Apadamtase Alfa

1 INDICATIONS AND USAGE ADZYNMA (ADAMTS13, recombinant-krhn) is a human recombinant “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) indicated for prophylactic or on demand enzyme replacement therapy (ERT) in adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (cTTP) [see Use in Specific Populations (8.4) , Clinical Studies (14) ]. ADZYNMA (ADAMTS13, recombinant-krhn) is a human recombinant “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) indicated for prophylactic or on demand enzyme replacement therapy (ERT) in adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (cTTP). ( 1 )

2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. For intravenous use after reconstitution only. ( 2 ) Prophylactic Therapy Administer 40 IU/kg body weight once every other week intravenously at a rate of 2 to 4 mL per minute. ( 2.1 ) The prophylaxis dosing frequency may be adjusted to 40 IU/kg body weight once weekly based on prior prophylactic dosing regimen or clinical response. ( 2.1 ) On-Demand Therapy Administer intravenously at a rate of 2 to 4 mL per minute: 40 IU/kg body weight on day 1. ( 2.1 ) 20 IU/kg body weight on day 2. ( 2.1 ) 15 IU/kg body weight on day 3 and beyond until two days after the acute event is resolved. ( 2.1 ) 2.1 Dosage Each vial of ADZYNMA is labeled with the actual rADAMTS13 activity, measured in terms of its potency in International Units (IU). Calculate administration dose and volume based on the patient's body weight using the actual potency (and not the nominal potency) as printed on ADZYNMA vial. For Intravenous (IV) Infusion at a rate of 2 to 4 mL per minute. Prophylactic Therapy The recommended prophylactic dosage regimen of ADZYNMA is as follows: Administer 40 IU/kg body weight once every other week. The prophylactic dosing frequency may be adjusted to 40 IU/kg body weight once weekly based on prior prophylactic dosing regimen or clinical response [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , Clinical Studies (14) ]. On-Demand Therapy A guide for dosing ADZYNMA for on demand treatment of an acute event is provided in Table 1 . Table 1: Dosing for On-Demand Therapy Treatment Day 1 Treatment Day 2 Treatment Day 3 and Beyond 40 IU/kg 20 IU/kg 15 IU/kg once daily until two days after the acute event is resolved. 2.2 Preparation and Administration Use aseptic technique (clean and germ-free) throughout the procedure. Check the expiration date of the product prior to use. Do not use ADZYNMA if the expiration date has passed. Reconstitution 1. Prepare a clean, germ-free, flat surface and gather all the materials you will need for the reconstitution and infusion. Figure A depicts the materials provided in the carton box. Figure A 2. Do not use ADZYNMA if the expiration date has passed. Use ADZYNMA within 3 hours after reconstitution and keep at room temperature not to exceed 86°F/30°C. Do not store at any other temperature. Discard any unused reconstituted product if not used within 3 hours after reconstitution. 3. Allow the vials of ADZYNMA and diluent to reach room temperature before use. If the patient needs more than one vial of ADZYNMA per injection, reconstitute each vial according to the instructions stated under ‘Reconstitution’. Inspect the reconstituted ADZYNMA solution for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. Do not administer if particulate matter or discoloration is observed. 4. Wash and dry your hands thoroughly, and put on clean exam gloves. 5. Remove plastic caps from the ADZYNMA and diluent vials and place the vials on a flat surface ( Figure B ). Figure B 6. Wipe the rubber stoppers with an alcohol swab and allow them to dry prior to use ( Figure C ). Figure C 7. Open the BAXJECT II Hi-Flow device package by peeling away the lid, without touching the inside ( Figure D ). Do not remove the BAXJECT II Hi-Flow device from the package. Do not touch the clear plastic spike . Figure D 8. Turn the package with the BAXJECT II Hi-Flow device upside down and place it over the top of the diluent vial. Press straight down until the clear plastic spike pierces through the diluent vial stopper ( Figure E ). Figure E 9. Grip the BAXJECT II Hi-Flow device package at its edge and pull the package off the device ( Figure F ). Do not remove the blue cap from the BAXJECT II Hi-Flow device. Do not touch the exposed purple plastic spike . Figure F 10. Turn the system over so that the diluent vial is now on top. Press the BAXJECT II Hi-Flow device straight down until the purple plastic spike pierces through the ADZYNMA powder vial stopper ( Figure G ). The vacuum will draw the diluent into the ADZYNMA powder vial . You may notice some bubbles or foam – this is normal and should soon disappear. Wait until foam or bubbles dissipate before administration. Figure G 11. Swirl the connected vials gently and continuously until the powder is completely dissolved ( Figure H ). Do not shake the vial. Figure H 12. Visually inspect the reconstituted solution for particulate matter before administration. The solution should be clear and colorless in appearance. Do not use the product if particulate matter or discoloration is observed. 13. If the dose requires more than one vial of ADZYNMA, repeat step 1 to step 12 to reconstitute each vial. Use a different BAXJECT II Hi-Flow device to reconstitute each vial of ADZYNMA and diluent. Administration Instructions 14. Take off the blue cap from the BAXJECT II Hi-Flow device ( Figure I ). Attach a Luer-lock syringe ( Figure J ). Do not inject air into the system. Figure I Figure J 15. Turn the system upside down (ADZYNMA vial is now on top). Draw the reconstituted solution into the syringe by pulling the plunger back slowly ( Figure K ). Use ADZYNMA within 3 hours after reconstitution and keep at room temperature not to exceed 86°F/30°C. Do not store at any other temperature. Discard any unused reconstituted product if not used within 3 hours after reconstitution. Do not administer ADZYNMA in the same tubing or container at the same time with other medicinal products for infusion. Figure K 16. If a patient is to receive more than one vial of ADZYNMA, the contents of multiple vials can be drawn into the same syringe. Repeat this process for all reconstituted vials of ADZYNMA until the total volume to be administered is reached. 17. Disconnect the syringe and attach a suitable injection needle or an infusion set. 18. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle. 19. Apply a tourniquet and clean the chosen infusion site with an alcohol swab ( Figure L ). Figure L 20. Insert the needle into the vein and remove the tourniquet. 21. Infuse the reconstituted ADZYNMA slowly , at a rate of 2 to 4 mL per minute ( Figure M ). A syringe pump may be used to control the rate of administration. Figure M 22. Take the needle out of the vein, place a cotton ball or gauze on the infusion site, and apply pressure for several minutes to stop bleeding. Do not recap the needle. 23. Place the needle, syringe, and empty vials in a puncture-resistant sharps container. Do not dispose of syringes and needles in the regular waste. Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M

