Label:ZOLGENSMA- onasemnogene abeparvovec-xioi kit
onasemnogene
Quick Facts
Used For
ZOLGENSMA is a gene therapy used to treat children under 2 years old with spinal...
Common Side Effects
What You Should Know About Side Effects from Clinical Studies Clinical studies...
What You Should Know
Liver Problems Your child’s doctor will tell you that ZOLGENSMA can cause liver problems. These...
Prescription
Not Required
Generic Available
No
Indications and Usage
ZOLGENSMA is a gene therapy used to treat children under 2 years old with spinal muscular atrophy (SMA) caused by mutations in the SMN1 gene.
Limitations of Use
• The safety of giving ZOLGENSMA more than once has not been studied.
• ZOLGENSMA has not been studied in patients with severe SMA (such as complete paralysis or needing a breathing machine all the time).
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 thesurvival motor neuron 1 (SMN1)gene.
Limitations of Use
• The safety and effectiveness of repeat administration of ZOLGENSMA have not been evaluated[see Adverse Reactions (6.2)].
• 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)].
Dosage and Administration
How Much to Give
The recommended dose is 1.1 × 10¹⁴ vector genomes per kilogram (vg/kg) of body weight.
Table 1: Dosing
Patient weight range (kg) | Dose volume (mL)
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
Before ZOLGENSMA Infusion:
The patient must be healthy and stable before getting ZOLGENSMA. This means good hydration, good nutrition, and no infections. If the patient has an infection, wait until it is gone and the patient is stable. There should be no signs of infection on the day of the infusion.
Check liver function.
Check creatinine and complete blood count (including hemoglobin and platelet count).
Test for anti-AAV9 antibodies.
One day before ZOLGENSMA infusion, start giving a steroid medicine (like prednisolone) at 1 mg per kg of body weight per day. Give this for 30 days total.
How to Give ZOLGENSMA:
Give ZOLGENSMA as a one-time IV infusion through a vein.
Follow these steps:
1. Put a main IV catheter into a vein (usually in the arm or leg). A backup catheter is recommended.
2. Set up the syringe pump with saline, or prime the tubing with saline by hand.
3. Give ZOLGENSMA slowly over 60 minutes. DO NOT GIVE AS A FAST PUSH OR BOLUS.
4. Flush the line with saline after the infusion is done.
After the Infusion:
Check liver function regularly through physical exams and lab tests.
At the end of the 30 days of steroid treatment, check liver health with a physical exam and blood tests (ALT, AST, total bilirubin, prothrombin time, and INR).
Watch closely for any worsening liver test results or signs of illness (like vomiting or getting sicker).
If liver tests are normal (normal exam, total bilirubin, prothrombin time, and INR, and ALT and AST levels below 2 times the upper limit of normal):
Slowly reduce the steroid dose over the next 28 days. Do not stop steroids suddenly.
If liver problems continue:
Keep giving steroids (1 mg/kg/day) until AST and ALT are both below 2 times the upper limit of normal and all other tests are normal. Then slowly reduce the steroid dose over the next 28 days or longer if needed. Do not stop steroids suddenly.
If liver problems are still high after 30 days of steroids:
Contact a pediatric stomach/liver specialist right away.
If the patient cannot take steroids by mouth:
Consider giving steroids through an IV if needed.
Preparing ZOLGENSMA:
Thaw ZOLGENSMA before use. It takes about 16 hours to thaw in the refrigerator, or about 6 hours at room temperature. If thawed in the refrigerator, take it out on the day of dosing.
When thawed, ZOLGENSMA is clear to slightly cloudy, colorless to faint white liquid with no particles. Look at the vials for particles or color changes before infusion. Do not use if you see particles or color changes.
DO NOT SHAKE.
Draw the correct dose from all vials into a syringe, remove air, cap the syringe, and bring it to the patient at room temperature.
Use ZOLGENSMA within 8 hours of drawing it into the syringe. Throw away the syringe if not used within 8 hours.
DO NOT REFREEZE.
Lab Tests and Monitoring:
Test for anti-AAV9 antibodies before ZOLGENSMA infusion. If antibody levels are higher than 1:50, you may need to retest.
