Nexviazyme

WARNING: SEVERE HYPERSENSITIVITY REACTIONS, INFUSION-ASSOCIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE IN SUSCEPTIBLE PATIENTS WARNING: SEVERE HYPERSENSITIVITY REACTIONS, INFUSION-ASSOCIATED REACTIONS, and RISK OF ACUTE CARDIORESPIRATORY FAILURE IN SUSCEPTIBLE PATIENTS See full prescribing information for complete boxed warning. Hypersensitivity Reactions Including Anaphylaxis Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available. If a severe hypersensitivity reaction occurs, discontinue NEXVIAZYME immediately and initiate appropriate medical treatment. ( 5.1 ) Infusion-Associated Reactions (IARs) If severe IARs occur, consider immediate discontinuation and initiation of appropriate medical treatment. ( 5.2 ) Risk of Acute Cardiorespiratory Failure in Susceptible Patients Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function, may be at risk of serious exacerbation of their cardiac or respiratory status during NEXVIAZYME infusion. ( 5.3 ) Hypersensitivity Reactions Including Anaphylaxis Patients treated with NEXVIAZYME have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue NEXVIAZYME immediately and initiate appropriate medical treatment. In patients with severe hypersensitivity reactions, a desensitization procedure to NEXVIAZYME may be considered [see Warnings and Precautions (5.1) ] . Infusion-Associated Reactions (IARs) Patients treated with NEXVIAZYME have experienced severe IARs. If severe IARs occur, consider immediate discontinuation of NEXVIAZYME, initiation of appropriate medical treatment, and the benefits and risks of readministering NEXVIAZYME following severe IARs. Patients with an acute underlying illness at the time of NEXVIAZYME infusion may be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs [see Warnings and Precautions (5.2) ] . Risk of Acute Cardiorespiratory Failure in Susceptible Patients Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during NEXVIAZYME infusion. More frequent monitoring of vitals should be performed during NEXVIAZYME infusion in such patients [see Warnings and Precautions (5.3) ] .

5 WARNINGS AND PRECAUTIONS See boxed warning . ( 5.1 , 5.2 , 5.3) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in NEXVIAZYME-treated patients. In NEXVIAZYME clinical studies, 67 (48%) NEXVIAZYME-treated patients experienced hypersensitivity reactions, including 6 (4%) patients who reported severe hypersensitivity reactions and 3 (2%) patients who experienced anaphylaxis; 2 (1%) patients who experienced anaphylaxis discontinued from the study. Some of the hypersensitivity reactions were IgE mediated. Symptoms of severe hypersensitivity reactions (e.g., anaphylaxis) included chest discomfort, erythema, generalized edema, hypotension, hypoxia, rash, respiratory distress, tongue edema, and urticaria. Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue NEXVIAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering NEXVIAZYME following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates at a dosage lower than the recommended dosage. In patients with severe hypersensitivity reaction, desensitization measures to NEXVIAZYME may be considered. If the decision is made to readminister NEXVIAZYME, ensure the patient tolerates the infusion. Once the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3) ] . 5.2 Infusion-Associated Reactions In clinical studies, IARs were reported to occur at any time during and/or within a few hours after the NEXVIAZYME infusion and were more likely to occur with higher infusion rates. IARs were reported in 48 (34%) NEXVIAZYME-treated patients in all clinical studies. In these studies, 5 (4%) NEXVIAZYME-treated patients reported 10 severe IARs including symptoms of chest discomfort, decreased or increased blood pressure, dysphagia, erythema, generalized edema, hypoxia, nausea, respiratory distress, tongue edema, and urticaria. The majority of IARs were assessed as mild to moderate. IARs that led to treatment discontinuation were chest discomfort, cough, dizziness, erythema, flushing, nausea, ocular hyperemia, respiratory distress, and urticaria. Increased incidence of IARs was observed in patients with higher ADA titers [see Adverse Reactions (6.1) ] . Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. However, IARs may still occur in patients after receiving pretreatment. If a severe IAR occurs, discontinue NEXVIAZYME immediately and initiate appropriate medical treatment. Consider the benefits and risks of readministering NEXVIAZYME following a severe IAR. Patients may be rechallenged using slower infusion rates at a dosage lower than the recommended dosage. Once the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage. If a mild or moderate IAR occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration (2.3) ]. Patients with an acute underlying illness at the time of NEXVIAZYME infusion appear to be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs. 5.3 Risk of Acute Cardiorespiratory Failure in Susceptible Patients Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function for whom fluid restriction is indicated may be at risk of serious exacerbation of their cardiac or respiratory status during the NEXVIAZYME infusion. More frequent monitoring of vitals should be performed during NEXVIAZYME infusion in these patients. Some patients may require prolonged observation times.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion-Associated Reactions (IARs) [see Warnings and Precautions (5.2) ] The most common adverse reactions (>5%) were headache, fatigue, diarrhea, nausea, arthralgia, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia and urticaria. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-633-1610, option 1 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trials in the Pompe Disease Population The pooled safety analysis from 4 clinical trials in the Pompe disease population (including Study 1) with a mean exposure of 26 months and up to 85 months of treatment included a total of 141 NEXVIAZYME-treated patients (118 adult and 23 pediatric patients [see Clinical Studies (14.1) ] . Adverse reactions were similar across both adult and pediatric populations. Serious adverse reactions reported in 2 or more NEXVIAZYME-treated patients were respiratory distress, chills, and pyrexia. A total of 4 NEXVIAZYME-treated patients in clinical trials permanently discontinued NEXVIAZYME due to adverse reactions, including 3 patients who discontinued the treatment because of a serious adverse reaction. The most frequently reported adverse reactions (>5%) in the pooled safety population were abdominal pain, arthralgia, chills, diarrhea, dizziness, dyspnea, erythema, fatigue, flushing, headache, hypertension, hypotension, myalgia, nausea, pruritus, pyrexia, rash, vomiting, and urticaria. Hypersensitivity reactions were reported in 67 (48%) NEXVIAZYME-treated patients, including 6 (4%) patients who reported severe hypersensitivity reactions. Symptoms of severe hypersensitivity reactions (e.g., anaphylaxis) included chest discomfort, erythema, generalized edema, hypotension, hypoxia, rash, respiratory distress, tongue edema, and urticaria. IARs were reported in 48 (34%) NEXVIAZYME-treated patients. Six (4%) NEXVIAZYME-treated patients reported 13 severe IARs including symptoms of chest discomfort, decreased or increased blood pressure, dysphagia, erythema, generalized edema, hypoxia, nausea, respiratory distress, tongue edema, and urticaria. IARs reported in more than 1 patient included chest discomfort, cyanosis, decreased or increased blood pressure, diarrhea, dizziness, erythema, fatigue, feeling hot or cold, generalized edema, headache, hyperhidrosis, hypoxia, influenza-like illness, nausea, pain, pruritus, pyrexia, rash, respiratory distress, tachycardia, throat irritation, tongue edema, tremor, urticaria, and vomiting. Adverse Reactions from Clinical Trials in Late-Onset Pompe Disease (LOPD) In Study 1, 100 patients aged 16 to 78 years of age with LOPD (naïve to enzyme replacement therapy) were treated with either 20 mg/kg of NEXVIAZYME (n=51) or 20 mg/kg of alglucosidase alfa (n=49) given every other week as an intravenous infusion for 49 weeks followed by an open-label extension period [see Clinical Studies (14.1) ] . During the double-blind active-controlled period of 49 weeks, serious adverse reactions were reported in 1 (2%) patient treated with NEXVIAZYME and in 3 (6%) patients treated with alglucosidase alfa. The most frequently reported adverse reactions in (>5%) NEXVIAZYME-treated patients were headache, fatigue, diarrhea, nausea, arthralgia, dizziness, myalgia, pruritus, vomiting, dyspnea, erythema, paresthesia, and urticaria. IARs were reported in 13 (25%) of the NEXVIAZYME-treated patients. IARs reported in more than 1 patient on NEXVIAZYME were mild to moderate and included headache, diarrhea, pruritus, urticaria, and rash. None of them were severe IARs. IARs were reported in 16 (33%) patients treated with alglucosidase alfa. IARs reported in more than 1 patient on alglucosidase alfa were mild to severe and included dizziness, flushing, dyspnea, nausea, pruritis, rash, erythema, chills, and feeling hot. Severe IARs were reported in 2 patients treated with alglucosidase alfa. Table 4 summarizes the adverse reactions that occurred in at least 3 NEXVIAZYME-treated patients (≥6%) in Study 1. Study 1 was not designed to demonstrate a statistically significant difference in the incidence of adverse reactions in the NEXVIAZYME and the alglucosidase alfa treatment groups. Table 4: Adverse Reactions Reported in at Least 6% of NEXVIAZYME-Treated Patients with LOPD in Study 1 Adverse Reaction NEXVIAZYME (N=51) n (%) Alglucosidase Alfa (N=49) n (%) Headache 11 (22%) 16 (33%) Fatigue 9 (18%) 7 (14%) Diarrhea 6 (12%) 8 (16%) Nausea 6 (12%) 7 (14%) Arthralgia 5 (10%) 8 (16%) Dizziness 5 (10%) 4 (8%) Myalgia 5 (10%) 7 (14%) Pruritus 4 (8%) 4 (8%) Vomiting 4 (8%) 3 (6%) Dyspnea 3 (6%) 4 (8%) Erythema 3 (6%) 3 (6%) Paresthesia 3 (6%) 2 (4%) Urticaria 3 (6%) 1 (2%) Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions In enzyme replacement therapy (ERT)-naïve NEXVIAZYME-treated patients (mean of 47 months, up to 100 months of treatment), the incidence of [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.6) ] IARs was 69% (9/13) in patients with an anti-drug antibody (ADA) peak titer ≥12,800, compared with incidences of 27% (12/44) in those with ADA peak titer <12,800 and 33% (1/3) in those who were ADA-negative . In ERT-experienced adult patients, the incidence of IARs and hypersensitivity reactions were higher in patients who developed ADA compared to patients who were ADA-negative [see Clinical Pharmacology (12.6) ]. In adults, one ERT-naïve patient (ADA peak titer 3,200) and 2 ERT-experienced patients (peak ADA titers; 800 and 12,800, respectively) developed anaphylaxis. One ERT-experienced pediatric patient (peak ADA titer 6,400) developed anaphylaxis [see Warnings and Precautions (5.1) ].

<table width="85%" ID="table2"><caption>Table 4: Adverse Reactions Reported in at Least 6% of NEXVIAZYME-Treated Patients with LOPD in Study 1</caption><col width="33%" align="left" valign="middle"/><col width="33%" align="center" valign="middle"/><col width="34%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reaction</th><th styleCode="Rrule" valign="top">NEXVIAZYME (N=51) n (%)</th><th styleCode="Rrule" valign="top">Alglucosidase Alfa (N=49) n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">11 (22%)</td><td styleCode="Rrule">16 (33%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">9 (18%)</td><td styleCode="Rrule">7 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">6 (12%)</td><td styleCode="Rrule">8 (16%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">6 (12%)</td><td styleCode="Rrule">7 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">5 (10%)</td><td styleCode="Rrule">8 (16%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">5 (10%)</td><td styleCode="Rrule">4 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">5 (10%)</td><td styleCode="Rrule">7 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">4 (8%)</td><td styleCode="Rrule">4 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">4 (8%)</td><td styleCode="Rrule">3 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea</td><td styleCode="Rrule">3 (6%)</td><td styleCode="Rrule">4 (8%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythema</td><td styleCode="Rrule">3 (6%)</td><td styleCode="Rrule">3 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paresthesia</td><td styleCode="Rrule">3 (6%)</td><td styleCode="Rrule">2 (4%)</td></tr><tr><td styleCode="Lrule Rrule">Urticaria</td><td styleCode="Rrule">3 (6%)</td><td styleCode="Rrule">1 (2%)</td></tr></tbody></table>