ature. If thawed in a refrigerator, remove from refrigerator onday of dosing.
• When thawed, ZOLGENSMA is a clear to slightly opaque, colorless to faint whiteliquid, free of particles. Visually inspect vials for particulate matter anddiscolorationprior to infusion. Do not use vials if particulates or discoloration are present.
• DO NOT SHAKE.
• Draw the appropriate dose volume from all vials into a syringe, remove air from thesyringe, cap the syringe, and deliver the syringe at room temperature to the patientinfusion location.
• Use ZOLGENSMA within 8 hours of drawing into syringe. Discard the vectorcontainingsyringe if the drug is not infused within the 8-hour timeframe.
• DO NOT REFREEZE.
2.3 Laboratory Testing and Monitoring to Assess SafetyPerform baseline anti-AAV9 antibody testing prior to ZOLGENSMA infusion. Retesting may beperformed if anti-AAV9 antibody titers are reported as >1:50 [see Dose and Administration(2.1)].
Conduct the following tests at baseline and as directed below [see Warnings and Precautions(5.1, 5.2, 5.3)]:
• Liver function (clinical exam, AST, ALT, total bilirubin, prothrombin time) weeklyfor the first month; every other week for the second and third months, until results areunremarkable (normal clinical exam, total bilirubin, and prothrombin results, andALT and AST levels below 2 × ULN).
• Platelet counts weekly for the first month, and then every other week for the secondand third months, until platelet counts return to baseline.
• Troponin-I weekly for the first month, and then monthly for the second and thirdmonths, until troponin-I level returns to baseline.
3 DOSAGE FORMS AND STRENGTHS
ZOLGENSMA is a suspension for intravenous infusion.
ZOLGENSMA is provided in a kit containing 2 to 9 vials. Vials are provided in 2 fill volumes:5.5 mL or 8.3 mL.
ZOLGENSMA has a nominal concentration of 2.0 × 1013 vg/mL, and each vial contains anextractable volume of not less than either 5.5 mL or 8.3 mL.
The intravenous dosage is determined by patient body weight, with a recommended dose of1.1 × 1014 vg/kg for pediatric patients.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Acute Serious Liver Injury and Elevated AminotransferasesAcute serious liver injury can occur with ZOLGENSMA. Prior to ZOLGENSMA infusion, apatient with infantile-onset SMA had elevated AST and ALT of unknown etiology (gammaglutamyltransferase (GGT), total bilirubin and prothrombin time were normal). The patient was
treated under an expanded access program in the United States. The patient receivedcorticosteroids 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 patientbecame jaundiced. Laboratory testing was consistent with acute serious liver injury, with ASTlevel approximately 80 × ULN and ALT level approximately 45 × ULN, total bilirubinapproximately 4 × ULN, and plasma prothrombin time approximately 4 × ULN. Liver biopsyshowed 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.
Administration of ZOLGENSMA may result in aminotransferase elevations. Two (2/44) patientsin clinical trials had increased AST and ALT levels up to 48 &ti |