Do these tests at the start and as directed below:
Liver function (physical exam, AST, ALT, total bilirubin, albumin, prothrombin time, PTT, and INR) at the start. Check liver function (AST, ALT, total bilirubin, prothrombin time, INR) every week for the first month after ZOLGENSMA and during the steroid taper period (28 days or longer if needed). If the patient is stable with normal results at the end of the taper period, continue checking liver function every other week for another month.
Platelet counts every week for the first month, then every other week for the second and third months, until platelet counts return to normal.
Dose and Administration
The recommended dose of ZOLGENSMA is 1.1 × 1014vector 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 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)].
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.
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.
Dosage Forms and Strengths
ZOLGENSMA is a liquid medicine given through an IV (into a vein).
ZOLGENSMA comes in a kit with 2 to 14 bottles. Bottles come in 2 sizes: 5.5 mL or 8.3 mL.
Each bottle contains a set amount of medicine.
The dose is based on the child’s weight. The recommended dose is 1.1 × 10 to the 14th power vg/kg.
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 × 1013vg/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 × 1014vg/kg for pediatric patients.
Contraindications
None.
None.
Warnings and Precautions
Liver Problems
ZOLGENSMA can cause serious liver problems, including liver failure. Some cases have been deadly. Your liver enzymes (chemicals in your blood that show how your liver is working) may go up. To help prevent this, you will get steroid medicine before and after ZOLGENSMA. Sometimes you may need to take steroids longer or at a higher dose.
People with liver problems or liver infections before treatment may have a higher risk of serious liver injury or liver failure. If you have liver test results more than 2 times higher than normal, you have not been studied in clinical trials with ZOLGENSMA. Your doctor will carefully think about the risks and benefits of ZOLGENSMA if you have liver problems.
In studies and after the medicine was approved, many patients had high liver enzyme levels but felt fine. However, some patients got serious liver injury and liver failure, and a few died. Some patients had very high liver enzyme levels (more than 20 times normal), blood clotting problems, and symptoms like vomiting and yellow skin. These patients needed steroids, sometimes for a long time or at higher doses. If your doctor thinks you have serious liver injury or liver failure, they will quickly contact a specialist.
Before you get ZOLGENSMA, your doctor will check your liver with an exam and blood tests (liver enzymes, bilirubin, albumin, and blood clotting tests). Your doctor will keep checking your liver function for at least 3 months after ZOLGENSMA and at other times if needed.
Your doctor will quickly check and closely watch you if your liver test results get worse or if you have signs of illness like vomiting or feeling worse. If liver injury is suspected, more blood tests are recommended.
Your doctor will check your liver function every week for the first month after ZOLGENSMA and while you are taking steroids (28 days or longer if needed). If you are doing well at the end of the steroid period, your doctor will check your liver every other week for another month.
Immune System Response
After getting ZOLGENSMA, your immune system becomes more active. If you have an infection (like a cold, stomach bug, or chronic hepatitis B), you could be at higher risk of a serious immune system response. This could make your infection worse. Serious immune system responses can cause different symptoms like high fever or low blood pressure. People with infections were not allowed in ZOLGENSMA studies. Your doctor will watch carefully for infections before and after ZOLGENSMA.
To lower the risk of serious immune system response, you will only get ZOLGENSMA when you are healthy and stable (good hydration, good nutrition, no infection). If you have an infection, ZOLGENSMA will be delayed until the infection is gone and you are stable. You should not have any signs of infection when you get ZOLGENSMA. Your doctor will recommend protection against flu and RSV during their seasons, and your vaccines should be up-to-date before getting ZOLGENSMA.
Low Platelet Count
Your platelet count (cells that help blood clot) may go down temporarily, usually within the first two weeks after ZOLGENSMA. Sometimes the count gets low enough to be called thrombocytopenia.
Your doctor will check your platelet count before ZOLGENSMA and watch it closely within the first two weeks after treatment and regularly after that (at least weekly for the first month, every other week for the second and third months, or until your platelet count returns to normal).
Blood Clotting Problem (Thrombotic Microangiopathy)
Cases of thrombotic microangiopathy (TMA) have been reported, usually within the first two weeks after ZOLGENSMA. TMA includes low platelet count, breakdown of red blood cells, and kidney problems. Some cases happened along with immune system activation from things like infections or vaccines.
TMA can be life-threatening or deadly, so it’s important to watch for signs and symptoms.
