APADAMTASE ALFA: 12 Adverse Event Reports & Safety Profile

ADZYNMA is a purified bivariant human recombinant “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) expressed in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology (a mixture of Native rADAMTS13 Q23 and Variant rADAMTS13 R23 with a controlled range of the two variants ratio). ADZYNMA is produced and formulated without the addition of any exogenous raw materials of human or animal origin in the cell culture, purification, or formulation of the final product. The purification process for rADAMTS13 does not include use of a monoclonal antibody reagent. To enhance viral safety, the production process also incorporates two dedicated viral clearance steps – a solvent/detergent treatment step for inactivation and a 20 nm filtration step for removal of viruses. Recombinant ADAMTS13 has a molecular weight of approximately 172 kDa. Proteins that may be present in the final product, other than rADAMTS13, are trace quantities of host cell (CHO) proteins. ADZYNMA (rADAMTS13) is a sterile, nonpyrogenic, preservative free, white powder supplied in single-dose vials for IV use after reconstitution. Each single-dose vial contains nominally 500 IU or 1500 IU of rADAMTS13, sodium chloride (9.4 mg), calcium chloride dihydrate (1.6 mg), L-histidine (16.7 mg), mannitol (161.4 mg), sucrose (53.8 mg), and polysorbate 80 (2.7 mg). Each vial of ADZYNMA is labeled with the specific number of units of ADAMTS13 potency expressed in IU as measured with a fluorescence resonance energy transfer (FRET) assay using a synthetic 73-amino-acid peptide (FRETS-VWF73). The potency assignment employs an ADAMTS13 concentrate standard that is referenced to a WHO (World Health Organization) international standard for ADAMTS13 concentrates and is evaluated by appropriate methodology to ensure accuracy of the results. After reconstitution with 5 mL of Sterile Water for Injection, USP, the 500 IU and the 1500 IU vials result in a nominal potency of 100 IU/mL and 300 IU/mL, respectively. All dosage strengths yield a clear, colorless solution, free from particles with a pH of approximately 7.0.

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 )

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

ADZYNMA is contraindicated in patients who have manifested life threatening hypersensitivity reactions to ADZYNMA or its components [see Description (11) ] . Do not use in patients who have manifested life threatening hypersensitivity reactions to ADZYNMA or its components. ( 4 )

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)

AND PRECAUTIONS Hypersensitivity reactions may occur. Discontinue ADZYNMA if hypersensitivity symptoms occur and administer appropriate emergency treatment. ( 5.1 ) Immunogenicity: Patients may develop antibodies to rADAMTS13 which could potentially result in a decreased or lack of response to rADAMTS13. Patients may develop antibodies to host cell proteins which could potentially result in adverse reactions. There are no data on risk in previously untreated patients (subjects naïve to plasma-based products). ( 5.2 )

5.1 Hypersensitivity Allergic-type hypersensitivity including anaphylactic reactions may occur with ADZYNMA. Patients should be informed of the early signs of hypersensitivity including but not limited to tachycardia, tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalized urticaria, pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paresthesia, and restlessness. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of ADZYNMA and provide appropriate supportive care.

5.2 Immunogenicity There is a potential for immunogenicity with ADZYNMA. Patients may develop neutralizing antibodies to ADAMTS13, which could potentially result in a decreased or lack of response to ADAMTS13. Neutralizing antibodies were not reported in the cTTP clinical trials. All subjects had been previously exposed to ADAMTS13 through plasma-based products. There are no data on immunogenicity with ADZYNMA in previously untreated patients (subjects naïve to plasma-based products) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.6) ]</span> . Patients may develop antibodies to host cell proteins which could potentially result in adverse reactions. There are no data on immunogenicity to host cell proteins in previously untreated patients (subjects naïve to plasma-based products).