Ravulizumab

12.1 Mechanism of Action Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]) thus preventing MAC formation. ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4 antibody-induced terminal complement C5b-9 deposition.

1 INDICATIONS AND USAGE ULTOMIRIS is a complement inhibitor indicated for: the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH). ( 1.1 ) the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). ( 1.2 ) Limitations of Use: ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. ( 1.3 ) the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody-positive. ( 1.4 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH). 1.2 Atypical Hemolytic Uremic Syndrome ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Limitations of Use: ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis ULTOMIRIS is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. 1.4 Neuromyelitis Optica Spectrum Disorder ULTOMIRIS is indicated for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody-positive.

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for instructions on dosage, preparation, and administration. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 ) Dilute ULTOMIRIS before use. ( 2.5 ) Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter. ( 2.5 ) 2.1 Important Dosage Information ULTOMIRIS is intended to be administered only as an intravenous infusion in adult or pediatric patients one month of age and older. 2.2 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of ULTOMIRIS [see Warnings and Precautions (5.1) ] . If urgent ULTOMIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe ULTOMIRIS must enroll in the ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . 2.3 Recommended Dosage for Intravenous Administration in Adult and Pediatric Patients with PNH or aHUS, and in Adult Patients with gMG or NMOSD The recommended intravenous (IV) ULTOMIRIS loading and maintenance dosing in adult and pediatric patients, one month of age or older weighing 5 kg or greater, with PNH or aHUS, or in adult patients with gMG or NMOSD weighing 40 kg or greater, is based on the patient's body weight, as shown in Table 1, with maintenance doses administered every 4 or 8 weeks, starting 2 weeks after loading dose. The IV dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but subsequent doses should be administered according to the original schedule. Following a missed IV ULTOMIRIS dose, the patient should contact their health care provider immediately. Table 1: IV Administration of ULTOMIRIS Weight-Based Dosing Regimen – PNH, aHUS, gMG, or NMOSD See Table 4 and Table 5 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5) ] Indications Body Weight Range (kg) Loading Dose (mg) See Table 2 for ULTOMIRIS treatment initiation instruction and timing of loading dose and maintenance dose Maintenance Dose (mg) and Dosing Interval PNH or aHUS 5 to less than 10 600 300 Every 4 weeks 10 to less than 20 600 600 20 to less than 30 900 2,100 Every 8 weeks 30 to less than 40 1,200 2,700 PNH, aHUS, gMG, or NMOSD 40 to less than 60 2,400 3,000 Every 8 weeks 60 to less than 100 2,700 3,300 100 or greater 3,000 3,600 Refer to Table 2 for treatment initiation instructions in patients who are complement inhibitor treatment-naïve or switching treatment from eculizumab. Table 2: IV Administration of ULTOMIRIS Treatment Initiation Instructions – PNH, aHUS, gMG, or NMOSD Population Weight-based ULTOMIRIS Loading Dose Time of First ULTOMIRIS Weight-based Maintenance Dose Not currently on ULTOMIRIS or eculizumab treatment At treatment start 2 weeks after ULTOMIRIS loading dose Currently treated with eculizumab At time of next scheduled eculizumab dose 2 weeks after ULTOMIRIS loading dose 2.4 Dosing Considerations Supplemental Dose of ULTOMIRIS Plasma exchange (PE), plasmapheresis (PP), and intravenous immunoglobulin (IVIg) have been shown to reduce ULTOMIRIS serum levels. A supplemental dose of ULTOMIRIS is required in the setting of PE, PP, or IVIg (Table 3). Table 3: Supplemental Dose of ULTOMIRIS after PE, PP, or IVIg See Table 6 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5) ] Body Weight Range (kg) Most Recent ULTOMIRIS Dose (mg) Supplemental Dose (mg) following each PE or PP Intervention Supplemental Dose (mg) following Completion of an IVIg Cycle Abbreviations: IVIg = intravenous immunoglobulin; PE = plasma exchange; PP = plasmapheresis 40 to less than 60 2,400 1,200 600 3,000 1,500 60 to less than 100 2,700 1,500 600 3,300 1,800 100 or greater 3,000 1,500 600 3,600 1,800 Timing of ULTOMIRIS Supplemental Dose Within 4 hours following each PE or PP intervention Within 4 hours following completion of an IVIg cycle 2.5 Preparation and Administration Preparation of ULTOMIRIS Vials for Intravenous Administration Each vial of ULTOMIRIS is intended for single-dose only. ULTOMIRIS vials are for intravenous administration by a healthcare provider and are intended for intravenous administration only. Dilute before use. Use aseptic technique to prepare ULTOMIRIS as follows: 1. The number of vials to be diluted is determined based on the individual patient's weight and the prescribed dose [see Dosage and Administration (2.3) ] . 2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation. 3

