eladocagene exuparvovec in pregnant women. Animal reproductive studies have not been conducted with eladocagene exuparvovec (see section 5.3).

Breast-feeding

It is unknown whether eladocagene exuparvovec is excreted in human milk.

Eladocagene exuparvovec is not absorbed systemically following intraputaminal administration, and no effect on the breastfed newborns/infants are anticipated.

Fertility

There are no clinical or nonclinical data available regarding the effect of eladocagene exuparvovec on fertility.

Not relevant.

Summary of the safety profile

The safety information was observed in 3 open-label clinical studies in which eladocagene exuparvovec was administered to 28 AADC-deficient patients aged 19 months to 8.5 years at the time of dosing. Patients were followed for a median duration of 52.3 months (minimum of 3.1 months to a maximum of 9.63 years). The most common adverse reaction was dyskinesia; it was reported in 24 (85.7%) patients and was prevalent during the first 2 months post-treatment.

Tabulated list of adverse reactions

The adverse reactions are reported in Table 1. The adverse reactions are listed by system organ class and frequency using the following convention: 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).

Table 1. Adverse reactions occurring in ≥2 patients in 3 open-label clinical studies (n=28):

Table 2. Neurosurgery-related adverse reactions occurring in ≥2 patients in 3 open-label clinical studies (n=28):

^a May include pseudomeningocele

Table 3. Anaesthesia and postoperative related adverse reactions in ≥2 patients within ≤2 weeks after administration, in 3 open label clinical studies (n=28):

Description of selected adverse reactions

Dyskinesia

Events of dyskinesia were reported in 24 (85.7%) subjects (see section 4.4). Of the 35 events of dyskinesia, 33 events were mild to moderate and 2 were severe. The majority of events resolved in approximately 2 months and all resolved within 7 months. The mean time to onset of events of dyskinesia was 25.8 days after receiving gene therapy. Events of dyskinesia were managed with routine medical care, such as anti-dopaminergic treatment.

Immunogenicity

Titres of anti-AAV2 antibodies were measured pre- and post-gene therapy in the clinical studies. All patients that received eladocagene exuparvovec had anti-AAV2 titres at or below 1:20 before treatment. Following treatment, most subjects (n=18) were positive for anti-AAV2 antibodies at least once within the first 12 months. In general, antibody levels stabilised or declined with time. There was no specific follow up program to capture potential immunogenicity reactions in any of the clinical studies, but presence of anti-AAV2 antibodies in the clinical studies was not reported to be associated with increase in severity, number of adverse reactions, or with decreased efficacy.

Experience with eladocagene exuparvovec in patients with anti-AAV2 antibody levels >1:20 prior to treatment is not available.

The immune response to the transgene and the cellular immune response were not measured.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.