Dosage & Administration
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Zolgensma Prescribing Information
- Cases of acute liver failure with fatal outcomes have been reported. Acute serious liver injury and elevated aminotransferases can also occur with ZOLGENSMA[see Warnings and Precautions ()].
5.1 Acute Serious Liver Injury, Acute Liver Failure or Elevated AminotransferasesAcute serious liver injury, acute liver failure and elevated aminotransferases can occur with ZOLGENSMA. Hepatotoxicity (which may be immune-mediated), generally manifested as elevated ALT and/or AST levels. Acute serious liver injury and acute liver failure, including fatal cases, have been reported with ZOLGENSMA use
[see Adverse Reactions ]. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid to all patients before and after ZOLGENSMA infusion. Immune-mediated hepatotoxicity may require adjustment of the corticosteroid treatment regimen, including longer duration, increased dose, or prolongation of the corticosteroid taper[see Dosage and Administration ].Patients with preexisting liver impairment or acute hepatic viral infection may be at higher risk of acute serious liver injury/acute liver failure. Patients with ALT, AST, or total bilirubin levels (except due to neonatal jaundice) > 2 × ULN have not been studied in clinical trials with ZOLGENSMA. Carefully consider the risks and benefits of ZOLGENSMA therapy in patients with preexisting liver impairment.
Although in the clinical trials and in postmarketing experience, asymptomatic aminotransferase elevations were very commonly reported
[see Adverse Reactions ], in the managed access program and in the postmarketing setting, cases of acute serious liver injury and acute liver failure, including a few cases with fatal outcomes, have been reported. Some patients have experienced elevations in ALT and AST > 20 × ULN, prolonged prothrombin time and have been symptomatic (e.g., vomiting, jaundice), which required the use of corticosteroids, sometimes with prolonged duration and/or a higher dose. If acute serious liver injury or acute liver failure is suspected, promptly consult a pediatric gastroenterologist or hepatologist.Prior to ZOLGENSMA infusion, assess liver function by clinical examination and laboratory testing (hepatic aminotransferases [AST and ALT], total bilirubin level, albumin, prothrombin time, PTT, and INR). Continue to monitor liver function (AST, ALT, total bilirubin, prothrombin time, INR) for at least 3 months after ZOLGENSMA infusion, and at other times as clinically indicated.
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). In case hepatic injury is suspected, further testing of albumin, PTT, and INR is recommended.
Monitor liver function 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 at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month
[see Dosage and Administration ]. - Patients with preexisting liver impairment may be at higher risk[see Warnings and Precautions ()].
5.1 Acute Serious Liver Injury, Acute Liver Failure or Elevated AminotransferasesAcute serious liver injury, acute liver failure and elevated aminotransferases can occur with ZOLGENSMA. Hepatotoxicity (which may be immune-mediated), generally manifested as elevated ALT and/or AST levels. Acute serious liver injury and acute liver failure, including fatal cases, have been reported with ZOLGENSMA use
[see Adverse Reactions ]. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid to all patients before and after ZOLGENSMA infusion. Immune-mediated hepatotoxicity may require adjustment of the corticosteroid treatment regimen, including longer duration, increased dose, or prolongation of the corticosteroid taper[see Dosage and Administration ].Patients with preexisting liver impairment or acute hepatic viral infection may be at higher risk of acute serious liver injury/acute liver failure. Patients with ALT, AST, or total bilirubin levels (except due to neonatal jaundice) > 2 × ULN have not been studied in clinical trials with ZOLGENSMA. Carefully consider the risks and benefits of ZOLGENSMA therapy in patients with preexisting liver impairment.
Although in the clinical trials and in postmarketing experience, asymptomatic aminotransferase elevations were very commonly reported
[see Adverse Reactions ], in the managed access program and in the postmarketing setting, cases of acute serious liver injury and acute liver failure, including a few cases with fatal outcomes, have been reported. Some patients have experienced elevations in ALT and AST > 20 × ULN, prolonged prothrombin time and have been symptomatic (e.g., vomiting, jaundice), which required the use of corticosteroids, sometimes with prolonged duration and/or a higher dose. If acute serious liver injury or acute liver failure is suspected, promptly consult a pediatric gastroenterologist or hepatologist.Prior to ZOLGENSMA infusion, assess liver function by clinical examination and laboratory testing (hepatic aminotransferases [AST and ALT], total bilirubin level, albumin, prothrombin time, PTT, and INR). Continue to monitor liver function (AST, ALT, total bilirubin, prothrombin time, INR) for at least 3 months after ZOLGENSMA infusion, and at other times as clinically indicated.
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). In case hepatic injury is suspected, further testing of albumin, PTT, and INR is recommended.
