Nexviazyme

1 INDICATIONS AND USAGE NEXVIAZYME is indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency). NEXVIAZYME is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients 1 year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency). ( 1 )

2 DOSAGE AND ADMINISTRATION Consider administering antihistamines, antipyretics, and/or corticosteroids prior to NEXVIAZYME administration to reduce the risk of IARs. ( 2.1 ) NEXVIAZYME is administered as intravenous infusion. For patients weighing ( 2.2 ): ≥30 kg, the recommended dosage is 20 mg/kg (of actual body weight) every two weeks. <30 kg, the recommended dosage is 40 mg/kg (of actual body weight) every two weeks. See the full prescribing information for dosage modifications due to hypersensitivity reactions or IARs. ( 2.3 ) Must be reconstituted and diluted prior to use. ( 2.4 ) For instructions on storage and administration, see full prescribing information. ( 2.5 , 2.6 ) 2.1 Recommendations Prior to NEXVIAZYME Treatment Prior to NEXVIAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1 , 5.2) ] . NEXVIAZYME must be reconstituted and diluted prior to use [see Dosage and Administration (2.4) ] . Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during NEXVIAZYME administration. 2.2 Recommended Dosage and Administration NEXVIAZYME is administered as intravenous infusion. For patients weighing: 30 kg or more- the recommended dosage is 20 mg/kg (of actual body weight) every two weeks [see Dosage and Administration (2.6) ] Less than 30 kg- the recommended dosage is 40 mg/kg (of actual body weight) every two weeks [see Dosage and Administration (2.6) ] The initial recommended infusion rate is 1 mg/kg/hour. Gradually increase the infusion rate every 30 minutes if there are no signs of infusion-associated reactions (IARs) [see Dosage and Administration (2.6) ] . If one or more doses are missed, restart NEXVIAZYME treatment as soon as possible, maintaining the 2 week interval between infusions thereafter. 2.3 Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue NEXVIAZYME administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction or IAR, [ see Warnings and Precautions (5.1 , 5.2) ] . In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 30 minutes or slowing the infusion rate by 50% [see Dosage and Administration (2.6) ] and initiating appropriate medical treatment [see Warnings and Precautions (5.1 , 5.2) ] . If symptoms persist for longer than 30 minutes despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider re-initiating the infusion on the same day when symptoms subside at 50% of the rate at which the reaction occurred with appropriate pretreatment. If symptoms subside after holding the infusion, resume infusion at 50% of the rate at which the reaction occurred, and subsequently increase the infusion rate every 15 to 30 minutes by 50% as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete the infusion at the reduced rate as tolerated. Starting with the next infusion, increase the infusion rate until the infusion rate at which the reaction occurred is reached. Consider continuing to increase the infusion rate in a stepwise manner until reaching the recommended infusion rate. Closely monitor the patient. 2.4 Reconstitution and Dilution Instructions Reconstitute and dilute NEXVIAZYME in the following manner. Use aseptic technique during preparation. Reconstitute the Lyophilized Powder Determine the number of NEXVIAZYME vials to be reconstituted based on actual body weight in kg and the recommended dose [see Dosage and Administration (2.2) ] . Round the number of vials up to the next whole number. Remove the required number of NEXVIAZYME vials from the refrigerator and allow the vials to sit for 30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use. Reconstitute each vial by injecting 10 mL of Sterile Water for Injection, down the inside wall of each vial. Avoid adding the Sterile Water for Injection to the vial forcefully or directly onto the lyophilized powder to minimize foaming. Gently tilt and roll each vial to enhance the dissolution process. Do not invert, swirl, or shake the vial. Allow the solution to become dissolved. Each vial will yield a concentration of 100 mg/10 mL (10 mg/mL) of avalglucosidase alfa-ngpt. Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The reconstituted solution should be clear, colorless to pale-yellow. Discard if particles are present or the solution is discolored. Dilute the Reconstituted Solution Select an appropriate size 5% Dextrose Injection infusion bag and prepare by removing a volume equal to the required NEXVIAZYME volume and any overfill to achieve a fixed total volume per Table 1 based on actual body weight. Slowly withdraw the required volume of reconstituted solution from the NEXVIAZYME vial(s). Discard any unused reconstituted solution remaining in the vial. Gently inject the NEXVIAZYME reconstituted solution into the port of the 5% Dextrose Injection bag. Avoid foaming or agitation of the infusion bag and avoid introducing air into the infusion bag. Gently invert the infusion bag to mix the solution. Do not shake. After dilution, the solution will have a final concentration of 0.5 to 4 mg/mL of avalglucosidase alfa-ngpt. Administer the diluted solution without delay. The recommended infusion duration is between 4 to 7 hours [see Dosage and Administration (2.6) ] . Discard any unused diluted solution after 9 hours. Table 1: Projected Intravenous Infusion Volume for NEXVIAZYME Administration According to Actual Body Weight Patient Actual Body Weight Range (kg) Total Infusion Volume (mL) for 20 mg/kg Total Infusion Volume (mL) for 40 mg/kg 5 to 9.9 kg N/A 100 mL 10 to 19.9 kg N/A 200 mL 20 to 29.9 kg N/A 300 mL 30 to 34.9 kg 200 mL N/A 35 to 49.9 kg 250 mL N/A 50 to 59.9 kg 300 mL N/A 60 to 99.9 kg 500 mL N/A 100 to 119.9 kg 600 mL N/A 120 to 140 kg 700 mL N/A 2.5 Storage Instructions for the Reconstituted and Diluted Product Storage of the Reconstituted Solution Dilute the reconstituted solution without delay. If the reconstituted solution is not diluted immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Do not freeze. Storage of the Diluted Solution If the diluted solution is not used immediately, refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The diluted solution must be infused within 9 hours after removal from the refrigerator, inclusive of infusion time, or discarded. Once the diluted solution is removed from the refrigerator, it must not be restored back into the refrigerator. Do not freeze. 2.6 Administration Instructions If the diluted solution was refrigerated, allow solution to equilibrate to room temperature for 30 minutes prior to infusion. It is recommended to use an in-line, low protein-binding, 0.2 micron filter during administration. Administer the infusion incrementally, as determined by the patient's response and comfort. When the recommended dose is 20 mg/kg Initial and Subsequent Infusions: The initial recommended infusion rate is 1 mg/kg/hour (see Table 2 ). If there are no signs of hypersensitivity or infusion-associated reactions (IARs), gradually increase the infusion rate every 30 minutes in each of the following three steps: 3 mg/kg/hour, 5 mg/kg/hour, and then 7 mg/kg/hour; then, maintain the infusion rate at 7 mg/kg/hour until the infusion is complete. The approximate total infusion duration is 4 to 5 hours. Table 2: Recommended Infusion Rates at 20 mg/kg Dose Dose Step 1 Step 2 Step 3 Step 4 Step 5 Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion every 30 minutes until completion (total time approximately 4 to 5 hours). 20 mg/kg 1 mg/kg/hour 3 mg/kg/hour 5 mg/kg/hour 7 mg/kg/hour Continue 7 mg/kg/hour When the recommended dose is 40 mg/kg Initial Infusion: The initial recommended infusion rate is 1 mg/kg/hour (see Table 3 ). If there are no signs of hypersensitivity or IARs, gradually increase the infusion rate every 30 minutes in each of the following three steps: 3 mg/kg/hour, 5 mg/kg/hour, and then 7 mg/kg/hour; then, maintain the infusion rate at 7 mg/kg/hour until the infusion is complete (4-step process). The approximate total infusion duration is 7 hours. Subsequent Infusions: The initial recommended infusion rate is 1 mg/kg/hour (see Table 3 ) with gradual increase in infusion rate every 30 minutes if there are no signs of hypersensitivity or IARs. The process may use either the above 4-step process or the following 5-step process: 3 mg/kg/hour, 6 mg/kg/hour, 8 mg/kg/hour, and then 10 mg/kg/hour; then, maintain the infusion rate at 10 mg/kg/hour until the infusion is complete. The approximate total 5-step infusion duration is 5 hours. Table 3: Recommended Infusion Rates at 40 mg/kg Dose Dose Step 1 Step 2 Step 3 Step 4 Step 5 Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion every 30 minutes until completion. Total time for initial infusion approximately 7 hours and can optionally increase rate of subsequent infusions to decrease total duration to 5 hours. 40 mg/kg Initial infusion rate 1 mg/kg/hour 3 mg/kg/hour 5 mg/kg/hour 7 mg/kg/hour Continue 7 mg/kg/hour Subsequent infusions (optional) 1 mg/kg/hour 3 mg/kg/hour 6 mg/kg/hour 8 mg/kg/hour Continue 10 mg/kg/hour After the infusion is complete, flush the intravenous line with 5% Dextrose Injection. Do not infuse NEXVIAZYME in the same intravenous line with other products.

