Zolgensma

2 DOSAGE AND ADMINISTRATION For single-dose intravenous infusion only. For single-dose intravenous infusion only ( 2 ). The recommended dosage of ZOLGENSMA is 1.1 × 10 14 vector genomes (vg) per kg of body weight. ( 2.1 ) Administer ZOLGENSMA as an intravenous infusion over 60 minutes. ( 2.1 , 2.3 ) Postpone ZOLGENSMA in patients with infections until the infection has resolved and the patient is clinically stable. ( 2.1 , 5.2 ) Starting one day prior to ZOLGENSMA infusion, administer systemic corticosteroids equivalent to oral prednisolone at 1 mg/kg of body weight per day for a total of 30 days. At the end of the 30-day period, check liver function by clinical examination and by laboratory testing. For patients with unremarkable findings, taper the corticosteroid dose gradually over the next 28 days. If liver function abnormalities persist, continue systemic corticosteroids (equivalent to oral prednisolone at 1 mg/kg/day) until findings become unremarkable, and then taper the corticosteroid dose gradually over the next 28 days or longer if needed. Do not stop systemic corticosteroids abruptly. ( 2.1 ) If liver function abnormalities continue to persist ≥ 2 × ULN after the 30-day period of systemic corticosteroids, promptly consult a pediatric gastroenterologist or hepatologist. ( 2.1 ) 2.1 Dose and Administration The recommended dose of ZOLGENSMA is 1.1 × 10 14 vector genomes per kilogram (vg/kg) of body weight. Table 1: Dosing Patient weight range (kg) Dose volume a (mL) a Dose volume is calculated using the upper limit of the patient weight range for pediatric patients less than 2 years of age between 2.6 kg and 21.0 kg. 2.6 – 3.0 16.5 3.1 – 3.5 19.3 3.6 – 4.0 22.0 4.1 – 4.5 24.8 4.6 – 5.0 27.5 5.1 – 5.5 30.3 5.6 – 6.0 33.0 6.1 – 6.5 35.8 6.6 – 7.0 38.5 7.1 – 7.5 41.3 7.6 – 8.0 44.0 8.1 – 8.5 46.8 8.6 – 9.0 49.5 9.1 – 9.5 52.3 9.6 – 10.0 55.0 10.1 – 10.5 57.8 10.6 – 11.0 60.5 11.1 – 11.5 63.3 11.6 – 12.0 66.0 12.1 – 12.5 68.8 12.6 – 13.0 71.5 13.1 – 13.5 74.3 13.6 – 14.0 77.0 14.1 – 14.5 79.8 14.6 – 15.0 82.5 15.1 – 15.5 85.3 15.6 – 16.0 88.0 16.1 – 16.5 90.8 16.6 – 17.0 93.5 17.1 – 17.5 96.3 17.6 – 18.0 99.0 18.1 – 18.5 101.8 18.6 – 19.0 104.5 19.1 – 19.5 107.3 19.6 – 20.0 110.0 20.1 – 20.5 112.8 20.6 – 21.0 115.5 Prior to ZOLGENSMA infusion: Due to the increased risk of serious systemic immune response, administer ZOLGENSMA to patients who are clinically stable in their overall baseline health status (e.g., hydration and nutritional status, absence of infection) prior to infusion. Postpone ZOLGENSMA in patients with infections until the infection has resolved and the patient is clinically stable. Clinical signs or symptoms of infection should not be evident at the time of ZOLGENSMA infusion [see Warnings and Precautions ( 5.2 , 5.4 ), Patient Counseling Information ( 17 )]. Assess liver function [see Boxed Warning, Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 )]. Obtain creatinine and complete blood count (including hemoglobin and platelet count) [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 , 5.4 )] . Perform baseline testing for the presence of anti-AAV9 antibodies [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.2 )]. One day prior to ZOLGENSMA infusion, begin administration of systemic corticosteroids equivalent to oral prednisolone at 1 mg per kg of body weight per day (mg/kg/day) for a total of 30 days. Administer ZOLGENSMA as a single-dose intravenous infusion through a venous catheter. Follow the steps below for infusion: 1. Place a primary catheter into a vein (generally a peripheral vein in the arm or leg). Insertion of a back-up catheter is recommended. 2. Program syringe pump for saline priming, or prime tubing manually with saline. 3. Administer ZOLGENSMA as a slow infusion over 60 minutes. DO NOT INFUSE AS AN INTRAVENOUS PUSH OR BOLUS. 