Your doctor will check your platelet count closely within the first two weeks after treatment and regularly after that. They will also watch for signs of TMA like high blood pressure, more bruising, seizures, or less urine. If these happen along with low platelet count, your doctor will quickly do more tests to check for red blood cell breakdown and kidney problems. If you have signs, symptoms, or test results that suggest TMA, your doctor will immediately contact a specialist to manage TMA.
Heart Enzyme Increase
Increases in a heart enzyme called troponin I have happened after ZOLGENSMA in studies. Heart problems were seen in animal studies. Your doctor may check your heart after ZOLGENSMA and contact a heart specialist if needed.
Gene Therapy DNA Integration and Cancer Risk
There is a theoretical risk of cancer because the gene therapy DNA could become part of your own DNA.
ZOLGENSMA contains a modified virus (AAV9) whose DNA mostly stays separate from your DNA. However, the gene therapy DNA can sometimes randomly become part of human DNA. This has been reported with ZOLGENSMA and other gene therapies. We don’t know what individual integration events mean, but they could possibly contribute to cancer risk. Cases of tumors have been reported in patients who got ZOLGENSMA after approval. We don’t know if ZOLGENSMA caused these tumors. However, in some cases, we had limited information. If you develop a tumor after getting ZOLGENSMA, your doctor should contact and report it to Novartis Gene Therapies, Inc. at 1-833-828-3947.
Infusion Reactions
Reactions during or after the infusion, including allergic reactions and severe allergic reactions (anaphylaxis), have happened with ZOLGENSMA. Signs may include rash, hives, vomiting, trouble breathing, breathing symptoms, or changes in heart rate and blood pressure. Your doctor will watch you during and after ZOLGENSMA treatment. If an infusion reaction happens, the ZOLGENSMA infusion will be stopped and you will get treatment for the reaction. The infusion may be restarted based on how you are doing.
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)].
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.
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)].
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.
Elevated Troponin I
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 (13.2)]. Consider cardiac evaluation after ZOLGENSMA infusion and consult a cardiologist as needed.
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 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.
Infusion-Related Reactions
Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred with ZOLGENSMA infusion[see Adverse Reactions (6.3)]. 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.
Adverse Reactions
What You Should Know About Side Effects from Clinical Studies
Clinical studies are done in different ways, so side effects seen in one study may not match another study or what happens in real life.
The safety information here comes from five studies with 68 patients total. Four studies tracked patients getting ZOLGENSMA [NCT03306277 (Study 1), NCT02122952 (Study 2), NCT03505099, NCT04851873 (Study 3)], and one study followed patients long-term [NCT03421977]. In three of these studies, patients were 0.3 to 7.9 months old when they got the medicine (average age was 3.3 months). They weighed 3.0 kg to 8.4 kg (average weight was 5.5 kg).
In Study 3 (NCT04851873), 24 children aged 1.5 to 9.1 years (average age 4.9 years) got ZOLGENSMA. They weighed 8.5 kg to 21 kg (average weight 15.8 kg). Only one child was under 2 years old. These patients had 2 to 4 copies of the SMN2 gene. Before getting ZOLGENSMA, 21 patients had stopped taking other medicines called nusinersen or risdiplam. The side effects in Study 3 were similar to Studies 1 and 2. However, liver enzyme increases happened more often in Study 3. Most patients (23 out of 24) had higher than normal liver enzymes (AST or ALT). This included 21 patients with ALT over 3 times normal and 5 patients with ALT over 20 times normal. These patients felt fine and had normal bilirubin levels. Doctors treated the high liver enzymes with steroids, often for longer time periods or at higher doses. Low platelet counts happened in 20 out of 24 patients. Four patients had platelet counts below 50,000 per µL.
Table 2: Most Common Side Effects in 44 Patients (3.0-8.4 kg)
– High liver enzymes: 12 patients (27%)
– ALT over 3 times normal: 7 patients (16%)
– ALT over 20 times normal: 4 patients (9%)
– Vomiting: 3 patients (7%)
One patient died in a study done outside the United States (NCT03461289). This patient got ZOLGENSMA at 5 months old (6 kg). Twelve days after treatment, the patient had trouble breathing and tested positive for RSV and parainfluenza viruses. The patient had very low blood pressure, then seizures, and was found to have brain damage about 30 days after treatment. The patient died 52 days after treatment when life support was stopped.
