Ravulizumab

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. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 50 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze. Refer to Table 4 (loading doses) , Table 5 (maintenance doses) , and Table 6 (supplemental doses) for IV preparation and minimum infusion duration. 4. Administer the prepared solution immediately following preparation. 5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 4 hours. Intravenous Administration of ULTOMIRIS (Healthcare Providers) Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter. Dilute ULTOMIRIS to a final concentration of 50 mg/mL. Prior to administration, allow the admixture to adjust to room temperature (18°C - 25°C, 64°F - 77°F). Do not heat the admixture in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After administration of ULTOMIRIS, flush the entire line with 0.9% Sodium Chloride Injection, USP. Table 4: Loading Dose Reference Table for ULTOMIRIS Body Weight Range (kg) Body weight at time of treatment. Loading Dose (mg) ULTOMIRIS Volume (mL) Volume of NaCl Diluent Dilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL) Total Volume (mL) Minimum Infusion Time (hr) Maximum Infusion Rate (mL/hr) 5 to less than 10 For PNH and aHUS indications only. 600 6 6 12 1.4 9 10 to less than 20 600 6 6 12 0.8 15 20 to less than 30 900 9 9 18 0.6 30 30 to less than 40 1,200 12 12 24 0.5 48 40 to less than 60 2,400 24 24 48 0.8 60 60 to less than 100 2,700 27 27 54 0.6 90 100 or greater 3,000 30 30 60 0.4 150 Table 5: Maintenance Dose Reference Table for ULTOMIRIS Body Weight Range (kg) Body weight at time of treatment. Maintenance Dose (mg) ULTOMIRIS Volume (mL) Volume of NaCl Diluent Dilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL) Total Volume (mL) Minimum Infusion Time (hr) Maximum Infusion Rate (mL/hr) 5 to less than 10 For PNH and aHUS indications only. 300 3 3 6 0.8 8 10 to less than 20 600 6 6 12 0.8 15 20 to less than 30 2,100 21 21 42 1.3 33 30 to less than 40 2,700 27 27 54 1.1 50 40 to less than 60 3,000 30 30 60 0.9 67 60 to less than 100 3,300 33 33 66 0.7 95 100 or greater 3,600 36 36 72 0.5 144 Table 6: Supplemental Dose Reference Table for ULTOMIRIS Body Weight Range (kg) Body weight at time of treatment. Supplemental Dose (mg) ULTOMIRIS Volume (mL) Volume of NaCl Diluent Dilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL) Total Volume (mL) Minimum Infusion Time (hr) Maximum Infusion Rate (mL/hr) Note: Refer to Table 3 for selection of ravulizumab supplemental dose 40 to less than 60 600 6 6 12 0.25 48 1,200 12 12 24 0.42 57 1,500 15 15 30 0.5 60 60 to less than 100 600 6 6 12 0.20 60 1,500 15 15 30 0.36 83 1,800 18 18 36 0.42 86 100 or greater 600 6 6 12 0.17 71 1,500 15 15 30 0.25 120 1,800 18 18 36 0.28 129 If an adverse reaction occurs during the administration of ULTOMIRIS, the infusion may be slowed or stopped at the discretion of the physician. Monitor the patient for at least 1 hour following completion of the infusion for signs or symptoms of an infusion-related reaction.

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.

12.3 Pharmacokinetics Following ULTOMIRIS treatment, ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg. Ravulizumab-cwvz C max and C trough parameters are presented in Table 14, Table 15, Table 16, and Table 17. Table 14: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with PNH who are Complement Inhibitor-Naïve and Patients Previously Treated with Eculizumab Pediatric Patients Adult Patients ALXN1210-PNH-304 ALXN1210-PNH-301 ALXN1210-PNH-302 N Complement Inhibitor-Naïve N Previously Treated with Eculizumab N Complement Inhibitor-Naïve N Previously Treated with Eculizumab Abbreviations: LD = Loading Dose; MD = Maintenance Dose C max (mcg/mL) LD 4 733 (14.5) 8 885 (19.3) 125 771 (21.5) 95 843 (24.1) MD 4 1490 (26.7) 8 1705 (9.7) 124 1,379 (20.0) 95 1,386 (19.4) C trough (mcg/mL) LD 4 368 (14.7) 8 452 (15.1) 125 391 (35.0) 96 405 (29.9) MD 4 495 (21.3) 8 566 (12.2) 124 473 (33.4) 95 501 (28.6) Table 15: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Patients with aHUS Pediatric Patients (ALXN1210-aHUS-312) Adult Patients (ALXN1210-aHUS-311) N < 20 kg MD Q4W N ≥ 20 to < 40 kg MD Q8W N ≥ 40 kg MD Q8W Abbreviations: LD = Loading Dose; MD = Maintenance Dose; Q4W = Every 4 Weeks; Q8W = Every 8 Weeks C max (mcg/mL) LD 8 656 (38.1) 4 600 (17.3) 52 754 (35.2) MD 7 1,467 (37.8) 6 1,863 (15.3) 46 1,458 (17.6) C trough (mcg/mL) LD 9 241 (52.1) 5 186 (16.5) 55 313 (33.9) MD 7 683 (46.1) 6 549 (34.1) 46 507 (42.5) Table 16: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with gMG N Adult Patients (ALXN1210-MG-306) Abbreviations: LD = Loading Dose; MD=Maintenance Dose C max (mcg/mL) LD 86 874 (21.1) MD 76 1548 (23.2) C trough (mcg/mL) LD 85 418 (27.6) MD 70 587 (29.6) Table 17: Mean (%CV) Pharmacokinetic Parameters Following ULTOMIRIS Treatment in Adult Patients with NMOSD N Adult Patients (ALXN1210-NMO-307) Abbreviations: LD = Loading Dose; MD=Maintenance Dose C max (mcg/mL) LD 58 935.3 (17.3) MD 56 1836.4 (19.4) C trough (mcg/mL) LD 58 459.1 (19.7) MD 54 796.9 (27.1) Distribution The mean (standard deviation [SD]) volume of distribution at steady state in patients with PNH, aHUS, gMG, or NMOSD are shown in Table 18. Elimination The mean (standard deviation [SD]) terminal elimination half-life and clearance of ravulizumab-cwvz are shown in Table 18. Table 18: Distribution, Biotransformation, and Elimination Parameters Following ULTOMIRIS Treatment Adult and Pediatric Patients with PNH Adult and Pediatric Patients with aHUS Adult Patients with gMG Adult Patients with NMOSD Distribution Volume of distribution at steady state (liters) Mean (SD) 5.30 (0.95) 5.22 (1.85) 5.74 (1.16) 4.77 (0.819) Biotransformation and Elimination Terminal elimination half-life (days) Mean (SD) 49.6 (9.08) 51.8 (16.2) 56.6 (8.36) 64.3 (11.0) Clearance (liters/day) Mean (SD) 0.08 (0.02) 0.08 (0.04) 0.08 (0.02) 0.05 (0.016) Specific Populations No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz. Drug Interactions No drug-drug interaction studies have been performed. Neonatal Fc Receptor blocker treatment may interfere with the endosomal neonatal FcRn recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations [see Drug Interactions (7.1 , 7.2) ] . Concomitant PE, PP, or IVIg treatment requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.5) ] .