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Infections [see Warnings and Precautions (5.3) ] Infusion-Related Reactions [see Warnings and Precautions (5.6) ] Most common adverse reactions in patients with PNH (incidence ≥ 10%) were upper respiratory tract infection and headache. ( 6.1 ) Most common adverse reactions in patients with aHUS (incidence ≥ 20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia. ( 6.1 ) Most common adverse reactions in adult patients with gMG (incidence ≥ 10%) were diarrhea and upper respiratory tract infection. ( 6.1 ) Most common adverse reactions in adult patients with NMOSD (incidence ≥ 10%) were COVID-19, headache, back pain, arthralgia, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. Paroxysmal Nocturnal Hemoglobinuria (PNH) Adult Population with PNH Treated with ULTOMIRIS The data described below reflect exposure of 441 adult patients with PNH in Phase 3 studies who received ULTOMIRIS (n = 222) or eculizumab (n = 219) at the recommended dosing regimens with median treatment duration of 6 months for ULTOMIRIS and 6 months for eculizumab. The most frequent adverse reactions (≥ 10%) with ULTOMIRIS were upper respiratory tract infection and headache. Table 7 describes adverse reactions that occurred at a rate of 5% or more among patients treated with ULTOMIRIS in PNH studies. Serious adverse reactions were reported in 15 (6.8%) patients with PNH receiving ULTOMIRIS. The serious adverse reactions in patients treated with ULTOMIRIS included hyperthermia and pyrexia. No serious adverse reaction was reported in more than 1 patient treated with ULTOMIRIS. One fatal case of sepsis was identified in a patient treated with ULTOMIRIS. Table 7: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor-Naïve and Eculizumab-Experienced Adult Patients with PNH Body System Adverse Reaction Number of Patients ULTOMIRIS (N=222) n (%) Eculizumab (N=219) n (%) Gastrointestinal disorders Diarrhea 19 (9) 12 (5) Nausea 19 (9) 19 (9) Abdominal pain 13 (6) 16 (7) General disorders and administration site conditions Pyrexia 15 (7) 18 (8) Infections and infestations Upper respiratory tract infection Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation 86 (39) 86 (39) Musculoskeletal and connective tissue disorders Pain in extremity 14 (6) 11 (5) Arthralgia 11 (5) 12 (5) Nervous system disorders Headache 71 (32) 57 (26) Dizziness 12 (5) 14 (6) Clinically relevant adverse reactions in 1% of patients include infusion-related reactions. Pediatric Population with PNH Treated with ULTOMIRIS In pediatric patients with PNH (aged 9 to 17 years old) included in the pediatric PNH Phase 3 study, the safety profile appeared similar to that observed in adult patients with PNH and in pediatric and adult patients with aHUS. The most common adverse reactions (> 20%) were upper respiratory tract infection, anemia, abdominal pain, and headache. Table 8 describes the adverse reactions that occurred at a rate of 10% or more among pediatric patients treated with ULTOMIRIS in Study ALXN1210-PNH-304. Table 8: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304 Body System Adverse Reaction Treatment Naïve (N=5) Eculizumab Experienced (N=8) Total (N=13) n (%) n (%) n (%) Blood and lymphatic system disorders Anemia Grouped term includes: anemia and iron deficiency anemia 1 (20) 2 (25) 3 (23) Gastrointestinal disorders Abdominal pain 0 (0) 3 (38) 3 (23) Constipation 0 (0) 2 (25) 2 (15) General disorders and administration site conditions Pyrexia 1 (20) 1 (13) 2 (15) Infections and infestations Upper Respiratory tract infection Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and viral upper respiratory tract infection 1 (20) 6 (75) 7 (54) Musculoskeletal and connective tissue disorders Pain in extremity 0 (0) 2 (25) 2 (15) Nervous system disorders Headache 1 (20) 2 (25) 3 (23) Atypical Hemolytic Uremic Syndrome (aHUS) The data described below reflect exposure of 58 adult and 16 pediatric patients with aHUS in single-arm trials who received ULTOMIRIS at the

7 DRUG INTERACTIONS Plasma Exchange, Plasmapheresis, or Intravenous Immunoglobulins: concomitant use requires supplemental dose of ULTOMIRIS. ( 7.1 ) Neonatal Fc Receptor Blockers (FcRn): Closely monitor for reduced effectiveness of ULTOMIRIS. ( 7.2 ) 7.1 Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.5) ]. 7.2 Neonatal Fc Receptor Blockers Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS.