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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Prior to ITVISMA injection, assess liver function of patients by clinical examination and laboratory testing. Continue to monitor liver function for at least 3 months after injection, and at other times as clinically indicated. ( 2.1 , 2.4 , 5.1 ) Thrombocytopenia: Monitor platelet counts before ITVISMA injection, and at least weekly for the first month and as clinically indicated until platelet counts return to baseline. ( 2.1 , 2.4 , 5.2 ) Peripheral Sensory Neuropathy: Consider complete neurologic evaluation and other testing and/or symptom management based on the patient's clinical presentation. ( 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 hematologist and/or nephrologist immediately to manage as clinically indicated. ( 5.4 ) Elevated Cardiac Troponin I: Increases in cardiac troponin I have occurred following ITVISMA injection. Consider cardiac evaluation after ITVISMA administration 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 ITVISMA, to Novartis Gene Therapies, Inc. ( 5.6 ) 5.1 Hepatotoxicity Hepatotoxicity, with elevated ALT and/or AST levels, has occurred with ITVISMA [see Adverse Reactions (6.1)] . Patients with preexisting hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid before and after ITVISMA injection. 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 (2.2)] . Prior to ITVISMA injection, assess liver function by clinical examination and laboratory testing. Continue to monitor liver function for at least 3 months after ITVISMA administration, and at other times as clinically indicated. Monitor AST, ALT and total bilirubin weekly for the month after ITVISMA administration and during the corticosteroid taper period. 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. Tapering of systemic corticosteroids should not be considered until AST/ALT levels are less than 2 × ULN [see Dosage and Administration (2.1, 2.4)] . 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 is recommended (e.g., albumin, prothrombin time, partial thromboplastin time (PTT) and international normalized ratio (INR)). Promptly consult with a gastroenterologist or hepatologist, as necessary. 5.2 Thrombocytopenia Transient decreases in platelet counts were observed within the first week after ITVISMA administration [see Adverse Reactions (6.1)] . The platelets counts are expected to return to baseline two weeks following ITVISMA injection. Monitor platelet counts before ITVISMA injection and on a regular basis afterwards (at least weekly for the first month and as clinically indicated until platelet counts return to baseline) [see Dosage and Administration (2.1, 2.4)] . 5.3 Peripheral Sensory Neuropathy Peripheral sensory neuropathy has occurred with ITVISMA administration [see Adverse Reactions (6.1)] . Signs and symptoms may include numbness, tingling, prickling, or pain in the arms, hands, legs and/or feet, with onset seen at approximately three weeks post-injection in clinical studies. Consider complete neurologic evaluation and other testing and/or symptom management based on the patient's clinical presentation. Inform patients and caregivers about the signs and symptoms of peripheral sensory neuropathy, and advise patients and caregivers to notify their physician promptly if such symptoms occur. 5.4 Thrombotic Microangiopathy Thrombotic microangiopathy (TMA) may occur with ITVISMA administration. TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Concurrent immune system activation (e.g., infections, vaccinations) may be a contributing factor. Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes. Monitor platelet counts on a regular basis following ITVISMA injection [see Warnings and Precautions (5.2)] , as well as signs and symptoms of TMA, such as hypertension, bruising easily, 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 hematologist and/or nephrologist immediately to manage TMA as clinically indicated. 5.5 Elevated Cardiac Troponin I Increases in cardiac troponin I levels have occurred following ITVISMA administration without clinical sequelae [see Adverse Reactions (6.1)] . Cardiac toxicity was observed in animal studies [see Nonclinical Toxicology (13.2)] . Consider cardiac evaluation after ITVISMA administration 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. ITVISMA 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 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. If a tumor develops in a patient receiving ITVISMA, health care providers should contact and report the tumor to Novartis Gene Therapies, Inc. at 1-833-828-3947.