ALTUVIIIO

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, have occurred with ALTUVIIIO. If symptoms occur, immediately discontinue ALTUVIIIO and initiate appropriate treatment. ( 5.1 ) Neutralizing antibodies (inhibitors) to Factor VIII have been reported. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor VIII inhibitor concentration. ( 5.2 , 5.3 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have occurred with ALTUVIIIO [see Postmarketing Experience (6.2) ] . Signs and symptoms include, but not limited to, hives, shortness of breath, chest tightness, wheezing, hypotension, nausea, vomiting, and itching. Discontinue ALTUVIIIO if hypersensitivity reaction occurs and manage symptoms as appropriate. 5.2 Neutralizing Antibodies Formation of neutralizing antibodies (inhibitors) to Factor VIII has been reported following administration of ALTUVIIIO [see Postmarketing Experience (6.2) ] . Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the patient's plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after ALTUVIIIO administration, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed [see Warnings and Precautions (5.3) ] . 5.3 Monitoring Laboratory Tests If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay [see Dosage and Administration (2) ] . The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid based aPTT reagent in one-stage clotting assay by approximately 2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient's ALTUVIIIO Factor VIII activity level. Use of a reference laboratory is recommended when a qualified one-stage clotting assay or chromogenic assay is not available locally. Monitor for the development of Factor VIII inhibitors. If bleeding is not controlled with ALTUVIIIO and the expected factor VIII activity plasma levels are not attained, perform an assay to determine if Factor VIII inhibitors are present (use Bethesda Units to titer inhibitors).

6 ADVERSE REACTIONS Most common adverse reactions (incidence >10%) are headache and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bioverativ Therapeutics Inc. (A SANOFI COMPANY) at 1-800-633-1610 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 data described in this section reflects exposure to ALTUVIIIO in two clinical studies, Study 1 and Study 2 and are pooled for analysis. In Study 1, a total of 159 previously treated patients (PTPs) (134 adults and 25 adolescents) with severe Hemophilia A) received at least one dose of ALTUVIIIO for either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management. A total of 152 (96%) patients achieved at least 25 exposure days and 115 (72%) patients achieved at least 50 exposure days with a median of 53.0 (range 2–63) for both exposure days and injections per patient. Overall exposure was monitored for a total of 151.5 patient-years [see Clinical Studies (14) ] . In Study 2, the safety of ALTUVIIIO was evaluated in 74 male PTPs <12 years of age with severe hemophilia A who received at least one dose of ALTUVIIIO. Sixty-six (89.2%) patients achieved at least 50 exposure days with a median of 53.0 (range 3–72). Adverse events were monitored for a total of 210.7 patient-years in 2 completed clinical studies in PTPs. Adverse drug reactions (ADRs) (summarized in Table 3) were reported in 79 (33.9%) of the 233 patients treated with routine prophylaxis or on-demand therapy. The most common ADRs (>10%) in adults and adolescents were headache (20.1%) and arthralgia (16.4%). In children below 12 years, pyrexia (12.2%) was the most common ADR (>10%). In the studies, no inhibitors to FVIII were detected and no ADRs of anaphylaxis were reported. The most common adverse reactions (>10% of patients) reported in clinical trials were headache and arthralgia. Table 3: Adverse Reactions with Frequency of ≥3% Reported in ALTUVIIIO Studies Pooled data from Study 1 and Study 2 including 233 patients across the adult and adolescent and pediatric studies. MedDRA System Organ Class Adverse Drug Reactions Number of Patients n (%) (N = 233) Nervous system disorders Headache 35 (15) Musculoskeletal and connective tissue disorders Arthralgia 31 (13) Pain in extremity 10 (4) Back pain 9 (4) General disorders and administration Pyrexia 10 (4) Gastrointestinal disorders Vomiting 7 (3) Thromboembolic events occurred in 1% (3/261) of patients in the long-term safety extension study; these three patients had pre-existing risk factors. 6.2 Postmarketing Experience The following adverse reactions have been identified during the post approval use of ALTUVIIIO. 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 drug exposure. Blood and lymphatic system disorders: Factor VIII inhibitor development [see Warnings and Precautions (5.2) ]. Immune system disorders: Hypersensitivity reactions, including anaphylaxis [see Warnings and Precautions (5.1) ].

<table width="70%" ID="TABLE3"><caption>Table 3: Adverse Reactions with Frequency of &#x2265;3% Reported in ALTUVIIIO Studies<footnote ID="foot">Pooled data from Study 1 and Study 2 including 233 patients across the adult and adolescent and pediatric studies.</footnote></caption><col width="36%" align="left" valign="top"/><col width="30%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><thead><tr><th align="center" styleCode="Lrule Rrule">MedDRA System Organ Class</th><th align="center" styleCode="Rrule">Adverse Drug Reactions</th><th styleCode="Rrule">Number of Patients n (%) (N = 233)<footnoteRef IDREF="foot"/></th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nervous system disorders</td><td styleCode="Rrule">Headache</td><td styleCode="Rrule">35 (15)</td></tr><tr><td styleCode="Lrule Rrule Botrule" rowspan="3">Musculoskeletal and connective tissue disorders</td><td styleCode="Rrule">Arthralgia</td><td styleCode="Rrule">31 (13)</td></tr><tr><td styleCode="Rrule">Pain in extremity</td><td styleCode="Rrule" align="center">10 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Rrule">Back pain</td><td styleCode="Rrule" align="center">9 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">General disorders and administration</td><td styleCode="Rrule">Pyrexia</td><td styleCode="Rrule">10 (4)</td></tr><tr><td styleCode="Lrule Rrule">Gastrointestinal disorders</td><td styleCode="Rrule">Vomiting</td><td styleCode="Rrule">7 (3)</td></tr></tbody></table>