Immune System Response
Before getting ZOLGENSMA, patients must have low levels of anti-AAV9 antibodies (1:50 or less). Your doctor will test your antibody levels before treatment. If levels are higher than 1:50, you may need another test. ZOLGENSMA has not been studied in patients with antibody levels above 1:50.
After getting ZOLGENSMA, all patients had higher anti-AAV9 antibody levels. In Study 2, every patient had antibody levels of at least 1:102,400, and most had levels over 1:819,200. Giving ZOLGENSMA again when antibody levels are high has not been studied.
Side Effects Reported After Approval
These side effects were reported after ZOLGENSMA was approved for use. Because people report these on their own, we cannot always know how often they happen or if ZOLGENSMA caused them.
– Blood problems: blood clots in small blood vessels, low platelet counts
– Liver problems: liver failure (some patients died), liver injury
– General problems: fever, reactions during the infusion
– Test results: high troponin levels (a heart marker)
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 five clinical studies enrolling a total of 68 patients. This includes four prospective open-label clinical trials [NCT03306277 (Study 1), NCT02122952 (Study 2), NCT03505099, NCT04851873 (Study 3)], and one observational long-term follow-up study [NCT03421977]. The patient population in NCT03306277, NCT03505099, and NCT02122952 ranged in age from 0.3 months to 7.9 months at the time of infusion (median age, 3.3 months), with weight range from 3.0 kg to 8.4 kg (median weight, 5.5 kg)[see Clinical Studies (14)].
In an open-label, post-authorization clinical study (Study 3, NCT04851873), safety of ZOLGENSMA was evaluated in 24 children, aged between 1.5 to 9.1 years (median age, 4.9 years), with weight range from ≥ 8.5 kg to ≤ 21 kg (median weight, 15.8 kg). Only one of the 24 patients was under the age of 2 years at the time of ZOLGENSMA administration. Patients in Study 3 had 2 to 4 copies ofSMN2. Before treatment with ZOLGENSMA, 21 patients discontinued their previous treatment with nusinersen or risdiplam. The types of adverse reactions observed in Study 3 were consistent with those of Studies 1 and 2. Liver enzyme increases in Study 3 occurred at a higher frequency compared with the previous 4 studies. AST or ALT elevations > 2 × ULN were observed in the majority of patients (23 out of 24 patients), including 21 patients with ALT elevations > 3 × ULN and 5 patients with ALT elevations > 20 × ULN. These patients were clinically asymptomatic and there were no elevations of bilirubin. The AST and ALT elevations were managed with the use of corticosteroids, typically with prolonged duration and/or given at a higher dose[see Warnings and Precautions (5.1)]. Transient decreases in platelet counts, which met the criteria for thrombocytopenia were observed in 20 out of 24 patients. Four patients had platelet counts below 50,000 per µL[see Warnings and Precautions (5.3)].
The most frequent adverse reactions (incidence ≥ 5%) and increases in alanine aminotransferase in the 4 studies (data cut-off date: September 27, 2018) are summarized inTable 2.
One death occurred in a patient, who received ZOLGENSMA at the age of 5 months (6 kg), in a completed non-United States clinical trial (NCT03461289). The patient 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.
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)].
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, infusion-related reactions[see Warnings and Precautions (5.7)]
Investigations: troponin increased[see Warnings and Precautions (5.5)]
Drug Interactions
If possible, your doctor will adjust your vaccine schedule to work with the steroid medicine you’ll take before and after ZOLGENSMA. Some vaccines like MMR (measles, mumps, rubella) and chickenpox should not be given if you’re taking high doses of steroids (20 mg or more of prednisone daily for 2 weeks or longer). Your doctor may recommend RSV prevention during RSV season.
Where feasible, adjust a patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ZOLGENSMA infusion[see Dosage and Administration (2.1)]. Certain vaccines, such as measles, mumps, and rubella (MMR) and varicella, are contraindicated for patients on a substantially immunosuppressive steroid dose (i.e., ≥ 2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisone or equivalent). Seasonal RSV prophylaxis is recommended (General Best Practice Guidelines for Immunization [www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf], eds2017).
Pregnancy
Pregnancy
What You Should Know
There is no information about using ZOLGENSMA in pregnant women. No animal studies have been done with ZOLGENSMA during pregnancy.
