2.1     Dose and Administration

The recommended dose of ZOLGENSMA is 1.1 × 1014 vector genomes per kilogram (vg/kg) of body weight.

• 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, complete blood count (including hemoglobin and platelet count), and troponin-I [see Dosage and Administration (2.3), Warnings and Precautions (5.3, 5.4, 5.5)].
  • 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 ALT, AST, total bilirubin, prothrombin time, and 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 international normalized ratio [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.
• Troponin-I weekly for the first month, and then monthly for the second and third months, until troponin-I level returns to baseline.

5.1     Acute Serious Liver Injury, Acute Liver Failure or Elevated Aminotransferases

Acute 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 (6)]. 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 (2.1)].

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 (6.1)], 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 (2.3)].

5.2     Systemic Immune Response

Due to activation of humoral and cellular immunity following ZOLGENSMA infusion, patients with underlying active infection, either acute (e.g., respiratory, gastrointestinal) or chronic uncontrolled (e.g., chronic active hepatitis B), could be at an increased risk of serious systemic immune response, potentially resulting in more severe clinical courses of the infection. Serious systemic immune response can present with a variety of findings (e.g., high fever, hypotension, etc.). Patients with infection were excluded from participation in ZOLGENSMA clinical trials. Recommend increased vigilance in the prevention, monitoring, and management of infection before and after ZOLGENSMA infusion.

To mitigate the risk of serious and life-threatening 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 Dosage and Administration (2.1)]. Recommend seasonal prophylaxis against influenza and respiratory syncytial virus (RSV) and vaccination status should be up-to-date prior to ZOLGENSMA administration.

5.3     Thrombocytopenia

Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were typically observed within the first two weeks after ZOLGENSMA infusion.

Monitor platelet counts before ZOLGENSMA infusion and closely monitor platelet counts within the first two weeks following infusion and on a regular basis afterwards (at least weekly for the first month; every other week for the second and third months or until platelet counts return to baseline) [see Dosage and Administration (2.3)].

5.4     Thrombotic Microangiopathy

Cases of thrombotic microangiopathy (TMA) were reported to occur generally within the first two weeks after ZOLGENSMA infusion in the post-marketing setting [see Adverse Reactions (6.3)]. TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Concurrent immune system activation (e.g., infections, vaccinations) was identified in some cases.

Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes.

Monitor platelet counts closely within the first two weeks following infusion and on a regular basis afterwards [see Warnings and Precautions (5.3)], as well as signs and symptoms of TMA, such as hypertension, increased bruising, seizures, or decreased urine output. In case these signs and symptoms occur in the presence of thrombocytopenia, further diagnostic evaluation for hemolytic anemia and renal dysfunction should be promptly undertaken. If clinical signs, symptoms and/or laboratory findings consistent with TMA occur, consult a pediatric hematologist and/or pediatric nephrologist immediately to manage TMA as clinically indicated.

5.5     Elevated Troponin-I

Increases in cardiac troponin-I levels (up to 0.176 mcg/L) were observed following ZOLGENSMA infusion in clinical trials. The clinical importance of these findings is not known. However, cardiac toxicity was observed in animal studies [see Nonclinical Toxicology (13.2)]. Monitor troponin-I before ZOLGENSMA infusion and on a regular basis for at least 3 months afterwards (weekly for the first month, and then monthly for the second and third months until troponin-I level returns to baseline). Consider consultation with a cardiologist, if troponin elevations are accompanied by clinical signs or symptoms (e.g., heart rate changes, cyanosis, tachypnea and respiratory distress) [see Dosage and Administration (2.3)].

5.6     AAV Vector Integration and Risk of Tumorigenicity

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 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; information on the cases is limited and causal relationship cannot be established. If a tumor develops in a patient receiving ZOLGENSMA, health care providers should contact and report the tumor to Novartis Gene Therapies, Inc. at 1-833-828-3947.

6.1     Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.

The safety data described in this section reflect exposure to ZOLGENSMA in four open-label studies conducted in the United States, including one completed clinical trial, two ongoing clinical trials, and one ongoing observational long-term follow-up study of the completed trial. A total of 44 patients with SMA received intravenous infusion of ZOLGENSMA, 41 patients at or above the recommended dose, and 3 patients at a lower dose. The patient population ranged in age from 0.3 months to 7.9 months at the time of infusion (weight range, 3.0 kg to 8.4 kg).

The most frequent adverse reactions (incidence ≥ 5%) observed in the 4 studies are summarized in Table 2.

One patient in an ongoing non-United States clinical trial initially presented with respiratory insufficiency 12 days after ZOLGENSMA infusion and was found to have RSV and parainfluenza in respiratory secretions. The patient had episodes of serious hypotension, followed by seizures, and was found to have leukoencephalopathy (brain white matter defects) approximately 30 days after ZOLGENSMA infusion. The patient died after withdrawal of life support 52 days after ZOLGENSMA infusion.

6.2     Immunogenicity

In 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 (2.1, 2.3)].

Following ZOLGENSMA infusion, increases from baseline in anti-AAV9 antibody titers occurred in all patients. In the completed clinical trial, 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.

