Zolgensma

— THERAPEUTIC CATEGORIES —
  • Miscellaneous musculoskeletal disorders
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Zolgensma Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Onasemnogene abeparvovec-xioi 2.0x10^13 vector genomes (vg); per mL; susp for IV infusion; preservative-free.

    Pharmacological Class

    Adeno-associated virus vector-based gene therapy.

    How Supplied

    Customized kit—1 (2–9 vials + alcohol wipes)

    How Supplied

    Zolgensma is supplied in 10 mL vials with 2 fill volumes (either 5.5 mL or 8.3 mL). 

    Zolgensma is provided as a customized kit to meet dosing requirements for each patient, with each kit containing:

    • 2 to 14 vials of Zolgensma.

    • 1 alcohol wipe per vial.

    • For kit sizes and NDC: see full labeling.

    Storage

    • Zolgensma is shipped frozen (≤ -60°C [-76°F]) in clear vials. 

    • Upon receipt, immediately place the kit in a refrigerator at 2°C to 8°C (36°F to 46°F). 

    • Zolgensma is stable for 14 days from receipt when stored at 2°C to 8°C (36°F to 46°F). 

    • Do not refreeze.

    • Must use within 14 days of receipt.

    Manufacturer

    Novartis Gene Therapies, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the SMN1 gene encoding the human SMN protein.

    Zolgensma Indications

    Indications

    Spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

    Limitations of Use

    Safety and efficacy 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.

    Zolgensma Dosage and Administration

    Prior to Treatment Evaluations

    Prior to Zolgensma infusion:

    • Due to the increased risk for serious systemic immune response, give Zolgensma to patients who are clinically stable in their overall baseline health status (eg, hydration and nutritional status absence of infection) prior to infusion.

    • Postpone infusion if patients have an infection until it has resolved and the patient is clinically stable.

    • Obtain liver function (clinical exam, AST, ALT, total bilirubin, albumin, prothrombin time, PTT, INR) at baseline. Obtain creatinine, CBC, and troponin-I.

    • Perform baseline testing for the presence of anti-AAV9 antibodies; may retest if anti-AAV9 antibody titers are >1:50.

    • Starting one day prior to Zolgensma infusion: give systemic corticosteroids equivalent to oral prednisolone 1mg/kg/day for 30 days. At the end of the 30-day period, check liver status clinically and assess ALT, AST, total bilirubin, prothrombin time, and INR.

      • For patients with unremarkable LFT findings after 30 days, taper corticosteroid dose gradually over the next 28 days.

      • If liver function abnormalities persist, continue systemic corticosteroids until AST and ALT values are both below 2×ULN and all other assessments return to normal range, then taper corticosteroid dose.

      • If liver function abnormalities continue to persist greater than or equal to 2×ULN after 30 days, consult a pediatric gastroenterologist or hepatologist.

      • Consider IV corticosteroids as clinically indicated if oral corticosteroid therapy is not tolerated.

    Adult

    ≥2yrs: not applicable.

    Children

    Give as a slow IV infusion over 60mins. <2yrs: 1.1×1014 vg/kg (see full labeling). Starting one day prior to Zolgensma infusion: give systemic corticosteroids equivalent to oral prednisolone 1mg/kg/day for 30 days, then taper dose gradually over the next 28 days if LFTs are unremarkable.

    Children

    Give as a slow IV infusion over 60mins. Recommended dose for <2yrs: 1.1×1014 vg/kg. 

    Dosing

    • Weight range: 2.6–3.0 kg. Dose volume: 16.5 mL.

    • Weight range: 3.1–3.5 kg. Dose volume: 19.3 mL.

    • Weight range: 3.6–4.0 kg. Dose volume: 22.0 mL.

    • Weight range: 4.1–4.5 kg. Dose volume: 24.8 mL.

    • Weight range: 4.6–5.0 kg. Dose volume: 27.5 mL.

    • Weight range: 5.1–5.5 kg. Dose volume: 30.3 mL.

    • Weight range: 5.6–6.0 kg. Dose volume: 33.0 mL.

    • Weight range: 6.1–6.5 kg. Dose volume: 35.8 mL.

    • Weight range: 6.6–7.0 kg. Dose volume: 38.5 mL.

    • Weight range: 7.1–7.5 kg. Dose volume: 41.3 mL.

    • Weight range: 7.6–8.0 kg. Dose volume: 44.0 mL.

    • Weight range: 8.1–8.5 kg. Dose volume: 46.8 mL.

    • Weight range: 8.6–9.0 kg. Dose volume: 49.5 mL.

    • Weight range: 9.1–9.5 kg. Dose volume: 52.3 mL.

    • Weight range: 9.6–10.0 kg. Dose volume: 55.0 mL.