In the United States, about 2% to 4% of babies are born with major birth defects and about 15% to 20% of known pregnancies end in miscarriage.
Breastfeeding
What You Should Know
There is no information about whether ZOLGENSMA gets into breast milk or affects a breastfed baby. Talk with your doctor about the benefits of breastfeeding and whether you need ZOLGENSMA treatment. Consider any possible effects on your baby from ZOLGENSMA or from your health condition.
There is no information about whether mothers with anti-AAV9 antibodies should avoid breastfeeding.
Use in Children
ZOLGENSMA safety was studied in babies who got the treatment between 0.3 and 7.9 months old (weighing 3.0 kg to 8.4 kg). Safety was also studied in children weighing 9.5 kg to 20.2 kg.
ZOLGENSMA was shown to work in babies who got the treatment between 0.5 and 7.9 months old (weighing 3.6 kg to 8.4 kg).
Do not give ZOLGENSMA to premature babies before they reach full-term age. The steroid medicine given with ZOLGENSMA may harm brain development. Wait until the baby reaches full-term age.
Liver Problems
Think carefully about using ZOLGENSMA in patients with liver problems. Some patients with liver problems before treatment have had serious liver injury and liver failure with ZOLGENSMA. In studies, liver enzyme levels went up in patients after getting ZOLGENSMA.
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.
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.
There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.
Pediatric Use
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[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)].
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.
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)].
Lactation
Breastfeeding
What You Should Know
We don’t know if ZOLGENSMA gets into breast milk. We also don’t know if it affects breastfed babies or milk production. Talk with your doctor about the benefits of breastfeeding and whether you need ZOLGENSMA. Your doctor will help you decide what’s best for you and your baby.
We don’t know if mothers who have anti-AAV9 antibodies should avoid breastfeeding.
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.
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.
There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.
Pediatric Use
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[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)].
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.
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)].
Pediatric Use
Pregnancy
Risk Summary
There is no information about using ZOLGENSMA in pregnant women. No animal studies have been done to see if ZOLGENSMA affects pregnancy or the baby.
In the United States, about 2% to 4% of babies are born with major birth defects and about 15% to 20% of pregnancies end in miscarriage.
Breastfeeding
Risk Summary
There is no information about whether ZOLGENSMA gets into breast milk or if it affects a breastfed baby. Talk with your doctor about the benefits of breastfeeding and whether you need ZOLGENSMA. Consider any possible effects on your baby from ZOLGENSMA or from your medical condition.
There is no information about whether mothers with anti-AAV9 antibodies should avoid breastfeeding.
Use in Children
The safety of ZOLGENSMA was studied in babies who got the medicine between 0.3 to 7.9 months old (weighing 3.0 kg to 8.4 kg). Safety was also studied in children weighing 9.5 kg to 20.2 kg.
ZOLGENSMA was shown to work in babies who got the medicine between 0.5 to 7.9 months old (weighing 3.6 kg to 8.4 kg).
Do not give ZOLGENSMA to premature babies before they reach full-term age. The steroid medicine given with ZOLGENSMA may harm brain development. Wait until the baby reaches full-term age.
Liver Problems
Think carefully before using ZOLGENSMA in patients with liver problems. Some patients with liver problems before treatment have had serious liver injury and liver failure with ZOLGENSMA. In studies, patients had high liver enzyme levels after getting ZOLGENSMA.
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.
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.
There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.
Pediatric Use
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[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)].
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.
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)].
Geriatric Use
Pregnancy
What You Should Know
There is no information about using ZOLGENSMA in pregnant women. No animal studies have been done with ZOLGENSMA during pregnancy.
In the United States, about 2% to 4% of babies are born with major birth defects and about 15% to 20% of known pregnancies end in miscarriage.
Breastfeeding
What You Should Know
There is no information about whether ZOLGENSMA gets into breast milk or how it might affect a breastfed baby. Talk with your doctor about the benefits of breastfeeding and whether you need ZOLGENSMA treatment. Consider any possible effects on your baby from ZOLGENSMA or from your medical condition.
There is no information about whether mothers with anti-AAV9 antibodies should avoid breastfeeding.
Use in Children
ZOLGENSMA safety was studied in babies who got the medicine between 0.3 and 7.9 months old (weighing 3.0 kg to 8.4 kg). Safety was also studied in children weighing 9.5 kg to 20.2 kg.