6.3     Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZOLGENSMA. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: thrombotic microangiopathy [see Warnings and Precautions (5.4)], thrombocytopenia [see Warnings and Precautions (5.3)].

Hepatobiliary Disorders: acute liver failure (fatal and non-fatal), acute liver injury [see Warnings and Precautions (5.1)].

General Disorders and Administration Site Conditions: pyrexia.

Investigations: troponin increased [see Warnings and Precautions (5.5)].

8.1     Pregnancy

Risk Summary

There are no available data regarding ZOLGENSMA use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with ZOLGENSMA.

In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2     Lactation

Risk Summary

There is no information available on the presence of ZOLGENSMA in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered 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.

8.4     Pediatric Use

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.

There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.

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) [see Adverse Reactions (6)].

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) [see Clinical Studies (14)].

8.6     Hepatic Impairment

ZOLGENSMA therapy should be carefully considered in patients with liver impairment. Cases of acute serious liver injury and acute liver failure have been reported with ZOLGENSMA in patients with preexisting liver abnormalities. In clinical trials, elevation of aminotransferases was observed in patients following ZOLGENSMA infusion [see Warnings and Precautions (5.1)].

12.1     Mechanism of Action

Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein. SMA is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression. Intravenous administration of ZOLGENSMA that results in cell transduction and expression of the SMN protein has been observed in two human case studies [see Clinical Pharmacology (12.3)].

12.2     Pharmacodynamics

There are no clinically relevant pharmacodynamics data for onasemnogene abeparvovec.

12.3     Pharmacokinetics

Vector shedding after infusion with onasemnogene abeparvovec was investigated at multiple time points during the completed clinical trial. Samples of saliva, urine and stool were collected the day after infusion, weekly through Day 30, and then monthly through Month 12 and every 3 months thereafter. Samples from 5 patients were used for onasemnogene abeparvovec vector DNA shedding analysis through the Month 18 visit.

Vector DNA was shed in saliva, urine and stool after infusion of onasemnogene abeparvovec, with much higher concentrations of vector DNA found in stool than in saliva or urine. The vector DNA concentration in saliva was low on Day 1 after infusion and declined to undetectable levels within 3 weeks. In urine, the vector DNA concentration was very low on Day 1 after infusion and declined to undetectable levels within 1 to 2 weeks. In stool, the vector DNA concentration was much higher than in saliva or urine for 1 to 2 weeks after infusion and declined to undetectable levels by 1 to 2 months after infusion.

Biodistribution was evaluated in two patients who died 5.7 months and 1.7 months, respectively, after infusion of onasemnogene abeparvovec at the dose of 1.1 x 1014 vg/kg. Both cases showed that the highest levels of vector DNA were found in the liver. Vector DNA was also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, gonads, spinal cord, brain, and thymus. Immunostaining for SMN protein showed generalized SMN expression in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver, skeletal muscles, and other tissues evaluated.

13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to evaluate the effects of onasemnogene abeparvovec on carcinogenesis, mutagenesis or impairment of fertility.

13.2     Animal Toxicology and/or Pharmacology

In toxicology studies conducted in neonatal mice, dose-dependent cardiac and hepatic toxicities were observed following intravenous administration of onasemnogene abeparvovec. Onasemnogene abeparvovec-related findings in the myocardium, at doses of 7.9 × 1013 vg/kg and higher, included slight to mild mononuclear cell inflammation accompanied by edema, slight to mild fibrosis, and scattered myocardial cell degeneration/regeneration. Additional cardiac findings at dose levels of 1.5 × 1014 vg/kg and higher included minimal to moderate atrial thrombosis and slight to marked atrial dilation. Liver findings included hepatocellular hypertrophy, Kupffer cell activation, perinuclear vacuolation, and scattered hepatocellular necrosis. Target organ toxicity in the heart and liver was associated with mortality in mice at dose levels of 2.4 × 1014 vg/kg and above, approximately 2.2-fold higher than the recommended clinical dose level.

In a 6-month toxicology study conducted in juvenile non-human primates, single intravenous administration of onasemnogene abeparvovec at the recommended clinical dose level of 1.1 × 1014 vg/kg, with or without corticosteroid treatment, resulted in microscopic findings in the dorsal root ganglia (DRG), trigeminal ganglia (TG), spinal cord, brainstem, and liver. At 6 weeks post-administration, microscopic findings included minimal to slight mononuclear cell inflammation and neuronal degeneration in the DRG and TG; axonal degeneration and gliosis in the spinal cord; mixed cell inflammation, gliosis, and axonal degeneration in the brainstem; and oval cell hyperplasia in the liver. These microscopic findings were still present at 6 months with decreased severity and incidence.

16.1     How Supplied

ZOLGENSMA is shipped frozen (≤ -60°C [-76°F]) 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 [see Dosage and Administration (2.1)], with each kit containing:

• Two (2) to fourteen (14) vials of ZOLGENSMA (see below)
• One alcohol wipe per vial

Kit sizes and National Drug Codes (NDC) are provided in Table 3.

16.2     Storage and Handling

• Product is shipped and delivered 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.