4 CONTRAINDICATIONS None. None. ( 4 )

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) ].

8.1 Pregnancy Risk Summary Available data from case reports of NEXVIAZYME use in pregnant women are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, available data from postmarketing reports and published case reports on alglucosidase alfa (another hydrolytic lysosomal glycogen-specific enzyme replacement therapy) use in pregnant women have not identified a drug-associated risk of adverse pregnancy outcomes. The continuation of treatment for Pompe disease during pregnancy should be individualized to the pregnant woman. Untreated Pompe disease may result in worsening disease symptoms in pregnant women (see Clinical Considerations ) . Embryo-fetal toxicity studies performed in pregnant mice resulted in maternal toxicity related to an immunologic response (including an anaphylactoid response) and embryo-fetal loss at 17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for LOPD patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg. Avalglucosidase alfa-ngpt did not cross the placenta in mice, therefore, the adverse effects were likely related to the immunologic response in the mothers. Embryo-fetal toxicity studies performed in pregnant rabbits showed no adverse effects on the fetuses at exposure up to 91 times the human steady-state AUC at the recommended biweekly dosage of 20 mg/kg for LOPD patients weighing ≥30 kg or 50 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Pregnant women exposed to NEXVIAZYME, or their healthcare providers, should report NEXVIAZYME exposure by calling 1-800-633-1610, option 1. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal symptoms in some pregnant women. Data Animal data The majority of reproductive toxicity studies in mice included the pretreatment with diphenhydramine (DPH) to prevent or minimize hypersensitivity reactions. The effects of NEXVIAZYME were evaluated based on comparison with a control group treated with DPH alone. Rabbits tested in reproductive toxicity studies were not pretreated with DPH because hypersensitivity reactions were not observed. Embryo-fetal toxicity studies performed in pregnant mice at doses of 0, 10, 20, or 50 mg/kg/day administered intravenously once daily on gestational days 6 through 15 resulted in an immunologic response, including an anaphylactoid response, in some dams at the highest dose of 50 mg/kg/day (17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for LOPD patients weighing ≥30 kg or 10 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg). Increased post-implantation loss and mean number of late resorptions were observed in this group. Placental transfer studies determined that avalglucosidase alfa-ngpt was not transported from the maternal to the fetal circulation in mice, suggesting that the embryo-fetal effects were due to maternal toxicity relating to the immunologic response. The maternal no observed adverse effect level (NOAEL) was 50 mg/kg/day intravenously (17 times the human AUC) and the developmental NOAEL was 20 mg/kg/day intravenously (4.8 times the human AUC). Embryo-fetal toxicity studies performed in rabbits at doses of 0, 30, 60, and 100 mg/kg/day administered intravenously once daily on gestational days 6 through 19 resulted in no adverse effects in the fetuses at the highest dose (100 mg/kg/day; 91 times the human steady-state AUC at the recommended biweekly dosage of 20 mg/kg for LOPD patients weighing ≥30 kg or 50 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for LOPD patients weighing <30 kg). Furthermore, the administration of NEXVIAZYME intravenously every other day in mice from gestational day 6 through postpartum day 20 did not produce adverse effects in the offspring at the highest dose of 50 mg/kg (maternal exposure not evaluated).