Monitor liver function 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 at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month
[see Dosage and Administration ]. - Prior to infusion, assess liver function of all patients by clinical examination and laboratory testing. Administer systemic corticosteroid to all patients before and after ZOLGENSMA infusion. Continue to monitor liver function for at least 3 months after infusion, and at other times as clinically indicated[see Dosage and Administration (,
2.1 Dose and AdministrationThe recommended dose of ZOLGENSMA is 1.1 × 1014vector genomes per kilogram (vg/kg) of body weight.
Table 1: Dosing Patient weight range (kg)Dose volumea(mL)aDose 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 , Patient Counseling Information ].
- Assess liver function[see Boxed Warning, Dosage and Administration , Warnings and Precautions , Use in Specific Populations ].
- Obtain creatinine and complete blood count (including hemoglobin and platelet count)[see Dosage and Administration , Warnings and Precautions ].
- Perform baseline testing for the presence of anti-AAV9 antibodies[see Dosage and Administration , Adverse Reactions ].
- 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
- 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:
1.000000000000000e+00 Place a primary catheter into a vein (generally a peripheral vein in the arm or leg). Insertion of a back-up catheter is recommended.2.000000000000000e+00 Program syringe pump for saline priming, or prime tubing manually with saline.3.000000000000000e+00 Administer ZOLGENSMA as a slow infusion over 60 minutes. DO NOT INFUSE AS AN INTRAVENOUS PUSH OR BOLUS.4.000000000000000e+00 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 ].
- 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 ].
- 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 ].
- 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 ].
- 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 ].
- If oral corticosteroid therapy is not tolerated, consider intravenous corticosteroids as clinically indicated[see Warnings and Precautions ].
)].2.3 Laboratory Testing and Monitoring to Assess SafetyPerform 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 ].Conduct the following tests at baseline and as directed below
[see Warnings and Precautions ]:- 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.
- Prior to ZOLGENSMA infusion:
Dosage and Administration (The recommended dose of ZOLGENSMA is 1.1 × 1014vector genomes per kilogram (vg/kg) of body weight.
Follow the steps below for infusion:
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 ] .Conduct the following tests at baseline and as directed below [see Warnings and Precautions ] :
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Warnings and Precautions (There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome.ZOLGENSMA is composed of a recombinant, non-replicating AAV9 vector whose DNA persists largely in episomal form. Random integration of recombinant AAV vector DNA into human DNA has been reported with ZOLGENSMA and in published literature about other AAV gene therapies. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumorigenicity. Cases of tumor have been reported in patients who received ZOLGENSMA post-approval. A causal relationship with ZOLGENSMA has not been established based on tumor analyses. However, in some cases, limited information was available. If a tumor develops in a patient receiving ZOLGENSMA, healthcare providers should contact and report the tumor to Novartis Gene Therapies, Inc. at 1-833-828-3947. | 10/2024 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Warnings and Precautions (Increases in cardiac troponin I levels (up to 0.176 mcg/L) have occurred following ZOLGENSMA infusion in clinical trials. Cardiac toxicity was observed in animal studies [see Nonclinical Toxicology ] . Consider cardiac evaluation after ZOLGENSMA infusion and consult a cardiologist as needed.Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred with ZOLGENSMA infusion [see Adverse Reactions ] . Signs and symptoms may include rash, urticaria, vomiting, dyspnea, respiratory symptoms and/or alterations in heart rate and blood pressure. Monitor patients during and after treatment with ZOLGENSMA. If an infusion-related reaction occurs, interrupt ZOLGENSMA infusion and administer supportive treatment to manage the infusion-related reaction as appropriate. Infusion of ZOLGENSMA may be resumed based on clinical assessment. | 2/2025 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
- The safety and effectiveness of repeat administration of ZOLGENSMA have not been evaluated [see Adverse Reactions (.)]
6.2 ImmunogenicityIn ZOLGENSMA clinical trials, patients were required to have baseline anti-AAV9 antibody titers of ≤ 1:50, measured using an enzyme-linked immunosorbent assay (ELISA). Evidence of prior exposure to AAV9 was uncommon. The safety and efficacy of ZOLGENSMA in patients with anti-AAV9 antibody titers above 1:50 have not been evaluated. Perform baseline testing for the presence of anti-AAV9 antibodies prior to ZOLGENSMA infusion. Retesting may be performed if anti-AAV9 antibody titers are reported as > 1:50
[see Dosage and Administration ].Following ZOLGENSMA infusion, increases from baseline in anti-AAV9 antibody titers occurred in all patients. In Study 2, anti-AAV9 antibody titers reached at least 1:102,400 in every patient, and titers exceeded 1:819,200 in most patients. Re-administration of ZOLGENSMA in the presence of high anti-AAV9 antibody titer has not been evaluated.
- The use of ZOLGENSMA in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator-dependence) has not been evaluated [see Clinical Studies (.)]
