Health Canada has issued a safety communication for Zolgensma (onasemnogene abeparvovec) after 2 cases of fatal acute liver failure were reported internationally in pediatric patients with spinal muscular atrophy. The deaths occurred 6 to 7 weeks post-infusion, following the initiation of a corticosteroid taper. Hepatotoxicity is an identified risk of Zolgensma, and patients with pre-existing liver impairment or hepatic viral infection may be at higher risk. Health care providers are advised to routinely monitor liver function and to administer corticosteroids before and after the infusion.
Further information may be found at https://recalls-rappels.canada.ca/en/alert-recall/zolgensma-onasemnogene-abeparvovec-and-fatal-cases-acute-liver-failure.
Acute serious liver injury, acute liver failure, and elevated aminotransferases can occur with onasemnogene abeparvovec. Patients with preexisting liver impairment may be at higher risk. Prior to infusion, assess liver function of all patients by clinical examination and laboratory testing (eg, hepatic aminotransferases [AST and ALT], total bilirubin, and PT). Administer systemic corticosteroid to all patients before and after onasemnogene abeparvovec infusion. Continue to monitor liver function for at least 3 months after infusion.
(For additional information see "Onasemnogene abeparvovec: Pediatric drug information")
Spinal muscular atrophy (SMA):
Note: Postpone therapy until resolution of any infection. One day prior to infusion, administer oral corticosteroids (eg, prednisolone 1 mg/kg/dose once daily or equivalent) and continue for at least 30 days; may use IV corticosteroids if oral therapy not tolerated. Evaluate baseline labs (SCr, CBC [platelets, Hb]), troponin-I, and for presence of anti-AAV9 antibodies and assess liver function.
Infants and Children <2 years: IV infusion: 1.1 × 1014 vector genomes/kg as a single dose.
Dose volume based on weight range:
|
Weight range (kg) |
Dose Volume (mL) |
|---|---|
|
2.6 to 3 |
16.5 |
|
3.1 to 3.5 |
19.3 |
|
3.6 to 4 |
22 |
|
4.1 to 4.5 |
24.8 |
|
4.6 to 5 |
27.5 |
|
5.1 to 5.5 |
30.3 |
|
5.6 to 6 |
33 |
|
6.1 to 6.5 |
35.8 |
|
6.6 to 7 |
38.5 |
|
7.1 to 7.5 |
41.3 |
|
7.6 to 8 |
44 |
|
8.1 to 8.5 |
46.8 |
|
8.6 to 9 |
49.5 |
|
9.1 to 9.5 |
52.3 |
|
9.6 to 10 |
55 |
|
10.1 to 10.5 |
57.8 |
|
10.6 to 11 |
60.5 |
|
11.1 to 11.5 |
63.3 |
|
11.6 to 12 |
66 |
|
12.1 to 12.5 |
68.8 |
|
12.6 to 13 |
71.5 |
|
13.1 to 13.5 |
74.3 |
|
≥13.6 |
Multiple kits will be required. |
Concomitant therapy: Beginning the day prior to onasemnogene abeparvovec infusion, oral prednisolone (1 mg/kg/day or equivalent) should be administered and continued for ≥30 days to help prevent hepatic toxicity. At the end of 30 days, clinically assess liver and test hepatic function (ALT, AST, total bilirubin, and PT); if unremarkable findings (normal clinical exam, total bilirubin, and PT, and ALT and AST concentrations <2 × ULN), taper prednisolone over 28 days. If evidence of hepatic impairment exists, continue oral prednisolone (1 mg/kg/day or equivalent) until AST/ALT <2 × ULN and all other assessments return to normal, then taper over 28 days or longer if needed. If unresponsive to corticosteroid therapy, consult expert.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling. Patients with preexisting hepatic impairment may be at increased risk for hepatotoxicity; patients with ALT, AST, or total bilirubin >2 × ULN were not included in clinical trials (this excludes neonatal jaundice); assess risk versus benefit. Acute liver injury may occur during therapy, which may require prolonged corticosteroid therapy (see "Dosing: Pediatric"). Monitor liver function.
