ULTOMIRIS

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 recommended dose and schedule. The most frequent adverse reactions reported in ≥ 20% of patients treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia. Table 9, Table 10 and Table 11 describe adverse reactions that occurred at a rate of 10% or more among patients treated with ULTOMIRIS in aHUS studies. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia, and abdominal pain. Four patients died during the ALXN1210-aHUS-311 study. The cause of death was sepsis in 2 patients and intracranial hemorrhage in 1 patient. The fourth patient, who was excluded from the trial after a diagnosis of STEC-HUS, died due to pretreatment cerebral arterial thrombosis. Table 9: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311 Body System Adverse Reaction ALXN1210-aHUS-311 (N=58) All Grades Graded per CTCAE v5.0. (n=53) n (%) ≥ Grade 3 (n=14) n (%) Blood and lymphatic system disorders Anemia 8 (14) 0 (0) Gastrointestinal disorders Diarrhea 18 (31) 2 (3) Nausea 15 (26) 2 (3) Vomiting 15 (26) 2 (3) Constipation 8 (14) 1 (2) Abdominal pain 7 (12) 1 (2) General disorders and administration site conditions Pyrexia 11 (19) 1 (2) Edema peripheral 10 (17) 0 (0) Fatigue 8 (14) 0 (0) Infections and infestations Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. 15 (26) 0 (0) Urinary tract infection 10 (17) 5 (9) Gastrointestinal infection Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious, infectious colitis, and enterocolitis. 8 (14) 2 (3) Metabolism and nutrition disorders Hypokalemia 6 (10) 1 (2) Musculoskeletal and connective tissue disorders Arthralgia 13 (22) 0 (0) Back pain 7 (12) 1 (2) Muscle spasms 6 (10) 0 (0) Pain in extremity 6 (10) 0 (0) Nervous system disorders Headache 23 (40) 1 (2) Psychiatric disorders Anxiety 8 (14) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 10 (17) 0 (0) Dyspnea 10 (17) 1 (2) Skin and subcutaneous tissue disorders Alopecia 6 (10) 0 (0) Dry skin 6 (10) 0 (0) Vascular disorders Hypertension 14 (24) 7 (12) Clinically relevant adverse reactions include viral tonsilitis (in < 10% of patients) and infusion-related reactions (in 3% of patients). Table 10: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312 Body System Adverse Reaction ALXN1210-aHUS-312 (N=16) All Grades Graded per CTCAE v5.0. (n=16) n (%) ≥ Grade 3 (n=6) n (%) Blood and lymphatic system disorders Anemia 2 (13) 1 (6) Lymphadenopathy 2 (13) 0 (0) Gastrointestinal disorders Diarrhea 6 (38) 0 (0) Constipation 4 (25) 0 (0) Vomiting 4 (25) 1 (6) Abdominal pain 3 (19) 0 (0) Nausea 2 (13) 0 (0) General disorders and administration site conditions Pyrexia 8 (50) 0 (0) Infections and infestations Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. 7 (44) 1 (6) Gastroenteritis viral 2 (13) 2 (13) Pneumonia 2 (13) 1 (6) Tonsillitis 2 (13) 0 (0) Injury, poisoning and procedural complications Contusion 3 (19) 0 (0) Investigations Vitamin D decreased 3 (19) 0 (0) Metabolism and nutrition disorders Decreased appetite 2 (13) 0 (0) Iron deficiency 2 (13) 0 (0) Musculoskeletal and connective tissue disorders Myalgia 3 (19) 0 (0) Pain in extremity 2 (13) 0 (0) Nervous system disorders Headache 5 (31) 0 (0) Respiratory, thoracic and mediastinal disorders Cough 3 (19) 0 (0) Dyspnea 2 (13) 0 (0) Skin and subcutaneous tissue disorders Rash 3 (19) 0 (0) Vascular disorders Hypertension 4 (25) 1 (6) Hypotension 2 (13) 0 (0) Clinically relevant adverse reactions in < 10% of patients include viral infection. Table 11: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312 Body System Adverse Reaction ALXN1210-aHUS-312 Age 0 to < 2 (N=2) Age 2 to < 12 (N=12) Age 12 to 16 (N=1) Total (N=15) n (%) n (%) n (%) n (%) Blood and lymphatic system disorders Lymphadenopathy 0 (0) 2 (17) 0 (0) 2 (13) Gastrointestinal disorders Diarrhea 1 (50) 3 (25) 1 (100) 5 (33) Constipation 0 (0) 4 (33) 0 (0) 4 (27) Vomiting 0 (0) 3 (25) 0 (0) 3 (20) Abdominal pain 0 (0) 2 (17) 0 (0) 2 (13) General disorders and administration site conditions Pyrexia 1 (50) 5 (42) 1 (100) 7 (47) Infections and infestations Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain 1 (50) 6 (50) 0 (0) 7 (47) Gastroenteritis viral 0 (0) 2 (17) 0 (0) 2 (13) Tonsillitis 1 (50) 1 (8) 0 (0) 2 (13) Injury, poisoning and procedural complications Contusion 0 (0) 2 (17) 0 (0) 2 (13) Investigations Vitamin D decreased 0 (0) 2 (17) 1 (100) 3 (20) Metabolism and nutrition disorders Decreased appetite 1 (50) 1 (8) 0 (0) 2 (13) Iron deficiency 0 (0) 2 (17) 0 (0) 2 (13) Musculoskeletal and connective tissue disorders Myalgia 1 (50) 1 (8) 0 (0) 2 (13) Pain in extremity 0 (0) 2 (17) 0 (0) 2 (13) Nervous system disorders Headache 0 (0) 4 (33) 0 (0) 4 (27) Respiratory, thoracic and mediastinal disorders Cough 0 (0) 3 (25) 0 (0) 3 (20) Dyspnea 1 (50) 1 (8) 0 (0) 2 (13) Skin and subcutaneous tissue disorders Rash 1 (50) 2 (17) 0 (0) 3 (20) Vascular disorders Hypertension 1 (50) 3 (25) 0 (0) 4 (27) Hypotension 0 (0) 2 (17) 0 (0) 2 (13) Clinically relevant adverse reactions in < 10% of patients include viral infection. Generalized Myasthenia Gravis (gMG) The safety of ULTOMIRIS has been evaluated in 175 adult patients with gMG, including 169 patients who received at least one dose of ULTOMIRIS, 142 patients who were exposed for at least 6 months, and 95 who were exposed for at least 12 months [see Clinical Studies (14.3) ]. In a randomized, double-blind, placebo-controlled trial (ALXN1210-MG-306), the most frequent adverse reactions (≥ 10%) with ULTOMIRIS were diarrhea and upper respiratory tract infection. Table 12 describes adverse reactions that occurred at a rate of 5% or more and at greater frequency than placebo. Serious adverse reactions were reported in 20 (23%) patients with gMG receiving ULTOMIRIS and in 14 (16%) patients receiving placebo. The most frequent serious adverse reactions were infections reported in at least 8 (9%) patients treated with ULTOMIRIS and in 4 (4%) patients treated with placebo [see Warnings and Precautions (5.3) ] . Of these infections, one fatal case of COVID-19 pneumonia was identified in a patient treated with ULTOMIRIS and one case of infection led to discontinuation of ULTOMIRIS. Table 12: Adverse Reactions Reported in ≥ 5% and at Greater Frequency than Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306 Body System Adverse Reaction Number of Patients ULTOMIRIS (N=86) n (%) Placebo (N=89) n (%) Gastrointestinal Disorders Diarrhea 13 (15) 11 (12) Abdominal pain 5 (6) 0 Infections and Infestations Upper respiratory tract infection 12 (14) 7 (8) Urinary tract infection 5 (6) 4 (4) Musculoskeletal and Connective Tissue Disorders Back Pain 7 (8) 5 (6) Nervous System Disorders Dizziness 8 (9) 3 (3) Neuromyelitis Optica Spectrum Disorder (NMOSD) The safety of ULTOMIRIS has been evaluated in 58 adult patients with NMOSD who received at least one dose of ULTOMIRIS [see Clinical Studies (14.3) ] . In Study ALXN1210-NMO-307, an open-label multicenter trial, the most frequent adverse reactions (≥10%) with ULTOMIRIS were COVID-19, headache, back pain, urinary tract infection and arthralgia. Table 13 describes adverse reactions that occurred at a rate of 5% or more in patients treated with ULTOMIRIS. Serious adverse reactions were reported in 8 (13.8%) patients with NMOSD receiving ULTOMIRIS. Table 13: Adverse Reactions Reported in ≥ 5% in ULTOMIRIS-Treated Adult Patients with NMOSD in Study ALXN1210-NMO-307 Body System Adverse Reaction ULTOMIRIS (N=58) n (%) Blood and Lymphatic System Disorder Lymphadenopathy 3 (5) Gastrointestinal Disorders Constipation 4 (7) Vomiting 4 (7) Diarrhea 3 (5) Gastroesophageal reflux disease 3 (5) General Disorders and Administration Site Reactions Pyrexia 5 (9) Chills 3 (5) Fatigue 3 (5) Malaise 3 (5) Non-cardiac chest pain 3 (5) Vaccination site pain 3 (5) Infections and Infestations COVID-19 14 (24) Urinary tract infection 6 (10) Cystitis 5 (9) Upper respiratory tract infection 5 (9) Nasopharyngitis 3 (5) Sinusitis 3 (5) Injury, Poisoning and Procedural Complications Infusion related reaction 4 (7) Musculoskeletal and Connective Tissue Disorders Back pain 7 (12) Arthralgia 6 (10) Myalgia 3 (5) Nervous System Disorders Headache 14 (24) Dizziness 4 (7) Migraine 3 (5) Respiratory, thoracic and mediastinal disorders Cough 3 (5) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ULTOMIRIS. 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 ULTOMIRIS exposure. Adverse Reactions from Postmarketing Spontaneous Reports Anaphylaxis [see Warnings and Precautions (5.6) ] Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with another C5 complement inhibitor. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks.

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.