14 CLINICAL STUDIESThe efficacy of ZOLGENSMA in pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the
SMN1gene was evaluated in an open-label, single-arm clinical trial (Study 1, NCT03306277) and an open-label, single-arm, ascending-dose clinical trial (Study 2, NCT02122952). Patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. All patients had genetically confirmed bi-allelicSMN1gene deletions, 2 copies of theSMN2gene, and absence of the c.859G>C modification in exon 7 ofSMN2gene (which predicts a milder phenotype). All patients had baseline anti-AAV9 antibody titers of ≤ 1:50, measured by ELISA. In both trials, ZOLGENSMA was delivered as a single-dose intravenous infusion.Efficacy was established on the basis of survival, and achievement of developmental motor milestones, such as sitting without support. Survival was defined as time from birth to either death or permanent ventilation. Permanent ventilation was defined as requiring invasive ventilation (tracheostomy), or respiratory assistance for 16 or more hours per day (including noninvasive ventilatory support) continuously for 14 or more days in the absence of an acute reversible illness, excluding perioperative ventilation. Efficacy was also supported by assessments of ventilator use, nutritional support and scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is an assessment of motor skills in patients with infantile-onset SMA.
Study 1 enrolled 21 patients (10 male and 11 female) with infantile-onset SMA. Before treatment with ZOLGENSMA, none of the 21 patients required noninvasive ventilator (NIV) support, and all patients could exclusively feed orally (i.e., no need for non-oral nutrition). The mean CHOP-INTEND score at baseline was 31.0 (range, 18 to 47). All the patients received 1.1 × 1014vg/kg of ZOLGENSMA. The mean age of the 21 patients at the time of treatment was 3.9 months (range, 0.5 to 5.9 months).
As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (i.e., event-free survival) and were continuing in the trial, while one patient died at age 7.8 months due to disease progression, and one patient withdrew from the study at age 11.9 months. The 19 surviving patients who were continuing in the trial ranged in age from 9.4 to 18.5 months. By the data cutoff, 13 of the 19 patients continuing in the trial reached 14 months of age without permanent ventilation, one of the study’s co-primary efficacy endpoints. In addition to survival, assessment of the other co-primary efficacy endpoint found that 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). Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support, and only approximately 25% of these patients would be expected to survive (i.e., being alive without permanent ventilation) beyond 14 months of age. In addition, 16 of the 19 patients had not required daily NIV use.
Comparison of the results of Study 1 to available natural history data of patients with infantile-onset SMA provides primary evidence of the effectiveness of ZOLGENSMA.
Study 2 enrolled 15 patients (6 male and 9 female) with infantile-onset SMA, 3 in a low-dose cohort and 12 in a high-dose cohort. At the time of treatment, the mean age of patients in the low-dose cohort was 6.3 months (range, 5.9 to 7.2 months), and 3.4 months (range, 0.9 to 7.9 months) in the high-dose cohort. 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. However, the precise dosages of ZOLGENSMA received by patients are unclear due to a change in the method of measuring ZOLGENSMA concentration, and to decreases in the concentration of stored ZOLGENSMA over time. The retrospectively-estimated dosage range in the high-dose cohort is approximately 1.1 × 1014to 1.4 × 1014vg/kg.
By 24 months following ZOLGENSMA infusion, one patient in the low-dose cohort met the endpoint of permanent ventilation; all 12 patients in the high-dose cohort were alive without permanent ventilation. None of the patients in the low-dose cohort were able to sit without support, or to stand or walk; in the high-dose cohort, 9 of the 12 patients (75.0%) were able to sit without support for ≥ 30 seconds, and 2 patients (16.7%) were able to stand and walk without assistance. Comparison of the results of the low-dose cohort to the results of the high-dose cohort shows a dose-response relationship that supports the effectiveness of ZOLGENSMA.
ZOLGENSMA is a suspension for intravenous infusion.
ZOLGENSMA is provided in a kit containing 2 to 14 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 an extractable 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 of 1.1 × 1014 vg/kg for pediatric patients.
Pediatric Use: Use of ZOLGENSMA in premature neonates before reaching full term gestational age is not recommended because concomitant treatment with corticosteroids may adversely affect neurological development. Delay ZOLGENSMA infusion until full-term gestational age is reached. (
The safety of ZOLGENSMA was studied in pediatric patients who received ZOLGENSMA infusion at age 0.3 to 7.9 months (weight range, 3.0 kg to 8.4 kg). Safety was also studied in Study 3 (post-authorization study) in patients weighing 9.5 kg to 20.2 kg
The efficacy of ZOLGENSMA was studied in pediatric patients who received ZOLGENSMA infusion at age 0.5 to 7.9 months (weight range, 3.6 kg to 8.4 kg)
Administration of ZOLGENSMA to premature neonates before reaching full-term gestational age is not recommended, because concomitant treatment with corticosteroids may adversely affect neurological development. Delay ZOLGENSMA infusion until the corresponding full-term gestational age is reached.