The Summary of Product Characteristics (SmPC) for Zolgensma has been updated.
The SmPC is a document describing the properties and the officially approved conditions of use of a medicine. Summaries of product characteristics form the basis of information for healthcare professionals on how to use the medicine safely and effectively.
Novartis Gene Therapies is committed to patient safety and the ongoing monitoring of adverse events as it relates to the use of Zolgensma® (onasemnogene abeparvovec). As with all commercially marketed products, they continuously monitor the safety of onasemnogene abeparvovec and share safety data as part of the required pharmacovigilance with health authorities. As a result of reports from post-marketing safety surveillance that have identified thrombotic microangiopathy (TMA) as a safety signal for onasemnogene abeparvovec, they have updated the Summary of Product Characteristics SmPC to add TMA as a Warning & Precaution.
TMA is a rare disease that is characterised by blood vessel damage in association with thrombocytopenia (low platelet counts), haemolytic anaemia (low red blood cell counts), and acute kidney injury (¹,²). TMA is treatable and can resolve with timely and proper interventions. Early detection is very important. If a child experiences any signs or symptoms of TMA, such as unexpected bruising or bleeding, seizures, or decreased urine output after receiving onasemnogene abeparvovec, it is important to seek medical attention right away (³). TMA has been reported to occur about 1 week after onasemnogene abeparvovec infusion.
*As of January 2021, more than 1,000 children have been treated with onasemnogene abeparvovec worldwide across clinical trials, managed access programmes and in the commercial setting (³). As of February 2021, a total of six confirmed TMA cases were reported globally in patients aged 4 months – 4.5 years, with the first case reported in October 2019 (³).
In all cases, TMA occurred within one to two weeks following dosing, each of the cases responded well to medical intervention and all patients had subsequent resolution of thrombocytopenia and anaemia, as well as recovery of renal function. Patient safety is the company's top priority and given these cases:
- Novartis Gene Therapies reported this information to study investigators last year and in addition, a series of patient case studies of TMA following treatment with onasemnogene abeparvovec was published in the Journal of Pediatrics in November 2020.
- Novartis Gene Therapies proposed incorporation of TMA into the product prescribing information in all countries where onasemnogene abeparvovec has been approved. In the European Union, European Commission decision is pending following CHMP opinion on February 25, 2021.
- Healthcare professionals are being informed of the label update via a Direct Healthcare Professional Communication. The purpose of the communication is to make doctors aware of the potential risk of TMA following administration of onasemnogene abeparvovec.
Novartis Gene Therapies continue to monitor product safety, including long-term safety follow-up studies in patients treated with onasemnogene abeparvovec. The benefit-risk profile for onasemnogene abeparvovec remains favourable and reported adverse events are monitorable and manageable.
*Please note the Direct Healthcare Professional Communication references five reported cases of TMA, as of January 15, 2021. As of February 2021, the company is aware of an additional report of TMA for a total of six cases.
Questions & Answers
- What is thrombotic microangiopathy (TMA)?
TMA is characterised by blood vessel damage resulting in thrombocytopenia (abnormal bruising or bleeding), haemolytic anaemia (feeling tired, weak or short of breath) and acute kidney injury (kidney problems).1,4 TMA can be genetic or acquired. Acquired TMA can occur in association with a wide range of infections, or can be drug-induced, although it is frequently unclear if this is a direct effect of the pathogen, a side effect of treatment, or a trigger of a latent complement defect.
- What is the incidence of TMA and is it more common in patients with SMA?
The incidence of TMA in children with SMA is unknown and it is unclear if there are any predisposing factors and therefore, each situation is unique (¹)
- What is the treatment for TMA?
Each reported case is unique, which means that treatment can vary from symptom management to interventional therapy that could include possible blood treatments such as plasmapheresis and/or dialysis (¹)
- What signs or symptoms should patient families/caregivers be looking for?
If a child experiences unexpected bruising or bleeding, seizures, or decreased urine output after receiving onasemnogene abeparvovec, medical attention should be sought. If a child is ill after receiving onasemnogene abeparvovec (fever, vomiting, etc.), it is also important to seek medical attention (²)
- What additional steps should health care providers take prior to onasemnogene abeparvovec infusion, based on this safety signal and what should they look for following treatment?
A Direct Healthcare Professional Communication will be distributed in all relevant regions where onasemnogene abeparvovec is marketed to inform health care providers of the risk of TMA after onasemnogene abeparvovec use.
- Does this change patient eligibility for onasemnogene abeparvovec?
No. This does not change patient eligibility for onasemnogene abeparvovec. As with any treatment, physicians should work closely with their patients/patient families to evaluate the benefit-risk profile and determine the best course of action for each individual patient.
TMA is an immune-related condition and immune activators (e.g., vaccines, infections) may contribute to its development (¹). Immune activators should be avoided or minimised close to onasemnogene abeparvovec dosing.
If you have any questions regarding the use of onasemnogene abeparvovec please speak to your health care provider.
1Chand DH, Zaidman C, Arya K, et al. Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: a case series [epub ahead of print]. J Pediatr. 2020 Nov 28:S0022-3476(20)31466-9.
2Onasemnogene abeparvovec Prescribing Information. Bannockburn, IL: AveXis, Inc; 2021.
3Data on File. Novartis Gene Therapies, Inc. 2021. 4. Joly BS, Zheng XL, Veyradier A. Understanding thrombotic microangiopathies in children. Intensive Care Med. 2018;44:1536–1538.