Safety

Safety profile demonstrated in 4 open-label clinical studies1,a

The data set in the Full Prescribing Information includes 44 patients who were treated with ZOLGENSMA and ranged in age from 0.3 to 7.9 months at the time of infusion1

aData from ZOLGENSMA Prescribing Information, based on September 2018 safety data from 4 open-label studies. 

Adverse reactions occurring in ≥5% of patients following treatment with ZOLGENSMA (N=44)1,2

ULN=upper limit of normal 

aAE data come from the ZOLGENSMA Prescribing Information. This is based on September 2018 safety data. 

b41 patients received the therapeutic or higher dose of ZOLGENSMA and 3 patients received a lower dose. 

cElevated aminotransferases include alanine aminotransferase and/or aspartate aminotransferase. 

dOne patient (the first patient enrolled in NCT02122952) was enrolled prior to the protocol amendment instituting administration of prednisolone pre- and post-ZOLGENSMA infusion. 

ULN=upper limit of normal 

aAE data come from the ZOLGENSMA Prescribing Information. This is based on September 2018 safety data. 

b41 patients received the therapeutic or higher dose of ZOLGENSMA and 3 patients received a lower dose. 

cElevated aminotransferases include alanine aminotransferase and/or aspartate aminotransferase. 

dOne patient (the first patient enrolled in NCT02122952) was enrolled prior to the protocol amendment instituting administration of prednisolone pre- and post-ZOLGENSMA infusion. 

In clinical trials, clinically asymptomatic, transient, elevated aminotransferases were the most common treatment-related adverse reactions and were resolved with a systemic corticosteroid regimen without clinical sequelae1

Acute serious liver injury can occur with ZOLGENSMA. Prior to ZOLGENSMA infusion, a patient with infantile-onset SMA had elevated AST and ALT of unknown etiology (gamma-glutamyl transferase [GGT], total bilirubin and prothrombin time were normal). The patient was treated under an expanded access program in the United States. The patient received corticosteroids equivalent to oral prednisolone at 1 mg/kg/day for approximately 30 days, followed by a 14-day taper. Approximately 7 weeks after receiving ZOLGENSMA, the patient became jaundiced. Laboratory testing was consistent with acute serious liver injury, with AST level approximately 80 × ULN and ALT level approximately 45 × ULN, total bilirubin approximately 4 × ULN, and plasma prothrombin time approximately 4 × ULN. Liver biopsy showed acute, massive degeneration of hepatocytes, and massive, mixed inflammatory infiltrate (primarily CD8-positive T lymphocytes). The patient recovered to baseline status after treatment with corticosteroids.1

In order to help manage a possible increase in liver aminotransferases, all patients should be treated with systemic corticosteroids before and after infusion. See Full Prescribing Information for important treatment steps, including 28-day corticosteroid taper, laboratory testing, and monitoring.

ZOLGENSMA postmarketing experience1

The following adverse reactions have been identified during post-approval use of ZOLGENSMA:

  • Thrombotic microangiopathy
  • Pyrexia 

Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 

ZOLGENSMA safety analysis update

The safety of ZOLGENSMA was evaluated in 102 patients in the clinical development program as of the June 2020 data cut3

Patients ranged in age from 0.3 months to 7.9 months at the time of administration. Follow-up time ranged from 1.0 to 25.7 months as of the data cut or at study completion. The most frequently reported adverse reactions (≥5%) following ZOLGENSMA administration were elevated hepatic transaminases and vomiting.3

As of June 2020 data cut, there have been no treatment-related serious adverse events reported in the ongoing observational long-term follow-up study of the completed START trial (LT-001). The 13 patients enrolled in the long-term follow-up were 4.6 to 6.2 years post dosing. Three patients received a low dose and 10 patients received a high dose. The dosage received by patients in the low-dose cohort was approximately one-third of the dosage received by patients in the high-dose cohort.3

Safety data continue to be collected.3

AE=any adverse event occurring after dosing, irrespective of causality (i.e., irrespective of related or not related); Related AE=any adverse event considered possibly, probably, or definitely related to the product administered

aIncludes all patients who received the therapeutic dose, but not those who received the low dose.

bCategories are not mutually exclusive; the same patient may be counted across multiple terms. Terms included in hepatotoxicity: transaminases increased; aspartate aminotransferase (AST) increased; hypertransaminasaemia; alanine aminotransferase (ALT) increased; hepatic enzyme increased; gamma-glutamyltransferase increased; liver function test increased; ammonia increased; blood alkaline phosphatase increased and hepatic steatosis.  

cCategories are not mutually exclusive; the same patient may be counted across multiple terms. Terms included in thrombocytopenia: contusion; thrombocytopenia; haematochezia; blood urine present; haematemesis; haemoglobin decreased; platelet count decreased; epistaxis; haematuria; post procedural haemorrhage; traumatic haematoma; vessel puncture site bruise

AE=any adverse event occurring after dosing, irrespective of causality (i.e., irrespective of related or not related); Related AE=any adverse event considered possibly, probably, or definitely related to the product administered

aIncludes all patients who received the therapeutic dose, but not those who received the low dose.

bCategories are not mutually exclusive; the same patient may be counted across multiple terms. Terms included in hepatotoxicity: transaminases increased; aspartate aminotransferase (AST) increased; hypertransaminasaemia; alanine aminotransferase (ALT) increased; hepatic enzyme increased; gamma-glutamyltransferase increased; liver function test increased; ammonia increased; blood alkaline phosphatase increased and hepatic steatosis.  

cCategories are not mutually exclusive; the same patient may be counted across multiple terms. Terms included in thrombocytopenia: contusion; thrombocytopenia; haematochezia; blood urine present; haematemesis; haemoglobin decreased; platelet count decreased; epistaxis; haematuria; post procedural haemorrhage; traumatic haematoma; vessel puncture site bruise

Perform the AAV9-antibody test prior to treatment with ZOLGENSMA

  • The safety and efficacy of ZOLGENSMA in patients with anti-AAV9 antibody titers above 1:50 have not been evaluated1
  • Retesting may be performed if anti-AAV9 antibody titers are reported as positive or elevated1

Elevated anti-AAV9 antibody titers are relatively uncommon in infants and young children4

In 2 US clinical trials, 2.4% (1/41) of patients screened were excluded for persistently elevated anti-AAV9 antibody titers.2

  • Confirmation of anti-AAV9 antibody titers ≤1:50 was required prior to infusion1
  • 1/16 patients in START and 0/25 patients in STR1VE were excluded in screening due to persistently elevated anti-AAV9 antibody titers2

Vector shedding

Temporary vector shedding of ZOLGENSMA may occur, primarily through bodily waste. Advise caregivers on the proper handling and disposal of patient stools. Instructions should be provided to patient families and caregivers regarding good hand hygiene when coming into direct contact with patient bodily waste for up to 1 month after ZOLGENSMA infusion. Disposable diapers should be sealed in disposable trash bags and then discarded into regular trash.1

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Dosing and Infusion

Preparing and infusing ZOLGENSMA

Dosing and Infusion

Chand 2021

Liver safety data from 325 patients treated with ZOLGENSMA

Chand 2021