Suspension, Injection [preservative free]:
Zolgensma: Onasemnogene abeparvovec-xioi 20000000000000 VG/mL (5.5 mL, 8.3 mL)
Suspension, Injection:
Zolgensma: Onasemnogene abeparvovec-xioi 20000000000000 VG/mL (5.5 mL, 8.3 mL)
IV: For slow IV infusion only; do not administer as IV push or bolus. Flush with saline before and after administration. Infuse onasemnogene abeparvovec slowly over 60 minutes.
Spinal muscular atrophy: Treatment of pediatric patients <2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene
Limitations of use: Safety and effectiveness of repeat administration has not been evaluated. Use in patients with advanced SMA (eg, complete paralysis of limbs, permanent ventilator-dependence) has not been evaluated.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in neonates, infants, and young children.
>10%:
Hepatic: Increased serum alanine aminotransferase (≤27%), increased serum aspartate aminotransferase (≤27%)
Immunologic: Antibody development (100%)
1% to 10%: Gastrointestinal: Vomiting (7%)
Postmarketing:
Hematologic & oncologic: Thrombocytopenia, thrombotic microangiopathy (Chand 2021)
Hepatic: Acute hepatic failure, acute hepatotoxicity
Miscellaneous: Fever, troponin increased in blood specimen
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to onasemnogene abeparvovec or any component of the formulation.
Concerns related to adverse effects:
• Cardiac effects: Increases in troponin-I levels have been observed, but clinical significance is unknown; cardiac toxicity was observed in animal studies. Consider cardiology consult in patients with troponin elevations accompanied by cyanosis, heart rate changes, respiratory distress, or tachypnea.
• Hepatotoxicity: Acute serious liver injury, acute liver failure, and elevated transaminases have been reported and may be immune mediated in nature; concomitant systemic corticosteroids therapy should be continued for ≥28 days after dose. Patients with preexisting hepatic impairment or acute hepatic viral illness may be at increased risk for hepatotoxicity; use with caution.
• Thrombocytopenia: Transient decreases in platelet counts have been observed, typically within the first 2 weeks after the infusion.
• Thrombotic microangiopathy: Cases of thrombotic microangiopathy (TMA), including acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia, have been reported approximately 1 week after therapy; concurrent immune system activation (eg, infections, vaccinations) was present in some cases. Monitor patients closely and further evaluate patients for hemolytic anemia and renal impairment if signs occur in the presence of thrombocytopenia. Consult a pediatric hematologist and/or nephrologist immediately if clinical symptoms or laboratory findings are consistent with TMA.
Disease related concerns:
• Infection: Postpone therapy in patients with concurrent infection until the infection has resolved; risk of serious systemic immune response may occur.
Concurrent drug therapy issues:
• Vaccines: Vaccination schedule may need to be adjusted due to corticosteroid administration before and after onasemnogene abeparvovec infusion.
Other warnings/precautions:
• Immunogenicity: Safety and efficacy have not been evaluated in patients with anti-AAV9 antibody titers above 1:50. Perform baseline testing for the presence of anti-AAV9 antibodies; retesting may be performed if anti-AAV9 antibody titers are reported as >1:50.
• Vector shedding: Temporary vector shedding of onasemnogene abeparvovec occurs primarily through body waste. Recommended procedures when handling patient feces include sealing disposable diapers in disposable trash bags and then discarding into regular trash. Use proper hand hygiene when coming into direct contact with patient body waste. Follow these precautions for 1 month after the infusion.
Administration to premature infants should be delayed until PMA is corrected to full term; concomitant use of corticosteroids may adversely affect neurological development.
None known.
There are no known significant interactions.
Animal reproduction studies have not been conducted. Onasemnogene abeparvovec is not approved for use in patients of reproductive age.
It is not known if onasemnogene abeparvovec is present in breast milk.
It is not known if breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother; however, onasemnogene abeparvovec is not approved for use in patients of reproductive age.
