Ultomiris

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS ULTOMIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1) ] . Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early . Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying therapy with ULTOMIRIS outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria. Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected. Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ]. WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning. ULTOMIRIS increases the risk of serious and life-threatening infections caused by Neisseria meningitidis . Complete or update meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients receiving a complement inhibitor. ( 5.1 ) Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by N. meningitidis , even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of meningococcal infections and evaluate immediately if infection is suspected. ( 5.1 ) ULTOMIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Other Infections: Use caution when administering ULTOMIRIS to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections ULTOMIRIS, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of ULTOMIRIS treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of ULTOMIRIS, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. 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 meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment with ULTOMIRIS, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. ULTOMIRIS is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 ULTOMIRIS and SOLIRIS REMS ULTOMIRIS is available only through a restricted program under a REMS called ULTOMIRIS and SOLIRIS REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ]. Notable requirements of the ULTOMIRIS and SOLIRIS REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ULTOMIRIS. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS. Healthcare settings and pharmacies that dispense ULTOMIRIS must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 8 months following treatment with ULTOMIRIS. Further information is available at www.UltSolREMS.com or 1-888-765-4747. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after ULTOMIRIS Discontinuation Treatment Discontinuation for PNH After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated lactate dehydrogenase (LDH) along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions. If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS. Treatment Discontinuation for aHUS ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months. TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures. 5.5 Thromboembolic Event Management The effect of withdrawal of anticoagulant therapy during ULTOMIRIS treatment has not been established. Therefore, treatment with ULTOMIRIS should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis [see Adverse Reactions (6.2) ] and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1 to 7% of patients treated with ULTOMIRIS [see Adverse Reactions (6.1) ] . These events included lower back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, rigors, limb discomfort, drug hypersensitivity (allergic reaction), and dysgeusia (bad taste). These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures.

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.

<table width="75%" ID="tab7"><caption>Table 7: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor-Na&#xEF;ve and Eculizumab-Experienced Adult Patients with PNH</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Body System Adverse Reaction</th><th styleCode="Rrule" colspan="2">Number of Patients</th></tr><tr><th styleCode="Rrule" align="center">ULTOMIRIS (N=222) n (%)</th><th styleCode="Rrule">Eculizumab (N=219) n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">19 (9)</td><td styleCode="Rrule">12 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">19 (9)</td><td styleCode="Rrule">19 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">13 (6)</td><td styleCode="Rrule">16 (7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">15 (7)</td><td styleCode="Rrule">18 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection<footnote>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</footnote></td><td styleCode="Rrule">86 (39)</td><td styleCode="Rrule">86 (39)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in extremity</td><td styleCode="Rrule">14 (6)</td><td styleCode="Rrule">11 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">11 (5)</td><td styleCode="Rrule">12 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">71 (32)</td><td styleCode="Rrule">57 (26)</td></tr><tr><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">12 (5)</td><td styleCode="Rrule">14 (6)</td></tr></tbody></table>

<table width="80%" ID="tab8"><caption>Table 8: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304</caption><col width="40%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule Botrule" rowspan="3">Body System Adverse Reaction</th><th styleCode="Rrule Botrule" valign="middle">Treatment Na&#xEF;ve (N=5)</th><th styleCode="Rrule Botrule" valign="middle">Eculizumab Experienced (N=8)</th><th styleCode="Rrule Botrule" valign="middle">Total (N=13)</th></tr><tr><th styleCode="Rrule" align="center">n (%)</th><th styleCode="Rrule">n (%)</th><th styleCode="Rrule">n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia<footnote>Grouped term includes: anemia and iron deficiency anemia </footnote></td><td styleCode="Rrule">1 (20)</td><td styleCode="Rrule">2 (25)</td><td styleCode="Rrule">3 (23)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">3 (38)</td><td styleCode="Rrule">3 (23)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">2 (25)</td><td styleCode="Rrule">2 (15)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">1 (20)</td><td styleCode="Rrule">1 (13)</td><td styleCode="Rrule">2 (15)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper Respiratory tract infection<footnote>Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and viral upper respiratory tract infection</footnote></td><td styleCode="Rrule">1 (20)</td><td styleCode="Rrule">6 (75)</td><td styleCode="Rrule">7 (54)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in extremity</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">2 (25)</td><td styleCode="Rrule">2 (15)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">1 (20)</td><td styleCode="Rrule">2 (25)</td><td styleCode="Rrule">3 (23)</td></tr></tbody></table>

<table width="80%"><caption>Table 9: Adverse Reactions Reported in &#x2265; 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Body System Adverse Reaction</th><th styleCode="Rrule" colspan="2">ALXN1210-aHUS-311 (N=58)</th></tr><tr><th styleCode="Rrule" align="center">All Grades<footnote>Graded per CTCAE v5.0.</footnote> (n=53) n (%)</th><th styleCode="Rrule">&#x2265; Grade 3 (n=14) n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">8 (14)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">18 (31)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">15 (26)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">15 (26)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">8 (14)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">7 (12)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">11 (19)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema peripheral</td><td styleCode="Rrule">10 (17)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">8 (14)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations </content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection<footnote>Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.</footnote></td><td styleCode="Rrule">15 (26)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">10 (17)</td><td styleCode="Rrule">5 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gastrointestinal infection<footnote>Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious, infectious colitis, and enterocolitis.</footnote></td><td styleCode="Rrule">8 (14)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypokalemia</td><td styleCode="Rrule">6 (10)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">13 (22)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">7 (12)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Muscle spasms</td><td styleCode="Rrule">6 (10)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in extremity</td><td styleCode="Rrule">6 (10)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">23 (40)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety</td><td styleCode="Rrule">8 (14)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough</td><td styleCode="Rrule">10 (17)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">10 (17)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alopecia</td><td styleCode="Rrule">6 (10)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry skin</td><td styleCode="Rrule">6 (10)</td><td styleCode="Rrule">0 (0)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Vascular disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Hypertension</td><td styleCode="Rrule">14 (24)</td><td styleCode="Rrule">7 (12)</td></tr></tbody></table>