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warnings and cautions
5 WARNINGS AND PRECAUTIONS 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. ( 5.2 ) Thrombocytopenia: Monitor platelet counts before ZOLGENSMA infusion, and at least weekly for the first month and then every other week for the second and third month or until platelet counts return to baseline. ( 2.3 , 5.3 ) Thrombotic Microangiopathy (TMA): Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes. If clinical signs, symptoms and/or laboratory findings occur, consult a pediatric hematologist and/or pediatric nephrologist immediately to manage as clinically indicated. ( 5.4 ) Elevated Troponin I: Increases in cardiac troponin I levels have occurred following ZOLGENSMA infusion. Consider cardiac evaluation after ZOLGENSMA infusion and consult a cardiologist as needed. ( 5.5 ) AAV Vector Integration and Risk of Tumorigenicity: There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome. Report cases of tumors in patients who received ZOLGENSMA, to Novartis Gene Therapies, Inc. ( 5.6 , 17 ) Infusion-Related Reactions: Monitor patients during and after ZOLGENSMA infusion. Interrupt ZOLGENSMA infusion if infusion-related reaction occurs and administer supportive treatment as appropriate. Infusion of ZOLGENSMA may be resumed based on clinical assessment. ( 5.7 ) 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) 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. 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 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. 5.7 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.