warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hepatotoxicity: Monitor transaminases and factor IX activity levels once or twice weekly for at least 4 months after BEQVEZ administration to mitigate the risk of potential hepatotoxicity. Consider corticosteroid treatment for transaminase elevation or a decline in factor IX activity. ( 2.3 , 5.1 ) • Infusion Reactions: Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or stop administration. Restart infusion at a slower rate once reaction has resolved. ( 5.2 ) • Malignancy: Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following administration. In the event that a malignancy occurs after treatment with BEQVEZ, contact Pfizer Inc. at 1-800-438-1985. ( 5.3 ) • Monitoring laboratory tests: Monitor for factor IX activity and factor IX inhibitors. ( 5.4 ) 5.1 Hepatotoxicity Intravenous administration of a liver-directed AAV vector could potentially lead to liver transaminase elevations. Transaminase elevations, particularly when observed in the first 4 months after BEQVEZ administration, is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of the AAV vector-based gene therapy. In clinical studies with BEQVEZ, transaminase elevations (defined as ≥1.5 x baseline) occurred in 29 of 45 and 7 of 15 patients in study 1 and study 2 respectively. Twenty-eight (62%) patients in clinical study 1 received corticosteroids for transaminase elevation and/or decline in factor IX activity. The mean time to corticosteroid initiation was 45 days. The mean duration of corticosteroid treatment was 113 days (range: 41 to 276 days). Three (20%) patients in clinical study 2 received corticosteroids for transaminase elevation and/or decline in factor IX activity with time to initiation and duration of corticosteroid use within the range seen in clinical study 1. Monitor ALT, AST and factor IX activity levels once or twice weekly for at least 4 months and institute corticosteroid treatment in response to transaminase elevation and/or decrease in FIX activity, as required [see Dosage and Administration (2.3) ] . Monitor for and manage adverse reactions secondary to corticosteroid therapy. For the first year following administration of BEQVEZ, advise patients to limit alcohol consumption, as alcohol may impact liver enzyme elevation and potentially reduce factor IX activity over time. 5.2 Infusion Reactions Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Symptoms of hypersensitivity may include but are not limited to hypotension, pyrexia, palpitation, nausea, vomiting, chills or headache. Closely monitor patients for clinical signs and symptoms of infusion reactions throughout the infusion period and for at least 3 hours after end of infusion. In the event of an infusion reaction during administration, the infusion may be slowed or stopped. If the infusion is stopped, restart at a slower rate when the infusion reaction has resolved. Consider treatment with an antihistamine, corticosteroid or other measures for management of an infusion reaction. 5.3 Malignancy The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. Integration of AAV vector DNA into the host cell DNA in other tissues may also occur [see Nonclinical Toxicology (13) ]. Monitor patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) with regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing for 5 years following BEQVEZ [see Dosage and Administration (2.3) ] . In the event that a malignancy occurs, contact Pfizer Inc. at 1-800-438-1985 to obtain instructions on collecting patient samples for testing. 5.4 Monitoring Laboratory Tests Factor IX Assays When using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay (OSA) for determining factor IX activity, plasma factor IX activity results can be affected by both the type of aPTT reagent, and the reference standard used in the assay. Higher inter-laboratory and inter-reagent variability in OSA results is observed at the lower factor IX activity levels (0.025 IU/mL). This is important to consider particularly when changing the laboratory and/or reagents used in the assay. It is recommended where possible to use the same laboratory (applicable to both, chromogenic or one-stage assays) for factor IX activity monitoring over time, particularly during the timeframe for corticosteroid treatment decision making, to minimize the impact of inter-laboratory variability [see Dosage and Administration (2.3) ] . In clinical study 1 with BEQVEZ, silica-based OSA returned consistently higher values of factor IX activity compared to ellagic acid-based OSA and chromogenic substrate assay (CSA). Generally, values of the ellagic acid-based OSA aligned with values of CSA [see Table 4 , Clinical Pharmacology (12.2) ] . Based on clinical trials (central laboratory), the approximate conversion factor between a silica-based OSA and ellagic acid-based OSA/CSA is 2. For example, a factor IX activity level of 10 IU/dL using CSA calculates approximately to a level of 20 IU/dL using silica-based OSA. At low factor IX activity levels (0.05 IU/mL) the conversion factor is approximately 2.5. Factor IX Inhibitors Monitor patients through appropriate clinical observations and laboratory tests for the development of inhibitors to factor IX after BEQVEZ administration. Perform an assay that detects factor IX inhibitors if bleeding is not controlled, or plasma factor IX activity levels decrease.