Pegunigalsidase Alfa

1 INDICATIONS AND USAGE ELFABRIO is indicated for the treatment of adults with confirmed Fabry disease. ELFABRIO is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme indicated for the treatment of adults with confirmed Fabry disease. ( 1 )

2 DOSAGE AND ADMINISTRATION For pretreatment recommendations, see Full Prescribing Information. ( 2.1 ) Recommended dosage is 1 mg/kg every 2 weeks administered as an intravenous infusion. ( 2.2 ) For dosage and administration modifications due to hypersensitivity reactions or infusion-associated reactions (IARs), see Full Prescribing Information. ( 2.3 ) For instructions on preparation (including dilution), storage, and administration (including rates for the initial 4-6 infusions for ERT-experienced and ERT-naïve patients), see Full Prescribing Information. ( 2.4 , 2.5 , 2.6 ) 2. 1 Recommendations Prior to ELFABRIO Treatment Pretreatment In enzyme replacement therapy (ERT)-experienced patients, if pretreatment with antihistamines, antipyretics, and/or corticosteroids was used prior to ERT administration, consider similar pretreatment with these medications before the first several ELFABRIO infusions. After 4 to 6 ELFABRIO infusions, a stepwise decrease in the pretreatment medication dose(s) and/or discontinuation of the pretreatment medication(s) may be considered if treatment with ELFABRIO was tolerated. In ERT-naïve patients, prior to ELFABRIO administration, pre-treating with antihistamines, antipyretics, and/or corticosteroids may be considered [see Warnings and Precautions ( 5.1 , 5.2 )] . Medical Support Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during ELFABRIO administration. 2. 2 Recommended Dosage and Administration The recommended dosage of ELFABRIO, based on actual body weight, is 1 mg/kg administered by intravenous infusion every 2 weeks. The initial recommended ELFABRIO infusion rates for ERT-experienced or ERT-naïve patients are based on actual body weight [ see Tables 1 and 2 ] . If one or more doses are missed, restart ELFABRIO treatment as soon as possible, maintaining the 2 week interval between infusions thereafter. Do not double a dose to compensate for a missed dose. 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 ELFABRIO 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 15 to 30 minutes or slowing the infusion rate by 25% to 50% [ see Dosage and Administration ( 2.6 )] , and initiating appropriate medical treatment [see Warnings and Precautions ( 5.1 , 5.2 )] . If symptoms persist despite holding or slowing the infusion, stop the infusion and monitor the patient. Consider re-initiating the infusion within 7 to 14 days at 25% to 50% of the rate at which the reaction occurred with appropriate pretreatment. If symptoms subside after holding the infusion, resume infusion at a 25% to 50% reduced rate as tolerated. Alternatively, if symptoms subside after slowing the infusion, complete infusion at the reduced rate as tolerated. Starting with the next infusion, increase the infusion rate by increments of 25% every third infusion as tolerated until the infusion rate at which the reaction occurred is reached. Closely monitor the patient. 2. 4 Preparation Instructions Use aseptic technique during preparation. Dilute ELFABRIO in the following manner: Determine the number of ELFABRIO vials to be diluted based on actual body weight in kg and the recommended dose [see Dosage and Administration ( 2.2 ) and Dosage Forms and Strengths ( 3 ) ] . Round the number of vials up to the next whole number. Remove the appropriate number of ELFABRIO vials from the refrigerator and allow the vials to sit for 15-30 minutes at room temperature 20°C to 25°C (68°F to 77°F) before use. Do not use an external heat source to heat the product because heat may damage the product. Visually inspect the solution in the vials for particulate matter and discoloration. The solution should be clear and colorless. Discard if the solution is discolored or if visible particulate matter is present. Dilute the supplied ELFABRIO solution required for a dose in 0.9% Sodium Chloride Injection to a total volume based on actual body weight specified in Tables 1 and 2 below. Prior to adding the volume of ELFABRIO required for the dose, remove the equal volume of 0.9% Sodium Chloride Injection from the infusion bag. Withdraw the volume of ELFABRIO required for the dose from the vials (discard any unused solution remaining in the vial). Inject the ELFABRIO solution directly into the 0.9% Sodium Chloride Injection solution through the port of the infusion bag. Do not inject in the airspace within the infusion bag. Gently invert infusion bag to mix the solution. Avoid vigorous shaking or agitation. 