ZOLGENSMA was shown to work in babies who got the medicine between 0.5 and 7.9 months old (weighing 3.6 kg to 8.4 kg).
Do not give ZOLGENSMA to premature babies before they reach full-term age. The steroid medicine given with ZOLGENSMA may harm brain development. Wait until the baby reaches full-term age.
Liver Problems
Think carefully about using ZOLGENSMA if you have liver problems. Some patients with liver problems before treatment have had serious liver injury and liver failure with ZOLGENSMA. In studies, patients had increased liver enzymes after getting ZOLGENSMA.
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.
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.
There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.
Pediatric Use
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[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)].
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.
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)].
Hepatic Impairment
Pregnancy
Risk Summary
There is no information about using ZOLGENSMA in pregnant women. No animal studies have been done to see if ZOLGENSMA affects pregnancy.
In the United States, about 2% to 4% of babies are born with major birth defects and about 15% to 20% of known pregnancies end in miscarriage.
Breastfeeding
Risk Summary
There is no information about whether ZOLGENSMA gets into breast milk or how it might affect a breastfed baby. Talk with your doctor about the benefits of breastfeeding and whether you need ZOLGENSMA. Consider any possible effects on your baby from ZOLGENSMA or from your health condition.
There is no information about whether mothers who have anti-AAV9 antibodies should avoid breastfeeding.
Use in Children
The safety of ZOLGENSMA was studied in children who got the medicine between 0.3 to 7.9 months old (weighing 3.0 kg to 8.4 kg). Safety was also studied in children weighing 9.5 kg to 20.2 kg.
ZOLGENSMA was tested to see if it works in children who got the medicine between 0.5 to 7.9 months old (weighing 3.6 kg to 8.4 kg).
Do not give ZOLGENSMA to premature babies before they reach full-term age. The steroid medicine given with ZOLGENSMA may harm brain development. Wait until the baby reaches full-term age.
Liver Problems
Think carefully before using ZOLGENSMA in patients with liver problems. Some patients with liver problems before treatment have had serious liver injury and liver failure with ZOLGENSMA. In studies, liver enzyme levels went up in patients after getting ZOLGENSMA.
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.
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.
There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.
Pediatric Use
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[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)].
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.
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)].
Renal Impairment
Pregnancy
Risk Summary
There is no information about using ZOLGENSMA in pregnant women. No animal studies have been done with ZOLGENSMA to see if it affects pregnancy.
In the United States, about 2% to 4% of babies are born with major birth defects and about 15% to 20% of known pregnancies end in miscarriage.
Breastfeeding
Risk Summary
There is no information about whether ZOLGENSMA gets into breast milk or if it affects a breastfed baby. Talk with your doctor about the benefits of breastfeeding and whether you need ZOLGENSMA. Consider any possible effects on your baby from ZOLGENSMA or from your health condition.
There is no information about whether mothers with anti-AAV9 antibodies should avoid breastfeeding.
Use in Children
The safety of ZOLGENSMA was studied in children who got the medicine between 0.3 to 7.9 months old (weighing 3.0 kg to 8.4 kg). Safety was also studied in children weighing 9.5 kg to 20.2 kg.
ZOLGENSMA was shown to work in children who got the medicine between 0.5 to 7.9 months old (weighing 3.6 kg to 8.4 kg).
Do not give ZOLGENSMA to premature babies before they reach full-term age. The steroid medicine given with ZOLGENSMA may harm brain development. Wait until the baby reaches full-term age.
Liver Problems
Think carefully before using ZOLGENSMA in patients with liver problems. Some patients with liver problems who got ZOLGENSMA had serious liver injury and liver failure. In studies, patients had high liver enzyme levels after getting ZOLGENSMA.
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.
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.
There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.
Pediatric Use
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[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)].
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.
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)].
Description
ZOLGENSMA is a gene therapy medicine given through an IV (into a vein). It contains a modified virus that carries a gene to help make a protein called SMN that the body needs.
ZOLGENSMA comes in vials (small bottles) containing either 5.5 mL or 8.3 mL of liquid. The medicine also contains salt, magnesium, and other ingredients that help keep it stable. ZOLGENSMA is sterile (germ-free) and does not contain any preservatives.
