ROCTAVIAN

5 WARNINGS AND PRECAUTIONS Infusion-related reactions: Infusion reactions, including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during and for at least 3 hours after ROCTAVIAN administration. If symptoms occur, slow or interrupt administration and give appropriate treatment. Restart infusion at slower rate once symptoms resolve. Discontinue infusion for anaphylaxis. ( 2.3 , 5.1 ) Hepatotoxicity: Monitor alanine aminotransferase (ALT) weekly for at least 26 weeks and institute corticosteroid treatment in response to ALT elevations as required. Continue to monitor ALT until it returns to baseline. Monitor factor VIII activity levels since ALT elevation may be accompanied by a decrease in factor VIII activity. Monitor for and manage adverse reactions from corticosteroid use. ( 5.2 ) Thromboembolic events: Thromboembolic events may occur in the setting of elevated factor VIII activity above the upper limit of normal (ULN). Factor VIII activity above ULN has been reported following ROCTAVIAN infusion. Evaluate for risk factors for thrombosis including cardiovascular risk factors prior to and after ROCTAVIAN use and advise patients accordingly. ( 5.3 ) Monitoring laboratory tests: Monitor for factor VIII activity and factor VIII inhibitors. ( 5.4 ) Malignancy: Monitor for hepatocellular malignancy in 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). Perform regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing following administration. In the event that any malignancy occurs after treatment with ROCTAVIAN, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100. ( 5.5 ) 5.1 Infusion-Related Reactions Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred during and/or following ROCTAVIAN administration . Symptoms included one or more of the following: urticaria, pruritus, rash, sneezing, coughing, dyspnea, rhinorrhea, watery eyes, tingling throat, nausea, diarrhea, hypotension, tachycardia, presyncope, pyrexia, rigors, and chills. Monitor patients during and for at least 3 hours after completion of ROCTAVIAN infusion. Do not infuse the product faster than 4 mL/min [see Dosage and Administration (2.3) ] . In the event of an infusion reaction, administration of ROCTAVIAN should be slowed or stopped. Restart at a lower rate after the infusion reaction has resolved. Discontinue infusion for anaphylaxis. Consider treatment with a corticosteroid, antihistamine, and other measures for management of an infusion reaction [see Dosage and Administration (2.3) ] . 5.2 Hepatotoxicity Intravenous administration of a liver-directed AAV vector could lead to liver enzyme elevations (transaminitis), especially ALT elevation. Transaminitis is presumed to occur due to immune-mediated injury of transduced hepatocytes and may reduce the therapeutic efficacy of AAV-vector based gene therapy. Majority of patients treated with ROCTAVIAN experienced ALT elevations. Most ALT elevations occurred within the first year following ROCTAVIAN administration, especially within the first 26 weeks, were low-grade, and resolved. The median time (range) to the first ALT elevation (defined as ALT ≥ 1.5 × baseline or above ULN) was 7 weeks (0.4, 159 weeks) and the median duration (range) was 4 weeks (0.1, 135 weeks). Some ALT elevations were associated with a decline in factor VIII activity. The majority of the 112 patients in the clinical trial of ROCTAVIAN required corticosteroids for ALT elevation [see Adverse Reactions (6.1) and Clinical Studies (14) ] . The median duration (range) of corticosteroid use was 35 weeks (3, 120 weeks). The median duration (range) of alternate immunosuppressive medications use was 26 weeks (6, 118 weeks). In 20 (18%) patients the duration of immunosuppression was > 1 year. Monitor ALT and institute corticosteroid treatment in response to ALT elevations, as required . Monitor ALT and factor VIII activity levels weekly and, as clinically indicated, during corticosteroid therapy [see Dosage and Administration (2.3) ] . Monitor for and manage adverse reactions secondary to corticosteroid therapy . Since some ALT elevations have been attributed to alcohol consumption in clinical studies, patients should abstain from alcohol consumption for at least a year following ROCTAVIAN infusion and limit alcohol use thereafter. Concomitant medications may cause hepatotoxicity, or decrease factor VIII activity, or change plasma corticosteroid levels which may impact liver enzyme elevation and/or factor VIII activity [see Drug Interactions (7.0 , 7.1 , 7.2) ] . Closely monitor concomitant medication use including herbal products and nutritional supplements and consider alternative medications in case of potential drug interactions. 5.3 Thromboembolic Events Elevated factor VIII activity level above the ULN as measured by the chromogenic substrate assays (CSA), or one-stage clotting assays (OSA), or both assays has occurred following ROCTAVIAN administration. Thirty-eight (28%) patients experienced elevations of factor VIII above ULN with a median time to first occurrence of 14 weeks and a median total duration above ULN of 12 weeks. An increase in factor VIII activity may increase the risk for venous and arterial thromboembolic events. There are no data in patients with a history of venous or arterial thromboembolism or known history of thrombophilia since such patients were excluded from clinical trials of ROCTAVIAN. Evaluate patients for risk of thrombosis including general cardiovascular risk factors before and after administration of ROCTAVIAN. Advise patients on their individual risk of thrombosis in relation to their factor VIII activity levels above ULN and consider prophylactic anticoagulation. Advise patients to seek immediate medical attention for signs or symptoms indicative of a thrombotic event. 5.4 Monitoring Laboratory Tests Factor VIII Assays Factor VIII activity produced by ROCTAVIAN in human plasma is higher if measured with OSA compared to CSA. In clinical studies, there was a high correlation between OSA and CSA factor VIII activity levels across the entire range of each assay's results [doi: 10.1182/blood.2020005683]. For routine clinical monitoring of factor VIII activity levels, either assay may be used. The conversion factor between the assays can be approximated based on clinical study results (central laboratory) to be: OSA = 1.5 × CSA. For example, a factor VIII activity level of 50 IU/dL using CSA calculates to a level of 75 IU/dL using OSA. The OSA to CSA ratio depends on the factor VIII assay reagents used by the laboratory and can range from 1.3 to 2.0, therefore, the same type of OSA or CSA reagents should be used to monitor factor VIII levels over time. When switching from hemostatic products prior to ROCTAVIAN treatment, physicians should refer to the relevant prescribing information to avoid the potential for factor VIII activity assay interference during the transition period. Factor VIII Inhibitors Monitor patients through appropriate clinical observations and laboratory tests for the development of factor VIII inhibitors after ROCTAVIAN administration. Perform an assay that detects factor VIII inhibitors if bleeding is not controlled, or plasma factor VIII activity levels decrease [see Dosage and Administration (2.3) ] . 5.5 Malignancy The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. ROCTAVIAN is composed of a non-replicating AAV5 vector whose DNA persists largely in episomal form. Low levels of vector integration were found following evaluation of liver samples from 5 patients and parotid gland tissue sample from 1 patient in clinical studies and liver samples from 12 nonhuman primates [see Clinical Pharmacology (12.2) and Nonclinical Toxicology (13.1) ] . ROCTAVIAN can also insert into the DNA of other human body cells. No malignancies assessed as being likely related to ROCTAVIAN were observed in clinical studies. 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 ROCTAVIAN administration [see Dosage and Administration (2.3) ] . In the event that a malignancy occurs, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100 to obtain instructions on collecting patient samples for testing.