2.5 Storage of the Diluted Solution If the diluted ELFABRIO 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 solution must be infused within 8 hours after removal from the refrigerator, inclusive of the total infusion time, or discarded. ○ Store the diluted solution at room temperature at 20°C to 25°C (68°F to 77°F) for up to 8 hours. The solution must be used within 8 hours, inclusive of infusion time, or discarded. Do not freeze or shake. 2. 6 Administration Instructions Administer ELFABRIO as follows: Use an in-line low protein-binding, 0.2 micron, in-line filter during administration. For the initial 4-6 infusions, infuse ELFABRIO using the infusion rates described in Table 1 for ERT-experienced patients and Table 2 for ERT-naïve patients. If a patient tolerates the initial 4-6 ELFABRIO infusions, the duration of every third infusion may be decreased in decrements of 30 minutes as tolerated. The minimum recommended infusion duration is 1.5 hours. At the end of the infusion, flush the line with 0.9% Sodium Chloride Injection using the same infusion rate as the one used for the last part of the ELFABRIO infusion. Do not infuse ELFABRIO in the same intravenous line with other products. Table 1 presents the recommended infusion rates for the initial 4-6 ELFABRIO infusions based on actual body weight for ERT-experienced patients. Table 1: Recommended Infusion Rate 1 for ERT-Experienced Patients for the Initial 4-6 ELFABRIO Intravenous Infusions Based on Actual Body Weight Actual Body Weight Total Infusion V olume Infusion R ate 1 ˂ 70 kg 150 mL 0.83 mL/min (50 mL/h) 70 -100 kg 250 mL 1.39 mL/min (83 mL/h) > 100 kg 500 mL 2.78 mL/min (167 mL/h) 1 Infusion rate may be increased if the patient tolerates the initial 4-6 infusions (see above). Infusion rate may be slowed in case of a hypersensitivity reaction or an IAR [see Dosage and Administration ( 2.3 )]. Table 2 presents the recommended infusion rates for the initial 4-6 ELFABRIO infusions based on actual body weight for ERT-naïve patients. Table 2: Recommended Infusion Rate 1 for ERT-Naïve Patients for the Initial 4-6 ELFABRIO Intravenous Infusions Based on Actual Body Weight Actual Body Weight Total Infusion Volume Infusion Rate 1 ˂ 70 kg 150 mL 0.63 mL/min (37.5 mL/h) 70 -100 kg 250 mL 1 mL/min (60 mL/h) > 100 kg 500 mL 1.38 mL/min (83 mL/h) 1 Infusion rate may be increased if the patient tolerates the initial 4-6 infusions (see above). Infusion rate may be slowed in case of a hypersensitivity reaction or an IAR [see Dosage and Administration ( 2.3 )]. Administration of ELFABRIO to Patients Previously Treated with ERT w ith an Infusion Duration Over 3 Hours In patients previously treated with an ERT with an infusion duration over 3 hours: Use the same infusion rate for the ELFABRIO infusion. May decrease the duration of every third infusion after the initial 4-6 ELFABRIO infusions in decrements of 30 minutes as tolerated. The recommended minimum infusion duration of the maintenance infusion is 1.5 hours. Home Infusion Home administration under the supervision of a healthcare provider may be considered for patients who have reached an infusion duration that is tolerated well [see Dosage and Administration ( 2.1 , 2.3 )] . The decision to have a patient move to home infusion should be made after evaluation and recommendation by a healthcare provider. The infusion duration should remain constant for home administration and the duration should only be decreased in a healthcare facility. In case of a missed dose or delayed infusion, a healthcare provider should be contacted.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions ( 5.1 ) ] Infusion-Associated Reactions (IARs) [see Warnings and Precautions ( 5.2 )] Membranoproliferative Glomerulonephritis [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (≥15%) are: infusion-associated reactions, nasopharyngitis, headache, diarrhea, fatigue, nausea, back pain, pain in extremity, and sinusitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 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 trial of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions From Trial 2 The safety of ELFABRIO in adults with confirmed Fabry disease who had been previously treated with agalsidase beta was evaluated in Trial 2 which included a total of 52 ELFABRIO-treated patients (29 male, 