ZOLGENSMA is a suspension of an adeno-associated viral vector-based gene therapy for intravenous infusion. It is a recombinant self-complementary AAV9 containing a transgene encoding the human survival motor neuron (SMN) protein, under the control of a cytomegalovirus enhancer/chicken-β-actin hybrid promoter.
ZOLGENSMA has a nominal concentration of 2.0 × 1013vg/mL. Each vial contains an extractable volume of not less than either 5.5 mL or 8.3 mL and the excipients 20 mM Tris (pH 8.0), 1 mM magnesium chloride (MgCl2), 200 mM sodium chloride (NaCl) and 0.005% poloxamer 188. ZOLGENSMA is packaged as a sterile suspension and contains no preservative.
Mechanism of Action
How This Medicine Works
This medicine is a gene therapy that gives the body a working copy of a gene that makes SMN protein. People with SMA have a problem with the SMN1 gene, so their bodies don’t make enough SMN protein. When this medicine is given through an IV, it helps cells make the SMN protein. This has been seen in two patient cases.
How the Medicine Acts in the Body
There is no important information available about how this medicine acts in the body.
How the Medicine Moves Through the Body
After the medicine was given, doctors checked how it left the body by testing spit, urine, and stool samples. They collected samples the day after treatment, weekly for 30 days, then monthly for 12 months, and every 3 months after that. They tested samples from 5 patients for up to 18 months.
The medicine’s DNA was found in spit, urine, and stool after treatment. Much more was found in stool than in spit or urine. In spit, the amount was low on day 1 and couldn’t be found after 3 weeks. In urine, the amount was very low on day 1 and couldn’t be found after 1 to 2 weeks. In stool, the amount was much higher than in spit or urine for 1 to 2 weeks and couldn’t be found after 1 to 2 months.
Doctors checked where the medicine went in the body by studying two patients who died 5.7 months and 1.7 months after treatment. The highest amounts were found in the liver. The medicine was also found in the spleen, heart, pancreas, lymph nodes, muscles, nerves, kidney, lung, intestines, reproductive organs, spinal cord, brain, and thymus. Tests showed SMN protein in spinal motor neurons, brain cells, heart, liver, muscles, and other body parts.
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 theSMN1gene, 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)].
Pharmacodynamics
There are no clinically relevant pharmacodynamics data for onasemnogene abeparvovec.
Pharmacokinetics
Vector shedding after infusion with onasemnogene abeparvovec was investigated at multiple time points during Study 2. 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 1014vg/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.
Patient Counseling Information
Liver Problems
Your child’s doctor will tell you that ZOLGENSMA can cause liver problems. These problems can be serious and may include liver damage or liver failure, which can cause death. Your child will take a steroid medicine by mouth before and after getting ZOLGENSMA. Your child will also have regular blood tests to check how the liver is working. Call your doctor right away if:
– Your child’s skin or the white part of the eyes look yellow
– Your child misses a dose of steroid medicine or throws it up
– Your child seems less alert than usual
Vaccines Before and After ZOLGENSMA
Talk to your doctor about whether your child’s vaccine schedule needs to change while taking steroid medicine. If possible, the vaccine schedule should be adjusted. Your child should get flu and RSV protection and be up-to-date on vaccines before getting ZOLGENSMA. Ask your doctor about this.
Infections and Immune System
An infection (like a cold, flu, stomach bug, ear infection, or lung infection) before or after ZOLGENSMA can cause serious problems. You and people close to your child should wash hands often, cover coughs and sneezes, and limit contact with others. Watch for signs of infection like coughing, wheezing, sneezing, runny nose, sore throat, or fever. Call your doctor right away if your child has any signs of infection before or after getting ZOLGENSMA.
Low Platelet Count
ZOLGENSMA can lower the number of platelets in the blood. This can cause easier bruising or bleeding. This usually happens in the first two weeks after ZOLGENSMA. Get medical help if your child has unexpected bruising or bleeding.
Blood Cell Problems and Kidney Problems
ZOLGENSMA can lower platelet and red blood cell counts, cause kidney problems, and increase the risk of bruising or bleeding. These problems usually happen in the first two weeks after ZOLGENSMA. Get medical help right away if your child has unexpected bruising or bleeding, seizures, or is not urinating as much as usual.