    • Weight range: 10.1–10.5 kg. Dose volume: 57.8 mL.

    • Weight range: 10.6–11.0 kg. Dose volume: 60.5 mL.

    • Weight range: 11.1–11.5 kg. Dose volume: 63.3 mL.

    • Weight range: 11.6–12.0 kg. Dose volume: 66.0 mL.

    • Weight range: 12.1–12.5 kg. Dose volume: 68.8 mL.

    • Weight range: 12.6–13.0 kg. Dose volume: 71.5 mL.

    • Weight range: 13.1–13.5 kg. Dose volume: 74.3 mL.

    • Weight range: 13.6–14.0 kg. Dose volume: 77.0 mL.

    • Weight range: 14.1–14.5 kg. Dose volume: 79.8 mL.

    • Weight range: 14.6–15.0 kg. Dose volume: 82.5 mL.

    • Weight range: 15.1–15.5 kg. Dose volume: 85.3 mL.

    • Weight range: 15.6–16.0 kg. Dose volume: 88.0 mL.

    • Weight range: 16.1–16.5 kg. Dose volume: 90.8 mL.

    • Weight range: 16.6–17.0 kg. Dose volume: 93.5 mL.

    • Weight range: 17.1–17.5 kg. Dose volume: 96.3 mL.

    • Weight range: 17.6–18.0 kg. Dose volume: 99.0 mL.

    • Weight range: 18.1–18.5 kg. Dose volume: 101.8 mL.

    • Weight range: 18.6–19.0 kg. Dose volume: 104.5 mL.

    • Weight range: 19.1–19.5 kg. Dose volume: 107.3 mL.

    • Weight range: 19.6–20.0 kg. Dose volume: 110.0 mL.

    • Weight range: 20.1–20.5 kg. Dose volume: 112.8 mL.

    • Weight range: 20.6–21.0 kg. Dose volume: 115.5 mL.

    Zolgensma Contraindications

    Not Applicable

    Zolgensma Boxed Warnings

    Boxed Warning

    Acute serious liver injury. Acute liver failure.

    Zolgensma Warnings/Precautions

    Warnings/Precautions

    Risk of acute serious liver injury and acute liver failure (esp. preexisting liver impairment or acute hepatic viral infection). ALT, AST, or total bilirubin levels (except due to neonatal jaundice) >2×ULN: not studied. Monitor liver function prior to infusion, weekly for the 1st month, then every other week for the 2nd/3rd months until unremarkable results. Monitor creatinine, CBC prior to infusion. Monitor platelets and troponin-I prior to infusion, weekly for the 1st month, then every other week (platelets) and monthly (troponin-I) for the 2nd/3rd months until levels return to baseline. Monitor for thrombotic microangiopathy (TMA); evaluate for hemolytic anemia and renal dysfunction if thrombocytopenia develops. Increased risk of serious systemic immune response; delay infusion in those with concurrent infections until resolved. Perform baseline anti-AAV9 antibody testing prior to infusion; may retest if titers are >1:50. Consult a specialist if acute serious liver injury/liver failure is suspected, troponin elevations accompanied by signs/symptoms, or TMA occurs. Premature neonates: delay infusion until full-term gestational age is reached.

    Warnings/Precautions

    Acute Serious Liver Injury, Acute Liver Failure or Elevated Aminotransferases

    • Risk of acute serious liver injury, acute liver failure and elevated aminotransferases. 

    • Increased risk for acute serious liver injury and acute liver failure in patients with preexisting liver impairment or acute hepatic viral infection. Patients with ALT, AST, or total bilirubin levels (except due to neonatal jaundice) >2×ULN: not studied. Carefully consider the risks/benefits in patients with preexisting liver impairment.

    • Prior to infusion, obtain liver function (AST, ALT, total bilirubin level, albumin, prothrombin time, PTT, and INR). Monitor liver function weekly for the 1st month, then every other week for the 2nd/3rd months until unremarkable results. 

    • Consult a specialist if acute serious liver injury/liver failure is suspected

    Systemic Immune Response 

    • Increased risk for serious and life-threatening systemic immune response. To reduce the risk, give Zolgensma to patients who are clinically stable in overall health status (eg, hydration and nutritional status, absence of infection).

    • Delay infusion in those with concurrent infections until resolved and clinically stable. 

    • Recommend seasonal prophylaxis against flu and RSV and vaccination status should be up-to-date prior to infusion. 

    Thrombocytopenia

    • Transient decreases in platelet counts were typically observed within the first 2 weeks after infusion.

    • Monitor platelet counts before infusion and within the first 2 weeks after infusion and on a regular basis thereafter (at least weekly for the 1st month; every other week for the 2nd/3rd months or until counts return to baseline).

    Thrombotic Microangiopathy 

    • Cases of thrombotic microangiopathy (TMA) were reported to occur generally within the first two weeks after infusion.

