FDA label 758b0d1f-9d6c-42f9-a23b-6f75e9181842

WARNING: NEUTRALIZING ANTIBODIES TO ADAMTS13 Neutralizing antibodies to ADAMTS13 with serious outcomes, including death, have been reported in patients treated with ADZYNMA. Neutralizing antibodies may result in decreased or lack of response to recombinant or plasma-derived ADAMTS13 see [ Warnings and Precautions (5.2) , Postmarketing Experience (6.2) ] . Monitor all patients closely for ADAMTS13 activity and development of ADAMTS13 neutralizing antibodies [see Warnings and Precautions (5.2) ] . WARNING: NEUTRALIZING ANTIBODIES TO ADAMTS13 Neutralizing antibodies to ADAMTS13 with serious outcomes, including death, have been reported in patients treated with ADZYNMA. Neutralizing antibodies may result in decreased or lack of response to recombinant or plasma-derived ADAMTS13 ( 5.2 , 6.2 ). Monitor all patients closely for ADAMTS13 activity and development of ADAMTS13 neutralizing antibodies ( 5.2 ).

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions may occur. Discontinue ADZYNMA if hypersensitivity symptoms occur and administer appropriate emergency treatment. ( 5.1 ) Neutralizing antibodies to ADAMTS13 with serious outcomes including death have been reported in patients with cTTP following administration of ADZYNMA. Monitor all patients, including those who were previously exposed or naïve to plasma-based products, by assessing ADAMTS13 activity and ADAMTS13 neutralizing antibodies prior to initiation of ADZYNMA and periodically during the course of treatment. ( 5.2 , 6.2 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions including anaphylaxis may occur with ADZYNMA. Monitor patients for sign and symptoms of hypersensitivity reactions which may include 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 hypersensitivity reactions occur, immediately discontinue administration of ADZYNMA and provide appropriate supportive care. 5.2 Neutralizing Antibodies Neutralizing antibodies to ADAMTS13 with serious outcomes including death have occurred following ADZYNMA administration [see Postmarketing Experience (6.2) ] . Neutralizing antibodies may result in a decreased or lack of response to ADZYNMA which could lead to serious disease related outcomes. 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) [see Clinical Pharmacology (12.6) ] . Monitor all patients, including those who were previously exposed or naïve to plasma-based products, by assessing ADAMTS13 activity and ADAMTS13 neutralizing antibodies prior to initiation of ADZYNMA and periodically during the course of treatment. If expected ADAMTS13 activity levels are not attained or if acute TTP exacerbation occurs despite appropriate dose, perform an assay that measures ADAMTS13 neutralizing antibody concentrations. Laboratory tests for monitoring neutralizing antibody levels are not capable of distinguishing between inhibitors directed against ADZYNMA, the patient’s endogenous ADAMTS13, or ADAMTS13 from other plasma sources.

6 ADVERSE REACTIONS 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) that treated 48 patients who had been previously exposed to ADAMTS13 through plasma-based products. Patients received ADZYNMA at the dose of 40 IU/kg/dose. 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) 6.2 Postmarketing Experience The following adverse reactions have been reported during the post-approval use of ADZYNMA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Blood and lymphatic system: Neutralizing antibodies to ADAMTS13 with serious outcomes including death [see Warnings and Precautions (5.2) ] .

<table width="80%" ID="table2"><caption>Table 2: Adverse Reactions Reported in &gt;5% of Patients Treated with ADZYNMA</caption><col width="50%" align="left" valign="middle"/><col width="50%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reaction</th><th styleCode="Rrule">ADZYNMA (N= 48) n (%)<footnote>Percentages by patient were calculated using the number of all subjects who had the listed adverse event.</footnote></th></tr></thead><tfoot><tr><td colspan="2" align="left" valign="top">N = Total number of patients treated with ADZYNMA in Study 1. n = Number of patients who had at least one event in the category.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">15 (31.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">8 (16.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Migraine</td><td styleCode="Rrule">7 (14.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">6 (12.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">6 (12.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">6 (12.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">5 (10.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">5 (10.4)</td></tr></tbody></table>