Possible Risk of Tumors
There is a possible risk that ZOLGENSMA could cause tumors. Call your doctor and Novartis Gene Therapies, Inc. (1-833-828-3947) if your child develops a tumor after getting ZOLGENSMA.
Handling Body Waste
ZOLGENSMA can be found in your child’s body waste for a short time. Here’s how to handle dirty diapers safely: Put dirty diapers in a disposable trash bag, seal it, and throw it in the regular trash. Wash your hands well after touching your child’s body waste. Do this for one month after ZOLGENSMA.
Reactions During or After the Infusion
Your child may have a reaction during or after getting ZOLGENSMA. Get medical help right away if your child has a rash, hives, vomiting, trouble breathing, breathing problems, or changes in heart rate or blood pressure.
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Acute Serious Liver Injury, Acute Liver Failure or Elevated Aminotransferases
Inform caregivers that ZOLGENSMA could increase liver enzyme levels and cause acute serious liver injury or acute liver failure, and death. Inform caregivers that patients will receive an oral corticosteroid medication before and after infusion with ZOLGENSMA, and will undergo regular blood tests to monitor liver function. Advise caregivers to contact their 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[see Warnings and Precautions (5.1)].
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. Inform caregivers that where feasible, the vaccination schedule should be adjusted appropriately to accommodate treatment with corticosteroid. Prophylaxis against influenza and RSV is recommended and vaccination status should be up-to-date prior to ZOLGENSMA administration. Please consult your healthcare provider[see Drug Interactions (7)].
Systemic Immune Response
Caregivers should be aware that an infection (e.g., cold, flu, gastroenteritis, otitis media, bronchiolitis, etc.) before or after ZOLGENSMA infusion could lead to more serious complications. Caregivers and close contacts of patients should follow infection prevention practices (e.g., hand hygiene, coughing/sneezing etiquette, limiting potential contacts). Advise caregivers of the signs of a possible infection, such as coughing, wheezing, sneezing, runny nose, sore throat, or fever. Caregivers should contact their healthcare provider immediately if the patient experiences any symptoms suggestive of infection before or after ZOLGENSMA infusion[see Warnings and Precautions (5.2)].
Thrombocytopenia
Inform caregivers that ZOLGENSMA could decrease blood platelet count and increase the risk of bruising or bleeding. Inform caregivers that thrombocytopenia has been reported to generally occur within the first two weeks after ZOLGENSMA infusion. Advise caregivers to seek medical attention if the patient experiences unexpected bruising or bleeding[see Warnings and Precautions (5.3)].
Thrombotic Microangiopathy
Inform caregivers that ZOLGENSMA could decrease blood platelet and red blood cell counts, cause acute kidney injury, and increase the risk of bruising or bleeding, which may be indicative of TMA. Inform caregivers that TMA has been reported to generally occur within the first two weeks after ZOLGENSMA infusion. Advise caregivers to seek immediate medical attention if the patient experiences unexpected bruising or bleeding, seizures, or decreased urine output[see Warnings and Precautions (5.4)].
AAV Vector Integration and Risk of Tumorigenicity
Inform caregivers that there is a theoretical risk of tumorigenicity with AAV therapies such as ZOLGENSMA. Advise caregivers to contact their healthcare provider and Novartis Gene Therapies, Inc. (1-833-828-3947) if the patient who received ZOLGENSMA develops a tumor[see Warnings and Precautions (5.6)].
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. Provide instructions to caregivers and family members regarding proper hand hygiene when coming into direct contact with patient body waste. These precautions should be followed for one month after ZOLGENSMA infusion.
Infusion-Related Reactions
Inform caregivers that infusion-related reactions may occur during and after ZOLGENSMA infusion. Advise caregivers to seek immediate medical evaluation if signs and symptoms of infusion related reaction occur which may include rash, urticaria, vomiting, dyspnea, respiratory symptoms and/or alterations in heart rate and blood pressure[see Warnings and Precautions (5.7)].
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Novartis Gene Therapies, Inc.
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Bannockburn, IL 60015 USA
©2025 Novartis Gene Therapies, Inc.
T2025-04
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References
Label:ZOLGENSMA- onasemnogene abeparvovec-xioi kit (onasemnogene) [prescribing information]. March 2026. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68cd4f06-70e1-40d8-bedb-609ec0afa471
Accessed: March 27, 2026