    • Monitor platelet counts before infusion and within the first 2 weeks after infusion and on a regular basis thereafter.

    • Consult a specialist if signs/symptoms and/or laboratory findings consistent with TMA occur.

    Elevated Troponin-I

    • Monitor troponin-I prior to infusion, weekly for the 1st month, then monthly for the 2nd/3rd months until levels return to baseline. 

    • Consult a specialist if troponin elevations are accompanied by clinical signs or symptoms (eg, HR changes, cyanosis, tachypnea, and respiratory distress).

    Pregnancy Considerations

    No available data on the use of Zolgensma in pregnant women.

    Nursing Mother Considerations

    Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Zolgensma and any potential adverse effects on the breastfed child from Zolgensma or from the underlying maternal condition.

    Pediatric Considerations

    Administration to premature neonates before reaching full-term gestational age is not recommended.

    Delay infusion until full-term gestational age is reached.

    Hepatic Impairment Considerations

    Carefully consider Zolgensma therapy in patients with liver impairment.

    Zolgensma Pharmacokinetics

    See Literature

    Zolgensma Interactions

    Interactions

    Adjust vaccination schedule to accommodate concomitant corticosteroid use before and after infusion.

    Zolgensma Adverse Reactions

    Adverse Reactions

    Elevated aminotransferases, vomiting; hepatotoxicity, thrombocytopenia, TMA, elevated troponin-I.

    Zolgensma Clinical Trials

    Clinical Trials

    • The efficacy of Zolgensma was based on data from the ongoing open-label, single-arm phase 3 STR1VE trial that included 21 pediatric patients less than 2 years of age. Patients were administered a single-dose intravenous infusion of Zolgensma.

    • Eligible patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. The mean age at the time of treatment was 3.9 months (range, 0.5 to 5.9 months). All patients had genetically confirmed bi-allelic SMN1 gene deletions, 2 copies of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of SMN2 gene (which predicts a milder phenotype). All patients had baseline anti-AAV9 antibody titers of ≤ 1:50, measured by ELISA.

    • The primary endpoints are based on achievement of independent sitting for at least 30 seconds (18 months of age visit) and event-free survival (defined as avoidance of death or permanent ventilation); secondary endpoints include the ability to thrive and ventilatory support independence through 18 months of age.

    • By the March 2019 data cutoff, results showed 13 of the 19 patients reached 14 months of age without permanent ventilation; 10 of the 21 patients (47.6%) achieved the ability to sit without support for ≥30 seconds between 9.2 and 16.9 months of age (mean age was 12.1 months); 16 of the 19 patients had not required daily non-invasive ventilator (NIV) use.

    Zolgensma Note

    Not Applicable

    Zolgensma Patient Counseling

    Patient Counseling

    Acute Serious Liver Injury, Acute Liver Failure or Elevated Aminotransferases

    • Advise that liver enzyme levels could increase and cause acute serious livery injury or acute liver failure, and death. Advise that patients will receive an oral corticosteroid medication before and after infusion with Zolgensma, and will undergo regular blood tests to monitor liver function.

    • Contact healthcare provider immediately if the patient’s skin and/or whites of the eyes appear yellowish, if the patient misses a dose of corticosteroid or vomits it up, or if the patient experiences a decrease in alertness.

    Vaccination Before and After Infusion With Zolgensma

    • Advise caregivers to consult with their healthcare provider to determine if adjustments to the patient’s vaccination schedule are necessary during corticosteroid use.

    • When feasible, adjust vaccination schedule appropriately to accommodate treatment with corticosteroid.

    • Recommended to administer prophylaxis against flu and RSV and vaccination status should be up-to-date prior to infusion.

    Systemic Immune Response

    • Inform caregivers that an infection prior to or after infusion could lead to serious complications. Follow infection prevention practices (eg, hand hygiene, coughing/sneezing etiquette, limiting potential contacts).

    • Contact healthcare provider immediately if any symptoms suggestive of infection occur prior to or after infusion.

    Thrombocytopenia and Thrombotic Microangiopathy (TMA)

    • Advise that Zolgensma could decrease blood platelet count and RBC counts leading to acute kidney injury and increase the risk of bruising or bleeding. 

    • Thrombocytopenia and TMA has been reported to generally occur within the first 2 weeks after infusion. 

    • Seek medical attention if unexpected bruising or bleeding, seizures, or decreased urine output occur.

    Vector Shedding

    • Temporary vector shedding of Zolgensma occurs primarily through body waste. Advise caregivers on the proper handling of patient feces; recommended procedures include sealing disposable diapers in disposable trash bags and then discarding into regular trash.

    • Caregivers and family members should follow proper hand hygiene when coming into direct contact with patient body waste.

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