4. Flush line with saline following completion of infusion. Monitor liver function by clinical examination and by laboratory testing on a regular basis, and at other times as clinically indicated [see Dosage and Administration ( 2.3 )] . At the end of the 30-day period of systemic corticosteroid treatment, check liver status clinically and by assessing alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, prothrombin time, and international normalized ratio (INR). Promptly assess and closely monitor patients with worsening liver function test results and/or signs or symptoms of acute illness (e.g., vomiting, deterioration in health) [see Warnings and Precautions ( 5.1 )] . For patients with unremarkable findings (normal clinical exam, total bilirubin, prothrombin time, and INR and ALT and AST levels below 2 × upper limit of normal [ULN]): Taper the corticosteroid dose gradually over the next 28 days. Do not stop systemic corticosteroids abruptly [see Warnings and Precautions ( 5.1 )] . If liver function abnormalities persist, continue systemic corticosteroids (equivalent to oral prednisolone at 1 mg/kg/day) until AST and ALT values are both below 2 × ULN and all other assessments return to normal range, and then taper the corticosteroid dose gradually over the next 28 days or longer if needed. Do not stop systemic corticosteroids abruptly [see Warnings and Precautions ( 5.1 )] . If liver function abnormalities continue to persist ≥ 2 × ULN after the 30-day period of systemic corticosteroids, promptly consult a pediatric gastroenterologist or hepatologist [see Warnings and Precautions ( 5.1 )] . If oral corticosteroid therapy is not tolerated, consider intravenous corticosteroids as clinically indicated [see Warnings and Precautions ( 5.1 )] . 2.2 Preparation Thaw ZOLGENSMA before use. The contents of the ZOLGENSMA kit will thaw in approximately 16 hours if placed in a refrigerator, or in approximately 6 hours if placed at room temperature. If thawed in a refrigerator, remove from refrigerator on day of dosing. When thawed, ZOLGENSMA is a clear to slightly opaque, colorless to faint white liquid, free of particles. Visually inspect vials for particulate matter and discoloration prior 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 the syringe, cap the syringe, and deliver the syringe at room temperature to the patient infusion location. Use ZOLGENSMA within 8 hours of drawing into syringe. Discard the vector-containing syringe if the drug is not infused within the 8-hour timeframe. DO NOT REFREEZE. 2.3 Laboratory Testing and Monitoring to Assess Safety Perform baseline anti-AAV9 antibody testing prior to ZOLGENSMA infusion. Retesting may be performed if anti-AAV9 antibody titers are reported as > 1:50 [see Dosage and Administration ( 2.1 )] . Conduct the following tests at baseline and as directed below [see Warnings and Precautions ( 5.1 , 5.3 , 5.5 )] : Liver function (clinical exam, AST, ALT, total bilirubin, albumin, prothrombin time, partial thromboplastin time [PTT], and INR) at baseline. Monitor liver function (AST, ALT, total bilirubin, prothrombin time, INR) weekly for the first month after ZOLGENSMA infusion and during the corticosteroid taper period (28 days or longer if needed). If the patient is clinically stable with unremarkable findings (normal clinical exam, total bilirubin, and prothrombin and INR results, and ALT and AST levels below 2 × ULN) at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month. Platelet counts weekly for the first month, and then every other week for the second and third months, until platelet counts return to baseline.

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1 INDICATIONS AND USAGE ZOLGENSMA is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.