6 ADVERSE REACTIONS Most common adverse reactions (>5% of subjects) reported in clinical trials were headache, diarrhea, migraine, abdominal pain, nausea, upper respiratory tract infection, dizziness, and vomiting. Most common adverse reactions (incidence >5%) are headache, diarrhea, migraine, abdominal pain, nausea, upper respiratory tract infection, dizziness, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. The safety profile of ADZYNMA was evaluated in one, prospective, randomized, active-controlled, open-label, multicenter, two-period crossover study (Study 1). The adverse drug reactions (ADR) are listed in Table 2 . Table 2: Adverse Reactions Reported in >5% of Patients Treated with ADZYNMA Adverse Reaction ADZYNMA (N= 48) n (%) Percentages by patient were calculated using the number of all subjects who had the listed adverse event. N = Total number of patients treated with ADZYNMA in Study 1. n = Number of patients who had at least one event in the category. Headache 15 (31.3) Diarrhea 8 (16.7) Migraine 7 (14.6) Abdominal pain 6 (12.5) Nausea 6 (12.5) Upper respiratory tract infection 6 (12.5) Dizziness 5 (10.4) Vomiting 5 (10.4)

12.3 Pharmacokinetics The PK profile of ADZYNMA was determined based on clinical trial ADAMTS13 activity data analyses. Following single-dose IV administration of ADZYNMA at 5 IU/kg, 20 IU/kg, and 40 IU/kg to adults and adolescents, dose-related increases in individual ADAMTS13 activity were observed and reached a maximum at approximately 1-hour post-infusion or earlier. At a dose of 40 IU/kg the mean (SD) half-life and mean residence time (MRT) in adults and adolescents were 47.8 (13.7) hours and 63.8 (16.0) hours, respectively. The PK parameters of ADAMTS13 activity following IV administration of ADZYNMA at 40 IU/kg in adults and adolescents are described in Table 3 . Table 3: Pharmacokinetic Parameters of ADAMTS13 Activity following IV Administration of ADZYNMA in cTTP Patients ≥12 Years Old Parameter (unit) Mean (SD) Min; Max (N=23) AUC = area under ADAMTS13 activity-time curve; C ave (0-168 h) = average ADAMTS13 activity from 0 to 168 hours dosing interval; C max = maximum ADAMTS13 activity; IR = incremental recovery; MRT = mean residence time; t 1/2 = half-life. Note: 1 IU/mL ADAMTS13 activity corresponds to 100% average normal activity. C max (IU/mL) 1.15 (0.25) 0.78; 1.56 IR [(IU/mL)/(IU/kg)] 0.03 (0.01) 0.02; 0.04 t ½ (h) 47.8 (13.70) 30.1; 90.8 AUC 0-inf (IUxh/mL) 57.6 (13.9) 37.0; 88.2 AUC (0-168 h) (IUxh/mL) 57.2 (13.67) 36.2; 87.2 MRT 0-inf N=22 (h) 63.8 (16.0) 44.8; 113 C ave (0-168 h) (IU/mL) 0.30 (0.07) 0.20; 0.46 Duration ADAMTS13 Activity above 10% (days) 5.8 (1.2) 4.5; 8.9 ADZYNMA IV administration at 40 IU/kg resulted in approximately 4- to 5-fold higher ADAMTS13 activity exposures (C max , AUC) and lower inter-subject variability when compared to plasma-based therapies. Mean time duration above 10% ADAMTS13 activity and mean average ADAMTS13 activity (C ave ) were both approximately 3- to 4-fold higher following ADZYNMA IV administration than plasma-based therapies. Based on Population PK analysis leveraging available data (N=65) from adults, adolescents and pediatric patients below 12 years of age, the mean (SD) steady state C max , AUC all , C ave , and duration of ADAMTS13 activity above 10% following IV administration of ADZYNMA every other week in cTTP patients below 12 years of age were 1.02 (0.19) IU/mL, 54.0 (12.2) IU*h/mL, 0.16 (0.04) IU/mL, and 6.8 (2.1) days, respectively. ADAMTS13 antigen and activity PK characteristics (MRT, V ss , and CL) were similar across age groups in patients with cTTP. Body-weight based ADZYNMA dosing provides similar ADAMTS13 activity PK parameters (C max and C ave ) across the different age groups including pediatric patients <12 years of age. Specific Populations Besides body-weight dosing regimen, no dose adjustment is required since no intrinsic factors such as age, gender, race, baseline estimated glomerular filtration rate (eGFR), and baseline bilirubin were identified as covariates impacting ADAMTS13 PK. Pediatric Patients Population pharmacokinetics (PK) analysis leveraging available data from adults, adolescents and pediatric patients below 12 years of age (N=65), suggests comparable ADAMTS13 activity exposures between patients below 12 years of age and patients aged 12 years and above receiving the recommended ADZYNMA dosing regimen [see Use in Specific Populations (8.4) ] .