23 female aged 20 to 60 years old) with Fabry disease [see Clinical Studies ( 14 )] . Patients received 1 mg/kg of ELFABRIO given intravenously every 2 weeks for at least 104 weeks. The most common adverse reactions (≥15%) reported with ELFABRIO were infusion-associated reactions which occurred in 17 patients (32%); followed by, nasopharyngitis and headache each in 11 patients (21%); diarrhea in 10 patients (19%); fatigue and nausea each in 9 patients (17%); and back pain, pain in extremity, and sinusitis each in 8 patients (15%) . One ELFABRIO-treated patient experienced a severe hypersensitivity reaction during the first infusion. The patient withdrew from the trial following a moderate hypersensitivity reaction during the second infusion. Table 3 lists adverse reactions reported in at least 5% of ELFABRIO-treated patients in Trial 2. Table 3: Adverse Reactions in Adults With Fabry Disease (Trial 2) 1 Adverse Reaction ELFABRIO N=52 n (%) Agalsidase beta N=25 n (%) Infusion-Associated Reaction 2,4 17 (32) 8 (32) Nasopharyngitis 11 (21) 4 (16) Headache 11 (21) 5 (20) Diarrhea 10 (19) 6 (24) Fatigue 9 (17) 4 (16) Nausea 9 (17) 3 (12) Back pain 8 (15) 5 (20) Pain in Extremity 8 (15) 4 (16) Sinusitis 8 (15) 3 (12) Abdominal Pain 6 (12) 0 (0) Proteinuria 6 (12) 0 (0) Hypersensitivity 3,4 5 (9) 4 (16) Upper Respiratory Tract Congestion 4 (8) 0 (0) Neuralgia 4 (8) 0 (0) Peripheral Neuropathy 3 (6) 0 (0) Sciatica 3 (6) 0 (0) Infusion Site Extravasation 3 (6) 0 (0) Hematuria 3 (6) 0 (0) 1 Adverse reactions were those that occurred in ≥ 5% of ELFABRIO-treated patients. 2 “Infusion-associated reaction” includes nausea, vomiting, abdominal pain, diarrhea, fatigue, chills, malaise, non-cardiac chest pain, hypersensitivity, body temperature increased, burning sensation, neuralgia, agitation, throat irritation, pruritic rash, and flushing. Events occurring within 24 hours. 3 “Hypersensitivity” includes macular rash, pruritic rash, and face swelling. Events occurring within 24 hours. 4 The events of hypersensitivity and pruritic rash fall in both hypersensitivity and IAR categories. Membranoproliferative Glomerulonephritis A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported in an ELFABRIO-treated patient. Immunogenicity: Anti - D rug Antibody-Associated Adverse Reactions Of the patients who experienced serious hypersensitivity reactions during the first ELFABRIO infusion and had pre-infusion samples and samples available for testing at the time of the event, all but one had pre-existing IgE ADAs and all tested positive for IgE ADAs at the time of the reaction. In the overall clinical program, IARs occurred in 51% (19/37) of patients who were IgG ADA positive at baseline compared to 16% (13/84) in IgG ADA negative patients [see Clinical Pharmacology ( 12.6 )] .

12.3 Pharmacokinetics The pharmacokinetics (PK) of pegunigalsidase alfa-iwxj were evaluated in adult patients with Fabry disease and are presented as mean (standard deviation, SD) unless otherwise specified. The pharmacokinetics of pegunigalsidase alfa-iwxj in plasma following intravenous infusion of ELFABRIO 1 mg/kg every 2 weeks in adult treatment-naïve patients with Fabry disease are summarized in Table 4. The maximum plasma concentration (C max ) and area under the concentration-time curve (AUC) of pegunigalsidase alfa-iwxj increased with longer duration of treatment. In adult ERT-experienced patients with Fabry disease, mean C max ranged from 21.2 to 23.3 μg/mL and mean AUC tau ranged from 958 to 1074 μg·h/mL following intravenous infusion of ELFABRIO 1 mg/kg every 2 weeks. Table 4: Pharmacokinetics of Pegunigalsidase Alfa-iwxj in Adult ERT-Naïve 1 Patients With Fabry Disease Following Intravenous Infusion of ELFABRIO 1 mg/kg Every 2 Weeks PK Parameters Pegunigalsidase Alfa-iwxj Day 1 Week 13 Week 26 Week 52 Mean Infusion Duration (h) 5.5 4.4 3.9 3.3 General Information C max (μg/mL) 11.1±2.4 11.9±2.4 13.3±3.0 17.3±6.1 AUC inf (μg·h/mL) 391±136 510±174 748±200 1428±875 Distribution V (mL/kg) 321±71 271±89 226±116 186±91 Elimination t 1/2 (h) 78.9±10.3 85.7±28.4 96.5±31.4 121±22 CL (mL/h/kg) 2.9±0.7 2.3±0.8 1.6±0.6 1.1±0.7 Metabolism Expected metabolism into small peptides by catabolic pathways C max =maximum plasma concentration; AUC=area under the plasma concentration-time curve; V= terminal volume of distribution; t 1/2 =elimination half-life; CL=clearance 1 Includes patients who had not received ERT for at least 26 Weeks and who tested negative for anti-pegunigalsidase alfa-iwxj antibodies at screening.