Baseline: Liver function (clinical exam, AST, ALT, total bilirubin, and PT), CBC (Hb, platelet count), SCr, troponin-I, and anti-AAV9 antibody test.
First month after treatment: Liver function (clinical exam, AST, ALT, total bilirubin, and PT), platelets, and troponin-I (check weekly); signs and symptoms of thrombotic microangiopathy (eg, hypertension, bruising, decreased urine output, seizures).
Second and third month after treatment: Liver function (clinical exam, AST, ALT, total bilirubin, and PT) every other week until AST/ALT are <2 × ULN, PT is normal, total bilirubin is normal, and clinical exam is normal; platelet count every other week until counts return to baseline, and troponin-I monthly until troponin-I level returns to baseline; signs and symptoms of thrombotic microangiopathy (eg, hypertension, bruising, decreased urine output, seizures).
A recombinant adeno-associated virus vector-based gene therapy that delivers a normal copy of the gene encoding human survival motor neuron (SMN) protein.
Following administration, generalized SMN expression was shown in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver, skeletal muscles, and other tissues. Vector DNA can be detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, spinal cord, brain, and thymus; the highest concentrations have been found in the liver. Vector DNA is shed in saliva, urine, and stool; undetectable levels here achieved within 3 weeks, 1 to 2 weeks, and 1 to 2 months, respectively, following infusion.
Kit (Zolgensma 10.1-10.5 kg Intravenous)
7x8.3 mL (per each): $0.00
Kit (Zolgensma 10.6-11.0 kg Intravenous)
2x5.5ML &6x8.3ML (per each): $0.00
Kit (Zolgensma 11.1-11.5 kg Intravenous)
1x5.5ML &7x8.3ML (per each): $0.00
Kit (Zolgensma 11.6-12.0 kg Intravenous)
8x8.3 mL (per each): $0.00
Kit (Zolgensma 12.1-12.5 kg Intravenous)
2x5.5ML &7x8.3ML (per each): $0.00
Kit (Zolgensma 12.6-13.0 kg Intravenous)
1x5.5ML &8x8.3ML (per each): $0.00
Kit (Zolgensma 13.1-13.5 kg Intravenous)
9x8.3 mL (per each): $0.00
Kit (Zolgensma 2.6-3.0 kg Intravenous)
2x8.3 mL (per each): $0.00
Kit (Zolgensma 3.1-3.5 kg Intravenous)
2x5.5ML &1x8.3ML (per each): $0.00
Kit (Zolgensma 3.6-4.0 kg Intravenous)
1x5.5ML &2x8.3ML (per each): $0.00
Kit (Zolgensma 4.1-4.5 kg Intravenous)
3x8.3 mL (per each): $0.00
Kit (Zolgensma 4.6-5.0 kg Intravenous)
2x5.5ML &2x8.3ML (per each): $0.00
Kit (Zolgensma 5.1-5.5 kg Intravenous)
1x5.5ML &3x8.3ML (per each): $0.00
Kit (Zolgensma 5.6-6.0 kg Intravenous)
4x8.3 mL (per each): $0.00
Kit (Zolgensma 6.1-6.5 kg Intravenous)
2x5.5ML &3x8.3ML (per each): $0.00
Kit (Zolgensma 6.6-7.0 kg Intravenous)
1x5.5ML &4x8.3ML (per each): $0.00
Kit (Zolgensma 7.1-7.5 kg Intravenous)
5x8.3 mL (per each): $0.00
Kit (Zolgensma 7.6-8.0 kg Intravenous)
2x5.5ML &4x8.3ML (per each): $0.00
Kit (Zolgensma 8.1-8.5 kg Intravenous)
1x5.5ML &5x8.3ML (per each): $0.00
Kit (Zolgensma 8.6-9.0 kg Intravenous)
6x8.3 mL (per each): $0.00
Kit (Zolgensma 9.1-9.5 kg Intravenous)
2x5.5ML &5x8.3ML (per each): $0.00
Kit (Zolgensma 9.6-10.0 kg Intravenous)
1x5.5ML &6x8.3ML (per each): $0.00
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